九州大学 研究者情報
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辰巳 隆一(たつみ りゆういち) データ更新日:2020.06.17

教授 /  農学研究院 資源生物科学部門 動物・海洋生物資源学講座


主な研究テーマ
物理刺激で作動する筋衛星細胞の活性化カスケード
キーワード:筋肥大, 衛星細胞, 肝細胞増殖因子, 活性化, 一酸化窒素,一酸化窒素合成酵素, カルモジュリン, カルシウム, プロテオグリカン, マトリックスメタロプテイナーゼ, 筋線維, 筋原線維, 骨格筋,
1996.02.
筋衛星細胞の休止化機構の解明と休止化抑制技術の開発
キーワード:筋肥大, 衛星細胞, 肝細胞増殖因子, 活性化, 休止化, マイオスタチン (GDF-8), プロテオグリカン, 筋線維, 筋原線維, 骨格筋, 食肉
2003.09.
筋特性変換の栄養応答
キーワード:筋線維型, 衛星細胞, 筋管細胞, 牛肉熱水抽出エキス, ポリフェノール
2005.04.
筋肉内運動神経ネットワークの構築機構に関する研究
キーワード:筋肥大再生, 筋幹細胞(衛星細胞), 神経細胞忌避因子, 筋線維, 骨格筋, 筋萎縮性側索硬化症(ALS)
2007.04.
従事しているプロジェクト研究
筋幹細胞と運動神経末端のローカルコミュニケーションの制御機構
2007.03, 代表者:辰巳隆一, 九州大学大学院農学研究院, 九州大学 大学院農学研究院 生物機能科学部門 生物機能化学講座畜産化学分野
動物の成長や運動に伴う骨格筋の肥大・再生は、1) 筋肉の主体である筋線維(極めて細長い巨大な筋細胞)の外側に存在する筋幹細胞(衛星細胞)や繊維芽細胞、2) 筋線維に付着している運動神経終盤、3) 筋線維を取り巻く毛細血管の相互の連携によって巧みに制御されていると予想される。本研究では、筋幹細胞と運動神経終盤とのコミュニケーションを担う分子基盤を明らかにすることを目的としている。この仕組みを解明できれば、家畜・家禽の骨格筋を効率的に肥大・再生させる画期的な食肉生産技術が創生されると期待される他、ALSなどの運動神経退行疾患の予防・治療法の開発などに大きく貢献すると予想される。.
植物成分による筋力向上の分子メカニズムの解明
2005.04, 代表者:辰巳隆一, 九州大学大学院農学研究院, 九州大学 大学院農学研究院 生物機能科学部門 生物機能化学講座畜産化学分野 (JPN).
筋衛星細胞の休止化機構の解明
2004.04, 代表者:辰巳隆一, 九州大学大学院農学研究院, 九州大学 大学院農学研究院 生物機能科学部門 生物機能化学講座畜産化学分野 (JPN)
活性化の逆方向の現象である衛星細胞の休止化の分子機構の解明を目指す。マイオスタチンと呼ばれる細胞増殖抑制因子(別名GDF-8、McPherron et al., Nature 387, 1997)が衛星細胞の休止化に関与することが示唆され(McCroskery et al., J. Cell Biol.162, 2003)、マイオスタチンの発現機構を含めた衛星細胞の休止化の仕組みを明らかにできれば、これを人為的に抑制し骨格筋を画期的に肥大させる新規技術が創生されると期待される。研究成果は食肉の生産性の向上はもとより、筋ジストロフィーの治療に関する再生医療やアスリートの運動能力の向上を目指すスポーツ科学とも密接に関連しており、食糧科学を越えた学際的な貢献が期待される。.
物理刺激をトリガーとした筋衛星細胞の活性化カスケードの解明
1996.02, 代表者:辰巳隆一, 九州大学大学院農学研究院, 九州大学 大学院農学研究院 生物機能科学部門 生物機能化学講座畜産化学分野
物理刺激をトリガーとした筋衛星細胞の活性化機構を追究している。これまでに、衛星細胞に物理刺激を負荷すると休止期からDNA構成準備期に復帰することを見出し、この活性化機構が、カルシウム・カルモジュリン複合体の形成、一酸化窒素合成酵素の活性化による一酸化窒素の産生、一酸化窒素依存的な肝細胞増殖因子(HGF)の細胞外マトリックスからの遊離、およびHGFのc-met受容体への結合と細胞内シグナル伝達系の活性化からなる大きなカスケードであることを突き止めた。現在、一酸化窒素依存的なHGF遊離機構を調べている。.
研究業績
主要著書
1. 辰巳 隆一, 肉の特徴, シリーズ<家畜の科学> ニワトリの科学(朝倉書店 古瀬充宏 編), 2014.04.
2. 辰巳 隆一, 衛星細胞による運動神経支配の再構築制御仮説, 生体の科学 (金原一郎記念医学医療振興財団・医学書院), 特集「特殊な幹細胞としての骨格筋サテライト細胞」, 第64巻2号 122-131, 2013.04.
3. 辰巳隆一(分担執筆), 食肉用語辞典(改訂版), 食肉通信社(日本食肉研究会編), 2009.12.
4. 辰巳隆一(分担執筆), 栄養・食糧学用語辞典, 建帛社, 2007.12.
5. 辰巳隆一(分担執筆), 畜産食品の辞典, 朝倉書店, 2002.12.
6. 辰巳隆一(分担執筆), 丸善食品総合辞典, 丸善, 1998.12.
主要原著論文
1. Yuji Matsuyoshi, Mariko Akahoshi, Mako Nakamura, Ryuichi Tatsumi, Wataru Mizunoya, Isolation and purification of satellite cells from young rats by percoll density gradient centrifugation, Methods in Molecular Biology, 10.1007/978-1-4939-8897-6_6, 81-93, 2019.01, [URL], Satellite cells (SCs) are myogenic stem cells that play an important role in skeletal muscle regeneration and hypertrophy. Primary cultures of SCs are useful to analyze cell functions; however, it is difficult to obtain highly pure SCs from young rats with the conventional procedures. The purpose of this study is to establish a purification method for SC isolation from young rats and quantitatively evaluate the purification procedure employing Percoll, a common research tool to purify cells. We elucidated the purity of SCs collected by Percoll density gradient centrifugation using real-time RT-qPCR and immunocytochemistry for desmin. Percoll treatment increased the purity of SCs isolated from young rats to nearly 90%, which was comparable to that achieved with the conventional method using middle-aged rats..
2. Ohtsubo H., Sato Y., Matsuyoshi Y., Suzuki T., Mizunoya W., Nakamura M., Tatsumi R., Ikeuchi, Y., Fluorescence microscopy data on expression of Paired Box Transcription Factor 7 in skeletal muscle of APOBEC2 knockout mice., Data in Brief, doi.org/10.1016/j.dib.2018.02.063, 17, 1348-1351, 2018.02.
3. Judy E. Anderson, Mai-Khoi Q. Do, N. Daneshvar, Takahiro SUZUKI, J. Dort, Wataru Mizunoya, Ryuichi Tatsumi, The role of semaphorin 3A in myogenic regeneration and the formation of functional neuromuscular junctions on new fibers, Biological Reviews, 10.1111/brv.12286, 10.1111/brv.12286, 2017.08.
4. Tatsumi, Ryuichi; Suzuki, Takahiro; Do, Mai-Khoi Q.; Ohya, Yuki; Anderson, Judy E.; Shibata, Ayumi; Kawaguchi, Mai; Ohya, Shunpei; Ohtsubo, Hideaki; Mizunoya, Wataru; Sawano, Shoko; Komiya, Yusuke; Ichitsubo, Riho; Ojima, Koichi; Nishimatsu, Shin-ichiro; Nohno, Tsutomu; Ohsawa, Yutaka; Sunada, Yoshihide; Nakamura, Mako; Furuse, Mitsuhiro; Ikeuchi, Yoshihide; Nishimura, Takanori; Yagi, Takeshi; Allen, Ronald E., Slow-Myofiber Commitment by Semaphorin 3A Secreted from Myogenic Stem Cells, STEM CELLS, 10.1002/stem.2639, 35, 7, 1815-1834, 2017.07, Recently, we found that resident myogenic stem satellite cells up-regulate a multi-functional secreted protein, semaphorin 3A (Sema3A), exclusively at the early- differentiation phase in response to muscle injury; however, its physiological significance is still unknown. Here we show that Sema3A impacts slow-twitch fiber generation through a signaling pathway, cell-membrane receptor (neuropilin2-plexinA3) → myogenin-myocyte enhancer factor 2D (MEF2D) → slow myosin heavy chain. This novel axis was found by small interfering RNA (siRNA)-transfection experiments in myoblast cultures, which also revealed an additional element that Sema3A-neuropilin1/plexinA1, A2 may enhance slow-fiber formation by activating signals that inhibit fast-myosin expression. Importantly, satellite cell-specific Sema3A conditional-knockout adult mice (Pax7CreERT2-Sema3Aflox activated by tamoxifen-i.p. injection) provided direct in vivo evidence for the Sema3A-driven program, by showing that slow-fiber generation and muscle endurance were diminished after repair from cardiotoxin-injury of gastrocnemius muscle. Overall, the findings highlight an active role for satellite cell-secreted Sema3A ligand as a key “commitment factor” for the slow-fiber population during muscle regeneration. Results extend our understanding of the myogenic stem-cell strategy that regulates fiber-type differentiation and is responsible for skeletal muscle contractility, energy metabolism, fatigue resistance, and its susceptibility to aging and disease..
5. Wataru Mizunoya, Shinpei Okamoto, Hideo Miyahara, Mariko Akahoshi, Takahiro SUZUKI, Mai-Khoi Q. Do, Hideaki Ohtsubo, Yusuke Komiya, Mulan Qahar, Toshiaki Waga, Koichi Nakazato, Yoshihide Ikeuchi, Judy E. Anderson, Ryuichi Tatsumi, Fast-to-slow shift of muscle fiber-type composition by dietary apple polyphenols in rats: Impact of the low-dose supplementation, Animal Science Journal, 10.1111/asj.12655, 88, 3, 489-499, 10.1111/asj.12655, 2017.04, Our previous studies demonstrated that an 8-week intake of 5% (w/w) apple polyphenol (APP) in the diet improves muscle endurance of young-adult rats. In order to identify a lower limit of the dietary contribution of APP to the effect, the experiments were designed for lower-dose supplementation (8-week feeding of 0.5% APP in AIN-93G diet) to 12-week-old male Sprague-Dawley rats. Results clearly showed that the 0.5% APP diet significantly up-regulates slower myosin-heavy-chain (MyHC) isoform ratios (IIx and IIa relative to total MyHC) and myoglobin expression in lower hind-limb muscles examined (P < 0.05). There was a trend to increased fatigue resistance detected from measurements of relative isometric planter-flexion force torque generated by a stimulus train delivered to the tibial nerve (F (98, 1372) = 1.246, P = 0.0574). Importantly, there was no significant difference in the animal body-phenotypes or locomotor activity shown as total moving distance in light and dark periods. Therefore, the present study encourages the notion that even low APP-intake may increase the proportions of fatigue-resistant myofibers, and has promise as a strategy for modifying performance in human sports and improving function in age-related muscle atrophy..
6. Hideaki Ohtsubo, Yusuke Sato, Takahiro SUZUKI, Wataru Mizunoya, Mako Nakamura, Ryuichi Tatsumi, Yoshihide Ikeuchi, Data supporting possible implication of APOBEC2 in self-renewal functions of myogenic stem satellite cells: toward understanding the negative regulation of myoblast differentiation, Data in Brief, 10.1016/j.dib.2017.03.051, 10.1016/j.dib.2017.03.051, 2017.04, This article provides in vitro phenotypical data to show that APOBEC2, a member of apoB mRNA editing enzyme, catalytic polypeptide-like family, may implicate in self-renewal functions of myogenic stem satellite cells, namely in the re-establishment of quiescent status after activation and proliferation of myoblasts in single-myofiber culture..
7. Hideaki Ohtsubo, Yusuke Sato, Takahiro SUZUKI, Wataru Mizunoya, Mako Nakamura, Ryuichi Tatsumi, Yoshihide Ikeuchi, APOBEC2 negatively regulates myoblast differentiation in muscle regeneration, International Journal of Biochemistry and Cell Biology , 10.1016/j.biocel.2017.02.005, 85, 91-101, 10.1016/j.biocel.2017.02.005, 2017.03, Recently we found that the deficiency of APOBEC2, a member of apoB mRNA editing enzyme, catalytic polypeptide-like family, leads to a diminished muscle mass and increased myofiber with centrally-located nuclei known as dystrophic phenotypes. APOBEC2 expression is predominant in skeletal and cardiac muscles and elevated exclusively at the early-differentiation phase of wild-type (WT) myoblast cultures; however the physiological significance is still un-known. Here we show that APOBEC2 is a key negative regulator of myoblast differentiation in muscle regeneration. APOBEC2-knockout (A2KO) mice myoblast cultures displayed a normal morphology of primary myotubes along with earlier increase in fusion index and higher expression levels of myosin heavy chain (MyHC), myogenin and its cooperating factor MEF2C than WT myoblasts. Similar response was observable in APOBEC2-knockdown cultures of WT myoblasts that were transfected with the specific siRNA at the differentiation phase (not proliferation phase). Importantly, cardiotoxin-injured A2KO gastrocnemius muscle provided in vivo evidence by showing larger up-regulation of neonatal MyHC and myogenin and hence earlier regeneration of myofiber structures with diminished cross-sectional areas and minimal Feret diameters. Therefore, the findings highlight a promising role for APOBEC2 in normal progression of regenerative myogenesis at the early-differentiation phase upon muscle injury..
8. Mai-Khoi Q. Do, Naomi Shimizu, Takahiro Suzuki, Hideaki Ohtsubo, Wataru Mizunoya, Mako Nakamura, Shoko Sawano, Mitsuhiro Furuse, Yoshihide Ikeuchi, Judy E. Anderson, Ryuichi Tatsumi, Transmembrane proteoglycans syndecan-2, 4, receptor candidates for the impact of HGF and FGF2 on semaphorin 3A expression in early-differentiated myoblasts, Physiological Reports, 10.14814/phy2.12553, 3, 9, e12553, 2015.09, Regenerative mechanisms that regulate intramuscular motor innervation are thought to reside in the spatiotemporal expression of axon-guidance molecules. Our previous studies proposed an unexplored role of resident myogenic stem cell (satellite cell)-derived myoblasts as a key presenter of a secreted neural chemorepellent semaphorin 3A (Sema3A); hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF2) triggered its expression exclusively at the early-differentiation phase. In order to advance this concept, the present study described that transmembrane heparan/chondroitin-sulfate proteoglycans syndecan-2, 4 may be the plausible receptor candidates for HGF and FGF2 to signal Sema3A expression. Results showed that mRNA expression of syndecan-2, 4 was abundant (two-magnitude higher than syndecan-1, 3) in early-differentiated myoblasts and their in vitro knock-down diminished the HGF/FGF2-induced expression of Sema3A down to a baseline level. Pre-treatment with heparitinase and chondroitinase ABC decreased the HGF and FGF2 responses, respectively in non-knock-down cultures, supporting a possible model that HGF and FGF2 may bind to heparan and chondroitin sulfate chains of syndecan-2, 4 to signal Sema3A expression. The findings, therefore, extend our understanding that HGF/FGF2-syndecan-2, 4 association may stimulate a burst of Sema3A secretion by myoblasts recruited to the site of muscle injury; this would ensure a coordinated delay in the attachment of motoneuron terminals onto fibers early in muscle regeneration, and thus synchronize the recovery of muscle-fiber integrity and the early resolution of inflammation after injury with reinnervation toward functional recovery..
9. Wataru Mizunoya, Hideo Miyahara, Shinpei Okamoto, Mariko Akahoshi, Takahiro Suzuki, Mai-Khoi Q. Do, Hideaki Ohtsubo, Yusuke Komiya, Mu Lan, Toshiaki Waga, Akira Iwata, Koichi Nakazato, Yoshihide Ikeuchi, Judy E. Anderson, Ryuichi Tatsumi, Improvement of endurance based on muscle fiber-type composition by treatment with dietary apple polyphenols in rats, PLoS ONE, 10.1371/journal.pone.0134303, 10, 7, e0134303, 2015.07, A recent study demonstrated a positive effect of apple polyphenol (APP) intake on muscle endurance of young-adult animals. While an enhancement of lipid metabolism may be responsible, in part, for the improvement, the contributing mechanisms still need clarification. Here we show that an 8-week intake of 5% (w/w) APP in the diet, up-regulates two features related to fiber type: the ratio of myosin heavy chain (MyHC) type IIx/IIb and myoglobin protein expression in plantaris muscle of 9-week-old male Fischer F344 rats compared to pair-fed controls (P < 0.05). Results were demonstrated by our SDS-PAGE system specialized for MyHC isoform separation and western blotting of whole muscles. Animal-growth profiles (food intake, body-weight gain, and internal-organ weights) did not differ between the control and 5% APP-fed animals (n = 9/group). Findings may account for the increase in fatigue resistance of lower hind limb muscles, as evidenced by a slower decline in the maximum isometric planter-flexion torque generated by a 100-s train of electrical stimulation of the tibial nerve. Additionally, the fatigue resistance was lower after 8 weeks of a 0.5% APP diet than after 5% APP, supporting an APP-dose dependency of the shift in fiber-type composition. Therefore, the present study highlights a promising contribution of dietary APP intake to increasing endurance based on fiber-type composition in rat muscle. Results may help in developing a novel strategy for application in animal sciences, and human sports and age-related health sciences..
10. Shoko Sawano, Takahiro Suzuki, Mai-Khoi Q. Do, Hideaki Ohtsubo, Wataru Mizunoya, Yoshihide Ikeuchi, Ryuichi Tatsumi, Supplementary immunocytochemistry of hepatocyte growth factor production in activated macrophages early in muscle regeneration, Animal Science Journal, 10.1111/asj.12264, 85, 12, 994-1000, 2014.12, Regenerative intramuscular motor-innervation is thought to reside in the spatiotemporal expression of axon-guidance molecules. Our previous studies showed that resident myogenic stem cells, satellite cells, up-regulate a secreted neural-chemorepellent semaphorin 3A (Sema3A) during the early-differentiation period, in response to hepatocyte growth factor (HGF) elevated in injured muscle. However, a paracrine source of the HGF release is still unknown. Very recently, we proposed a possible contribution of anti-inflammatory macrophages (CD206-positive M2) by showing that M2 cells infiltrate predominantly at the early-differentiation phase (3-5 days post-injury) and produce/secrete large amounts of HGF. In understanding this concept, however, there still remains a critical need to examine if phagocytotic pro-inflammatory macrophages (CD86-positive M1), another activated-phenotype still present at the early-differentiation phase concerned, produce HGF upon muscle injury. The current immunocytochemical study demonstrated that the HGF expression is negative for M1 prepared from cardiotoxin-injured tibialis anterior muscle at day-5, in contrast to the intense fluorescent-signal of M2 served as a positive control. This supplementary result advances our understanding of a spatiotemporal burst of HGF secretion from M2 populations (not M1) to impact Sema3A expression, which ensures a coordinated delay in attachment of motoneuron terminals onto damaged and generating fibers during early phase of muscle regeneration..
11. Shohei Sakaguchi, Jun-ichi Shono, Takahiro Suzuki, Shoko Sawano, Judy E. Anderson, Mai-Khoi Q. Do, Hideaki Ohtsubo, Wataru Mizunoya, Mako Nakamura, Mitsuhiro Furuse, Yoshihide Ikeuchi, Ryuichi Tatsumi, Anti-inflammatory macrophages implicate in regenerative moto-neuritogenesis, by promoting myoblast migration and Sema3A expression, Animal Science Congress 2014 of the Asian-Australian Association of Animal Production Societies (AAAP)
Grha Sabha Pramana, Universitas Gadjah Mada (UGM), Yogyakarta, Indonesia (November 10-14, 2014)
, 2014.11, Successful regeneration and remodeling of neuromuscular connections are critical for restoring functional properties of muscle fiber contractility. While the spatiotemporal regulatory mechanisms coordinating these processes (moto-neuritogenesis) with myogenesis itself remain unclear, various neural factors including attractive and repulsive axon-guidance cue ligands may be involved. Our previous studies proposed a heretofore unexplored role of resident myogenic stem cell (satellite cell)-derived myoblasts as a key presenter of a secreted neural chemorepellent semaphorin 3A (Sema3A); hepatocyte growth factor (HGF) triggered its expression exclusively at the early-differentiation phase. In order to verify this concept, the present study was designed to clarify a paracrine source of HGF release. In vitro experiments demonstrated that activated anti-inflammatory macrophages (CD206-positive M2) produce HGF and thereby promote myoblast chemoattraction and Sema3A expression. Media from pro-inflammatory macrophage cultures (M1) did not show any significant effect. M2 also enhanced the expression of myoblast-differentiation markers in culture, and infiltrated predominantly at the early-differentiation phase (3-5 d post-injury); M2 were confirmed to produce HGF as monitored by in vivo/ex vivo immunocytochemistry of CD11b/CD206/HGF-positive cells and by HGF in situ hybridization of cardiotoxin- or crush-injured tibialis anterior muscle, respectively. Findings, therefore, encourage the idea that M2 contribute to spatiotemporal up-regulation of extracellular Sema3A concentrations by producing HGF that, in turn, stimulates a burst of Sema3A secretion by myoblasts that are recruited to site of injury. This model may ensure a coordinated delay in re-attachment of motoneuron terminals onto damaged fibers early in muscle regeneration, and thus synchronize the recovery of muscle-fiber integrity after injury.
(Key Words: Mouse muscle, Activated macrophages, Hepatocyte growth factor (HGF), Semaphorin 3A (Sema3A), Regenerative moto-neuritogenesis).
12. Tatsumi, R.,* Sakaguchi, S.,* Shono, J.,* Suzuki, T.,* Sawano, S., Anderson, J.E., Do, M.-K.Q., Ohtsubo, H., Mizunoya, W., Nakamura, M., Furuse, M., and Ikeuchi, Y. (*equal contributors), M2 macrophages may implicate in regenerative moto-neuritogenesis, by promoting myoblast migration and Sema3A expression, 2014 FASEB Science Research Conference on “Skeletal Muscle Satellite and Stem Cells”
Steamboat Springs, CO, USA (July 20-25, 2014)
, 2014.07, Successful regeneration and remodeling of neuromuscular connections are critical for restoring functional properties of muscle fiber contractility. While the spatiotemporal regulatory mechanisms coordinating these processes (moto-neuritogenesis) with myogenesis itself remain unclear, various neural factors including attractive and repulsive axon-guidance cue ligands and their membrane receptors may be involved. Our previous studies proposed a heretofore unexplored role of resident myogenic stem cell (satellite cell)-derived myoblasts as a key presenter of a secreted neural chemorepellent semaphorin 3A (Sema3A); hepatocyte growth factor (HGF) triggered its expression exclusively at the early-differentiation phase (Tatsumi et al., 2009; Do et al., 2011, 2012; Sato et al., 2013; Suzuki et al., 2013). In order to verify this concept, the present study was designed to clarify a paracrine source of HGF release. In vitro experiments demonstrated that activated anti-inflammatory macrophages (CD206-positive M2) produce HGF and thereby promote myoblast chemoattraction and Sema3A expression. Media from pro-inflammatory macrophage cultures (CD86-positive M1) did not show any significant effect. M2 infiltrated predominantly at the early-differentiation phase (3-5 d post-injury) and enhanced the expression of myoblast-differentiation markers; M2 were confirmed to produce HGF as monitored by in vivo/ex vivo immunocytochemistry of CD11b/CD206/HGF-positive cells and by HGF in situ hybridization of cardiotoxin- or crush-injured tibialis anterior muscle, respectively. Findings, therefore, encourage the idea that M2 contribute to spatiotemporal up-regulation of extracellular Sema3A concentrations by producing HGF that, in turn, stimulates a burst of Sema3A secretion by myoblasts that are recruited to site of injury. This regulatory axis of “M2 macrophages → satellite cell-derived myoblasts → intramuscular motoneuron terminals” may ensure a coordinated delay in attachment of motoneuron terminals onto regenerating/generating (new) fibers early in muscle regeneration, and thus synchronize the recovery of muscle-fiber integrity after injury..
13. Suzuki, T., Ohya, Y., Ojima, K., Mizunoya, W., Sawano, S., Ohtsubo, H., Nishimatsu, S., Anderson, J. E., Do, M.-K. Q., Nakamura, M., Furuse, M., Ikeuchi, Y., Nohno, T., and Tatsumi, R., Sema3A secreted from satellite cells promotes slow-twitch fiber generation, 2014 FASEB Science Research Conference on “Skeletal Muscle Satellite and Stem Cells”
Steamboat Springs, CO, USA (July 20-25, 2014)
, 2014.07.
14. Ryuichi Tatsumi, Investigating muscle regeneration: The secret of Sema3A, International Innovation, 139, 89-91, 2014.06, Sema3A is a multifunctional molecule involved in several significant processes, but studies have so far neglected its potential impact in muscle biology. Research from Kyushu University in Japan is beginning to unravel its important role and results to date are promising..
15. Shohei Sakaguchi, Jun-ichi Shono, Takahiro Suzuki, Shoko Sawano, Judy E. Anderson, Mai-Khoi Q. Do, Hideaki Ohtsubo, Wataru Mizunoya, Yusuke Sato, Mako Nakamura, Mitsuhiro Furuse, Koji Yamada, Yoshihide Ikeuchi, Ryuichi A Tatsumi, Implication of anti-inflammatory macrophages in regenerative moto-neuritogenesis: promotion of myoblast migration and neural chemorepellent semaphorin 3A expression in injured muscle, International Journal of Biochemistry and Cell Biology, 10.1016/j.biocel.2014.05.032, 54, 272-285, 2014.06, Regenerative mechanisms that regulate intramuscular motor innervation are thought to reside in the spatiotemporal expression of axon-guidance molecules. Our previous studies proposed a heretofore unexplored role of resident myogenic stem cell (satellite cell)-derived myoblasts as a key presenter of a secreted neural chemorepellent semaphorin 3A (Sema3A); hepatocyte growth factor (HGF) triggered its expression exclusively at the early-differentiation phase. In order to verify this concept, the present study was designed to clarify a paracrine source of HGF release. In vitro experiments demonstrated that activated anti-inflammatory macrophages (CD206-positive M2) produce HGF and thereby promote myoblast chemoattraction and Sema3A expression. Media from pro-inflammatory macrophage cultures (M1) did not show any significant effect. M2 also enhanced the expression of myoblast-differentiation markers in culture, and infiltrated predominantly at the early-differentiation phase (3-5 days post-injury); M2 were confirmed to produce HGF as monitored by in vivo/ex vivo immunocytochemistry of CD11b/CD206/HGF-positive cells and by HGF in situ hybridization of cardiotoxin- or crush-injured tibialis anterior muscle, respectively. These studies advance our understanding of the stage-specific activation of Sema3A expression signaling. Findings, therefore, encourage the idea that M2 contribute to spatiotemporal up-regulation of extracellular Sema3A concentrations by producing HGF that, in turn, stimulates a burst of Sema3A secretion by myoblasts that are recruited to site of injury. This model may ensure a coordinated delay in re-attachment of motoneuron terminals onto damaged fibers early in muscle regeneration, and thus synchronize the recovery of muscle-fiber integrity and the early resolution of inflammation after injury..
16. Jun-ichi Shono, Shohei Sakaguchi, Takahiro Suzuki, Mai-Khoi Q. Do, Wataru Mizunoya, Mako Nakamura, Yusuke Sato, Mitsuhiro Furuse, Koji Yamada, Yoshihide Ikeuchi, Ryuichi A Tatsumi, Preliminary Time-Course Study of Antiinflammatory Macrophage Infiltration in Crush-Injured Skeletal Muscle, Animal Science Journal, 10.1111/asj.12105, 84, 11, 744-750, 2013.11, Muscle damage induces massive macrophage infiltration of the injury site, in which activated proinflammatory and antiinflammatory phenotypes (currently classified as M1 and M2, respectively) have been documented as distinct functional populations predominant at different times after the conventional acute injury by intramuscular injection of snake venoms (cardiotoxin, notexin) or chemicals (bupivacaine hydrochloride, barium chloride). The present study employed a muscle-crush injury model that may reflect the more physiologic damage and repair processes initiated by contusing a gastrocnemius muscle in lower hind-limb of adult mice with hemostat forceps, and examined the time-course invasion of M1 and M2 macrophages during muscle regeneration by immunocytochemistry of CD197 and CD206 marker proteins. CD197-positive M1 macrophages were observed exclusively at 1-4 days after crush followed by the alternative prevalence of CD206-positive M2 at 7-days of myogenic differentiation time-point characterized by increasing levels of myogenin mRNA expression. Preliminary PCR analysis showed that M2 may produce hepatocyte growth factor (HGF) in culture, providing additional benefit to understanding that M2 populations actively promote regenerative myogenesis (muscle fiber repair) and moto-neuritogenesis (re-attachment of motoneuron terminals onto damaged fibers) through their time-specific infiltration and release of the growth factor at the injury site early in muscle regeneration. .
17. Takahiro Suzuki, Koichi Ojima, Mai-Khoi Q. Do, Minako Hara, Wataru Mizunoya, Mako Nakamura, Yoshihide Ikeuchi, Judy E. Anderson, Ryuichi Tatsumi, Semaphorin 3A secreted from myogenic stem cells promotes slow-twitch muscle fiber generation, 2013 EMBO Workshop on “Semaphorin Function and Mechanism in Action”, Cemay-la-Ville, France (October 29-31, 2013), 2013.10, Semaphorin 3A (Sema3A), a class 3 vertebrate-secreted semaphorin originally characterized as a potent neural chemorepellent, is now recognized to play crucial roles in angiogenesis, organogenesis, osteoclastogenesis and immune responses as a multi-functional modulator. Recently, we found that resident myogenic stem cells, satellite cells, up-regulate Sema3A expression and secretion exclusively at the early-myogenic differentiation phase in response to in vivo crush injury and hepatocyte growth factor treatment in the primary cultures (Tatsumi et al., 2009); however, its physiological significance in muscle regeneration is still unknown. Here we show that Sema3A impacts slow-type myosin heavy chain (slow-MyHC) expression in mouse satellite cell cultures. Sema3A-siRNA transfection significantly reduced expression of slow-MyHC as well as the muscle-specific transcription factor myogenin, and the down-stream mediators MEF2 as revealed by qPCR and western blotting analyses. Total MyHC expression level was unchanged, likely due to compensatory up-regulation of fast-MyHC during the 72-hr transfection period. Similar responses (except for fast-MyHC) were also observed in myogenin-knockdown cultures. In addition, reduced myogenin expression induced by immunoneutralization of the receptor neuropilin1 (Npn1) was rescued by co-addition of Sema3A protein. These results therefore indicate that Sema3A may activate a slow-MyHC expression-signaling axis consisting of Npn1, myogenin and MEF2. This model is supported by our comparative observations that satellite cells from soleus muscle (abundant in slow fibers) showed higher expression of Sema3A, myogenin and a co-receptor plexinA2 than those from EDL (Suzuki et al. 2013). Overall, the findings highlight a heretofore unexplored and active role for satellite cell-derived Sema3A as a key modulator of slow fiber generation during muscle regeneration, and advance our understanding of the multi-functional contributions of Sema3A..
18. Ryuichi Tatsumi, Judy E. Anderson, Ronald E. Allen, Muscle regeneration dynamics mediated by resident myogenic stem cells: a possible implication in moto-neuritogenesis and fiber-type regulation, Tucson Symposium 2013 on “The Biology of Muscle Growth and Repair”, 2013.09, Skeletal muscle regeneration and work-induced hypertrophy are initiated by mechanical insult or other perturbation and one of the earliest events is triggering the activation (re-entry to cell cycle from G0) of quiescent resident myogenic stem cells, satellite cells. Recent studies of satellite cells in culture and in vivo addressed the possible dual-roles of hepatocyte growth factor (HGF) in the stretch-induced activation and the re-establishing quiescence. In the proposed scenario, the time-coordinated increase in extracellular HGF is a key modulator for the two contrary pathways having low and high thresholds to impact activation and the counterpart quiescence of satellite cells, respectively. Moreover, the role of HGF in muscle repair may not be restricted to myogenesis; we demonstrated that HGF up-regulates expression of secreted axon-guidance molecule semaphorin 3A (Sema3A) in satellite cells at early-differentiation phase in primary cultures and in vivo. The results encourage a possible implication of satellite cells in the spatiotemporal regulation of extracellular Sema3A concentrations, which potentially mediates restoration or remodeling of nerve-muscle connections in muscle regeneration in synchrony with recovery of muscle-fiber integrity and types (fast and slow). Very recently, we found in satellite cell cultures that the Sema3A ligand impacts slow-twitch fiber generation through a muscle-specific transcription factor myogenin-dependent pathway; Sema3A-siRNA transfection significantly reduced expression of slow-type myosin heavy chain (slow-MyHC) as well as myogenin and its co-mediator MEF2. Total MyHC protein expression level was likely unchanged, due to compensatory up-regulation of fast-MyHC and similar responses (except for fast-MyHC) were also observed in myogenin-knockdown cultures. Overall our results highlight the “programmed mechano-biology dynamics” that successful muscle regeneration, comprised of satellite cell-driving myogenesis, intramuscular moto-neuritogenesis and fiber-type regulation (survival), may be a programmed sequence of events that respond to a mechanical perturbation in a synchronous, HGF-dependent and time-coordinated manner..
19. Yusuke Sato, Mai-Khoi Q. Do, Takahiro Suzuki, Hideaki Ohtsubo, Wataru Mizunoya, Mako Nakamura, Mitsuhiro Furuse, Yoshihide Ikeuchi, Ryuichi A Tatsumi, Satellite Cells Produce Neural Chemorepellent Semaphorin 3A upon Muscle Injury, Animal Science Journal, 10.1111/asj.12104, 84, 185-189, Listed on ScienceAlerts.com, 2013.02, Regenerative mechanisms that regulate intramuscular motor innervation including configuration of the neuromuscular connections are thought to reside in the spatiotemporal expression of axon-guidance molecules. Our previous studies proposed a heretofore unexplored role of satellite cells as a key source of a secreted neural chemorepellent semaphorin 3A (Sema3A) expression. In order to verify this concept, there is still a critical need to provide direct evidence to show the up-regulation of Sema3A protein in satellite cells in vivo upon muscle injury. The present study employed a Sema3A/MyoD double-immunohistochemical staining for cryo-sections prepared from cardiotoxin (CTX)-injected gastrocnemius muscle of adult mouse lower hind-limb. Results clearly demonstrated that Sema3A expression was up-regulated in MyoD-positive satellite cells at 4-12 days post-injury period, the time that corresponds to the cell differentiation phase characterized by increasing myogenin mRNA expression. This direct proof encourages a possible implication of satellite cells in the spatiotemporal regulation of extracellular Sema3A concentrations, which potentially ensures coordinating a delay in neurite sprouting and re-attachment of motoneuron terminals onto damaged muscle fibers early in muscle regeneration in synchrony with recovery of muscle-fiber integrity..
20. Takahiro Suzuk, Mai-Khoi Q. Do, Yusuke Sato, Koichi Ojima, Minako Hara, Wataru Mizunoya, Mako Nakamura, Mitsuhiro Furuse, Yoshihide Ikeuchi, Judy E. Anderson, Ryuichi A Tatsumi, Comparative Analysis of Semaphorin 3A in Soleus and EDL Muscle Satellite Cells In Vitro toward Understanding Its Role in Modulating Myogenin Expression, International Journal of Biochemistry and Cell Biology, 45, 2, 476-482, Listed on ScienceAlerts.com, 2013.02, Resident myogenic stem cells, satellite cells, up-regulate a secreted multi-functional modulator, semaphorin 3A (Sema3A), exclusively at the early-differentiation phase in response to muscle-crush injury and treatment with hepatocyte growth factor (HGF) or basic fibroblast growth factor (FGF2). Here, we add evidence that the Sema3A expression and secretion induced by the growth factors is significantly higher in primary cultures from adult rat soleus than from the fast-twitch extensor digitorum longus (EDL) muscle. The higher Sema3A response, revealed by quantitative PCR and western blotting of cell lysates and conditioned media, may account for the higher myogenin expression of soleus muscle satellite cells early in differentiation since addition of recombinant Sema3A stimulates myogenin expression in cultures. These experiments also showed that mRNA expression of plexin A2, which together with neuropilins, constitutes Sema3A composite-receptors, was higher in satellite cells from soleus than EDL with no difference in plexin A1 and A3 and neuropilin-1 and 2 levels. These comparative studies, therefore, highlight a possible Sema3A-plexin A2-myogenin signaling axis that may ensure promoting early differentiation by soleus muscle satellite cells. .
21. Mai-Khoi Q. Do, Takahiro Suzuki, Borjigin Gerelt, Yusuke Sato, Wataru Mizunoya, Mako Nakamura, Yoshihide Ikeuchi, Judy E. Anderson, and Ryuichi Tatsumi, Time-Coordinated Prevalence of Extracellular HGF, FGF2 and TGF-β3 in Crush-Injured Skeletal Muscle, Animal Science Journal, 83, 712-717, 2012.10, Successful regeneration and remodeling of neuromuscular junctions are critical for restoring functional capacities and properties of skeletal muscle after damage, and axon-guidance molecules may be involved in the signaling that regulates such restoration. Recently, we found that early-differentiated satellite cells up-regulate a secreted neural chemorepellent Sema3A upon in vivo muscle-crush injury. The study also revealed that Sema3A expression is up-regulated in primary satellite-cell cultures in response to hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF2) and prevented by transforming growth factor (TGF)-β2, 3 (Tatsumi et al. 2009. Am J Physiol Cell Physiol; Do et al. 2011. Am J Physiol Cell Physiol). In order to verify the physiological significance of this regulation in vitro, the present study was designed to estimate the time-course of extracellular HGF, FGF2 and TGF-β3 concentrations after crush-injury of gastrocnemius muscle in the rat lower hind-limb, using a combination of a non-homogenization/non-spin extraction of extracellular wound fluids and ECL-western blotting analyses. Results clearly demonstrated that active HGF and FGF2 are prevalent in 2-8 days post-crush, whereas active TGF-β3 increases after 12 days, providing a better understanding of the time-coordinated levels of HGF, FGF2, and TGF-β3 that drive regulation of Sema3A expression during regenerative intramuscular moto-neuritogenesis..
22. Tatsumi, R.,* Hara, M.,* Tabata, K.,* Suzuki, T., Do, M.-K. Q., Mizunoya, W., Nakamura, M., Ikeuchi, Y., Anderson, J. E., and Allen, R. E. (*equal contributors), Mechano-Sensing Calcium-Influx Machinery that Instigates Skeletal Muscle Satellite Cell Activation, 2012 FASEB Science Research Conference on “Skeletal Muscle Satellite & Stem Cells",
Lucca, Italy
, 2012.08, When skeletal muscle is stretched or injured, satellite cells, resident myogenic stem cells positioned beneath the basal lamina of mature muscle fibers, are activated to enter the cell cycle. This signaling pathway is a cascade of events including calcium-calmodulin formation, nitric oxide (NO) radical production by NO synthase, matrix metalloproteinase activation, release of hepatocyte growth factor (HGF) from the extracellular matrix, and presentation of HGF to the receptor c-met, as demonstrated by assays of primary cultures and in vivo experiments. Here, we add evidence that two ion channels, the mechano-sensitive cation channel (MS-channel) and the long-lasting-type voltage-gated calcium-ion channel (L-VGC-channel), mediate the influx of extracellular calcium ions in response to cyclic stretch in satellite-cell cultures. When applied to 1-hr stretch cultures with individual inhibitors for MS- and L-VGC-channels (GsMTx-4 and nifedipine, respectively) or with a less specific inhibitor for MS-channels (gadolinium chloride, Gd), satellite cell activation and upstream HGF release were abolished, as revealed by bromodeoxyuridine-incorporation assays and western blotting of conditioned media, respectively. The inhibition was dose-dependent with a maximum at 0.1 μM (GsMTx-4), 10 μM (nifedipine) or 100 μM (Gd) and cancelled by addition of HGF to the culture media; a potent inhibitor for transient-type VGC-channels (NNC55-0396, 100 μM) did not show any significant inhibitory effect. The stretch response was also abolished when calcium-chelator EGTA (1.8 mM) was added to the medium, indicating the significance of extracellular free calcium ions in our present activation model. Finally, cation/calcium channel dependencies were further documented by calcium-imaging analyses on stretched cells; results clearly demonstrated that calcium ion influx was abolished by GsMTx-4, nifedipine and EGTA. Therefore, these results provide an additional insight that calcium ions may flow in through L-VGC-channels by possible coupling with adjacent MS-channel gating that promotes the local depolarization of cell membranes to impact the satellite cell activation cascade..
23. Suzuki, T., Ojima, K., Do, M.Q., Hara, M., Mizunoya, W., Nakamura, M., Ikeuchi, Y., Anderson, J.E. and Tatsumi, R., Semaphorin 3A regulates the early differentiation of satellite cells, 2012 FASEB Science Research Conference on “Skeletal Muscle Satellite & Stem Cells",
Lucca, Italy
, 2012.08, Semaphorin 3A (Sema3A), a class 3 vertebrate-secreted semaphorin, is a potent axon-guidance molecule for sensory, sympathetic and motor neurons. Recently, we found that resident myogenic stem cells, satellite cells, up-regulate Sema3A expression and secretion exclusively at the early-myogenic differentiation phase in response to in vivo crush injury and HGF/FGF2 treatments in the primary cultures, suggesting possible implication of satellite cells in regenerative motoneuritogenesis including sprouting and attachment of motoneuron terminals onto damaged muscle fibers in synchrony with recovery of muscle-fiber structures (Tatsumi et al., Am. J. Physiol. Cell Physiol. 2009; Do et al., Am. J. Physiol. Cell Physiol. 2011). Here, we show that Sema3A also mediates post-natal myogenesis by stimulating the early differentiation of satellite cells. When recombinant Sema3A (R&D Systems) was added to satellite cell cultures for 24 hr from 48-hr post-plating, myogenin message (an early differentiation marker) was up-regulated in a dose-dependent manner with a maximum at 10 ng/ml. Sema3A-specific knock-down by RNAi technique (about 60-75% reduction efficiency) remarkably down-regulated myogenin expression at message and protein levels at the early-differentiation stage, however showed no significant effect on MyoD expression at the same phase and myosin heavy chain expression and myotube formation at the later stage. Immunofluorescence analysis revealed the presence of Sema3A membrane-receptor neuropilin1 (Npn1) at 48-hr post-plating, which is the early-differentiation time-point which siRNA was transfected to cells; immunoneutralization of Npn1 activity also reduced the myogenin expression, which can be rescued competitively by co-addition of Sema3A protein, to a level equivalent to control cultures without anti-Npn1 antibody and Sema3A. These results indicate that satellite cell-secreted Sema3A may bind to the receptor Npn1 to generate myogenin expression signaling that stimulates early differentiation of satellite cells in autocrine and/or paracrine fashions. This topic may be supported potentially by our comparative observations that rat soleus muscle satellite cells showed higher expression activities of Sema3A, myogenin, and plexinA2 (a signaling co-receptor protein for Sema3A) than EDL muscle cells at the early-differentiation stage. Overall, the data highlight again a heretofore unexplored and active role for Sema3A as a key regulator of the early myogenic differentiation of satellite cells during muscle regeneration, therefore providing a better understanding of multi-functional contributions of Sema3A..
24. Do, M.Q., Shimizu, N., Suzuki, T., Mizunoya, W., Nakamura, M., Ikeuchi, Y., Anderson, J.E. and Tatsumi, R., Heparan/chondroitin sulfate chains may mediate HGF/FGF2-induced up-regulation of neural chemorepellent Sema3A in satellite cell cultures, 2012 FASEB Science Research Conference on “Skeletal Muscle Satellite & Stem Cells",
Lucca, Italy
, 2012.08, Semaphorin 3A (Sema3A, also referred to as SemaIII, SemD and collapsin), a class 3 vertebrate-secreted semaphorin, is a potent axon-guidance cue for sensory, sympathetic and motor axons. Recently, we found that satellite cells up- or down-regulate Sema3A in time-dependent responses to in vivo muscle crush-injury and in vitro treatment with recombinant HGF, FGF2 or TGF-βs. Such responses imply that satellite cells are involved in regenerative motoneuritogenesis, including sprouting and re-attachment of motoneuron terminals onto damaged muscle fibers. In order to explore the mechanism of HGF/FGF2-induced Sema3A up-regulation, the present study was designed to investigate possible membrane receptors that are present on satellite cells and could be involved in that signaling pathway. First, we tested whether c-met and FGFR1, high-affinity receptors of HGF and FGF2 respectively, are responsible for Sema3A up-regulation. Treatment with anti-c-met and anti-FGFR1 neutralizing antibodies did not diminish Sema3A up-regulation, indicating that c-met and FGFR1 may not mediate the response. In addition to such high-affinity receptors, HGF and FGF2 also bind with lower affinity to glycosaminoglycan (GAG) chains of proteoglycans - an important component of extracellular matrix- for a variety of biological functions. We therefore hypothesized that the association between HGF/FGF2 and GAG chains might mediate the Sema3A up-regulation. To test the hypothesis, satellite cell cultures were pretreated with GAG-degrading enzymes before the addition of HGF or FGF2, and the level of Sema3A expression was quantified by real-time qPCR. Results showed that treatment with heparitinase for partial removal of heparan sulfate chains significantly decreased induction of Sema3A up-regulation by HGF, but not FGF2. Similarly, treatment with chondroitinase ABC for partial removal of chondroitin sulfate chains significantly diminished the Sema3A up-regulation induced by FGF2, but not HGF. These results suggest that HGF and FGF2 bind to receptors carrying heparan and/or chondroitin sulfate chains; syndecans or other transmembrane-type proteoglycans appear to be plausible receptor candidates for signaling via growth factors to up-regulate Sema3A in satellite cells in culture. .
25. Komiya, Y., Mizunoya, W., Anderson, J.E., Goto, T., Takahashi, N., Kawada, T., Sato, Y., Nakamura, M., Tatsumi, R., and Ikeuchi, Y., Change of skeletal muscle fiber types by n-3 poly unsaturated fatty acid, 2012 FASEB Science Research Conference on “Skeletal Muscle Satellite & Stem Cells",
Lucca, Italy
, 2012.08, Skeletal muscle fibers are classified as type I (red/oxidative/slow) and type II (white/glycolytic/fast) based on color, metabolism and contractile properties. Type I fibers are especially mitochondria-rich and use oxidative metabolism for energy production. Thus, an increase of type I fibers can counteract obesity and reduce fatigue. In a recent study, the nuclear receptor peroxisome proliferator-activated receptor (PPAR) δ attracted attention as a factor regulating muscle fiber type. Over-expression of activated PPARδ caused a shift to slow-type fibers (Wang et al. 2004, PLoS Biol., 2: 1532-1539) and polyunsaturated fatty acid (PUFA) has the ligand activity of PPARδ (Forman et al. 1996, Ann. N.Y.Acad.Sci., 804: 266-275). Recently, we found in rat skeletal muscle that fiber type distribution was slower in vivo after feeding with fish oil. To elucidate this phenomenon, we hypothesized that the change to slow muscle with fish oil results from fish oil PUFA activating the receptor activity of PPARδ. Here, we tested the hypothesis using a rat muscle fiber culture assay. Since muscle fiber-type transformation generally occurs in mature fibers, this culture model has the advantage that fibers can express mature MyHC isoforms while differentiated cell lines such as C2C12 and L6 cannot. Rat fiber cultures were established according to the mouse protocol (Wozniak and Anderson 2005, Biochem.Cell Biol., 83: 674-676) and over 90% muscle fibers were alive until 7 days of culture. When the PPARδ−specific agonist (GW501516) was added to fibers cultured for 7 days, transcript expression of MyHC1and 2A was up-regulated at day 1, lipoprotein lipase message was up-regulated at day 3, and pyruvate dehydrogenase kinase (PDK) 4 and uncoupling protein 3 were up-regulated at day 7. Using luciferase reporter assays, PPARδ ligand activity was measured for several kinds of fatty acid. Results showed that, eicosapentaenoic acid (EPA), abundant in fish oil, had higher ligand activity to PPARδ compared with other fatty acids. When EPA was added to fiber cultures for 24 hours, PDK4 mRNA was up-regulated. In addition, when both EPA and PPARδ-specific antagonist (GSK0660) were added to fiber cultures, the up-regulation of PDK4 mRNA by addition of EPA was reseted to the control level. In conclusion, EPA up-regulates a protein characteristic of slow-type muscle via PPARδ activation and may transform muscle fiber type into slow type. .
26. Minako Hara, Kuniko Tabata, Takahiro Suzuki, Mai-Khoi Q. Do, Wataru Mizunoya, Mako Nakamura, Shotaro Nishimura, Shoji Tabata, Yoshihide Ikeuchi, Kenji Sunagawa, Judy E. Anderson, Ronald E. Allen, and Ryuichi Tatsumi, Calcium Influx through a Possible Coupling of Cation Channels Impacts Skeletal Muscle Satellite Cell Activation in Response to Mechanical Stretch, American Journal of Physiology-Cell Physiology, 2012年3月26日掲載受理、セットで先行公開, 2012.03.
27. Do, M.-K. Q., Sato, Y., Shimizu, N., Suzuki, T., Shono, J.-I., Mizunoya, W., Nakamura, M., Ikeuchi, Y., Anderson, J. E., and Tatsumi, R., Growth Factor Regulation of Neural Chemorepellent Sema3A Expression in Satellite Cell Cultures, American Journal of Physiology-Cell Physiology, 301, C1270-C1279, Listed on the March edition of Global Medical Discovery Series, 2011.11, 筋肥大・再生において筋幹細胞(衛星細胞)が合成・分泌する神経軸索ガイダンス因子Sema3Aによって運動神経末端の再接着(神経支配の回復)が制御されていることをはじめて見出した他、このSema3Aの発現がHGF/FGF2/TGF-beta2,3によって時系列的に調節されていることを示した。.
28. Tatsumi, R., Mizunoya, W., Ikeuchi, Y., Hattori, A., Anderson, J. E., and Allen, R. E., Mechano-Biology of Resident Myogenic Stem Cells: Implication in Postnatal Myogenesis and Intramuscular Motoneuritogenesis, Animal Science Congress 2010 of the Asian-Australian Association of Animal Production Societies (AAAP),
National Pingtung University of Science and Technology (NPUST), Pingtung, Taiwan
, 2010.08.
29. Tatsumi, R.,* Do, M.-K. Q.,* Shimizu, N.,* Sankoda, Y.,* Anderson, J. E., Sato, Y., Suzuki, T., Mizunoya, W., Ikeuchi, Y., and Allen, R. E. (*equal contributors), Possible Implication of Satellite Cells in Regenerative Motoneuritogenesis: HGF and FGF2 Upregulate Neural Chemorepellent Sema3A Expression, Theme 3: Tissue Mechanics, Track 3.6 Muscle Mechanics and Motor Control, at the 6th World Congress on Biomechanics (WCB) 2010,
in conjunction with the 14th International Conference on Biomedical Engineering (ICBME) 2010 and the 5th Asian Pacific Conference on Biomechanics (APBiomech) 2010,
Suntec Convention and Exhibition Center, Singapore
, 2010.08, 筋肥大・再生の過程で、筋幹細胞(衛星細胞)が肝細胞増殖因子HGF依存的に神経軸索ガイダンス因子Sema3Aを合成・分泌することを見出し、衛星細胞が運動神経末端の再接着制御に能動的に関与している可能性を提起した。このアイデアが評価され、掲載雑誌のEditorial Focusに選定された。.
30. Tatsumi, R., Anderson, J. E. and Allen, R. E.., Mechano-Biology on Stretch-Induced Activation of Resident Myogenic Stem Cells, Symposium on “Muscle Injury” section at the 6th World Congress on Biomechanics (WCB) 2010, in conjunction with the 14th International Conference on Biomedical Engineering (ICBME) 2010 and the 5th Asian Pacific Conference on Biomechanics (APBiomech) 2010,
Suntec Convention and Exhibition Center, Singapore
, 2010.08, In undamaged postnatal muscle fibers with normal contraction and relaxation activities, quiescent satellite cells of resident
myogenic stem cells are interposed between the overlying external lamina and the sarcolemma of a subjacent mature
muscle fiber. When muscle is injured, exercised, overused or mechanically stretched, these cells are activated to enter the
cell proliferation cycle, divide, differentiate, and fuse with the adjacent muscle fiber, and are responsible for regeneration
and work-induced hypertrophy of muscle fibers. Therefore, a mechanism must exist to translate mechanical changes in
muscle tissue into chemical signals that can activate satellite cells. Recent studies of satellite cells or single muscle fibers in
culture and in vivo demonstrated the essential role of hepatocyte growth factor (HGF) and nitric oxide (NO) radical in the
activation pathway. These experiments have also reported that mechanically stretching satellite cells or living skeletal
muscles triggers the activation by rapid release of HGF from its extracellular tethering and the subsequent presentation to
the receptor c-met. HGF release has been shown to rely on calcium-calmodulin formation and NO radical production in
satellite cells and/or muscle fibers in response to the mechanical perturbation, and depend on the subsequent
up-regulation of matrix metalloproteinase (MMP) activity. These results indicate that the activation mechanism is a cascade
of events including calcium ion influx, calcium-calmodulin formation, NO synthase activation, NO radical production, MMP
activation, HGF release and binding to c-met. Better understanding of ‘mechano-biology’ on the satellite cell activation is
essential for designing procedures that could enhance muscle growth and repair activities in meat-animal agriculture and
also in neuromuscular disease and aging in humans..
31. Do, M.-K. Q.,* Shimizu, N.,* Sato, Y., Suzuki, T., Tatsumi, R., Mizunoya, W., Ikeuchi, Y., Anderson, J. E., and Allen, R. E. (*equal contributors), Possible Implication of Satellite Cells in Regenerative Motoneuritogenesis: Temporal Coordination of HGF/FGF-2/TGF-beta may Regulate Neural Chemorepellent Sema3A expression, 2010 FASEB Summer Research Conference on “Skeletal Muscle Satellite & Stem Cells",
Carefree, AZ, US
, 2010.07, 筋肥大・再生の過程で、筋幹細胞(衛星細胞)が肝細胞増殖因子HGF依存的に神経軸索ガイダンス因子Sema3Aを合成・分泌することを見出し、衛星細胞が運動神経末端の再接着制御に能動的に関与している可能性を提起した。このアイデアが評価され、掲載雑誌のEditorial Focusに選定された。.
32. Suzuki, T., Takaishi, H., Sakata, T., Do, M. Q., Hara, M., Sato, A., Mizunoya, W., Nishimura, T, Hattori, A., Ikeuchi, Y., and Tatsumi, R., In Vitro Measurement of Postnatal Changes in Proliferating Satellite Cell Frequency during Rat Muscle Growth, Animal Science Journal, 81, 2, 245-251, 2010.04.
33. Sato, Y., Probst, H. C., Tatsumi, R., Ikeuchi, Y., Neuberger, M. S., and Rada, C., Deficiency in APOBEC2 Leads to a Shift in Muscle Fiber Type, Diminished Body Mass and Myopathy, Journal of Biological Chemistry, 285, 7111-7118 , 2010.03.
34. Yamada, M., Tatsumi, R., Yamanouchi, K., Hosoyama, T., Shiratsuchi, S., Sato, A., Mizunoya, W., Ikeuchi, Y., Furuse, M., and Allen, R. E. , High Concentrations of HGF Inhibit Skeletal Muscle Satellite Cell Proliferation In Vitro By Inducing Expression of Myostatin: A Possible Mechanism for Re-Establishing Satellite Cell Quiescence In Vivo. , American Journal of Physiology-Cell Physiology, 298, C465–C476 , Editorial Focusに選定, 2010.03, 骨格筋の肥大・再生は筋幹細胞である衛星細胞の増殖活性に依存しており、これは衛星細胞の活性化と休止化のバランスによって制御されている。これまでに、肝細胞増殖因子HGFによる衛星細胞の活性化機構を明らかにしてきたが、これと逆反応の休止化もまたHGFによって誘導されることを見出した。物理刺激をトリガーにして、HGF濃度依存的に衛星細胞が活性化・増殖した後に自立的に休止化するという、独創的な時系列進行モデルを提起した。.
35. Ryuichi A Tatsumi, Mechano-Biology of Skeletal Muscle Hypertrophy and Regeneration: Possible Mechanism of Stretch-Induced Activation of Resident Myogenic Stem Cells, Animal Science Journal, 81, 11-20, invited review, 2010.01, 筋幹細胞である衛星細胞が物理刺激を引き金として活性化・増殖し筋肥大・再生に寄与する分子メカニズムを解明した一連の研究を、Animal Science Jouranlの招待総説論文として発表した。.
36. Ryuichi Tatsumi, Yoriko Sankoda, Judy E. Anderson, Yusuke Sato, Wataru Mizunoya, Naomi Shimizu, Takahiro Suzuki, Michiko Yamada, Robert P. Rhoads, Jr., Yoshihide Ikeuchi, and Ronald E. Allen, Possible Implication of Satellite Cells in Regenerative Motoneuritogenesis: HGF Up-Regulates Neural Chemorepellent Sema3A during Myogenic Differentiation, American Journal of Physiology-Cell Physiology, 297, C238-C252, Editorial Focusに選定, 2009.08.
37. Sato, Y., Shimizu, M., Mizunoya, W., Wariishi, H., Tatsumi, R., Buchman, V. L., and Ikeuchi, Y. , Differential Expression of Sarcoplasmic and Myofibrillar Proteins of Rat Soleus Muscle during Denervation Atrophy, Bioscience, Biotechnology and Biochemistry, 73, 1748-1756, 2009年度BBB論文賞を受賞, 2009.06.
38. Sato, Y., Shimizu, M., Mizunoya, W., Tatsumi, R., Probst, H., Rada, C., Neuberger, M. S., and Ikeuchi, Y., Skeletal Muscle Fiber Type Change and Myopathy in APOBEC-2 KO Mouse, A Joint meeting of Frontiers in Myogenesis and Skeletal Muscle Satellite and Stem Cells, 2009.05.
39. Yamada, M., Tatsumi, R., Mizunoya, W., Ikeuchi, Y., and Allen, R. E., HGF Induces Myostatin Expression and the Subsequent Satellite Cell Quiescence in a Neuropilin-1 Dependent Manner, A Joint meeting of Frontiers in Myogenesis and Skeletal Muscle Satellite and Stem Cells, 2009.05.
40. Tatsumi, R., Sankoda, Y., Anderson, J. E., Sato, Y., Mizunoya, W., Shimizu, N., Suzuki, T., Yamada, M., Rhoads, R. P., Jr., Ikeuchi, Y., and Allen, R. E. , A Possible Role for Satellite Cells in Regenerative Motoneurogenesis: HGF Up-Regulates Neural Chemorepellent Sema3A Expression, A Joint meeting of Frontiers in Myogenesis and Skeletal Muscle Satellite and Stem Cells, 2009.05.
41. Tatsumi, R., Wuollet, A. L., Tabata, K., Nishimura, S., Tabata, S., Mizunoya, W., Ikeuchi, Y., and Allen, R. E., A Role for Calcium-Calmodulin in Regulating Nitric Oxide Production during Skeletal Muscle Satellite Cell Activation, American Journal of Physiology-Cell Physiology, 296, C922-C929, 2009.03.
42. Yamada, M., Shiratsuchi, S.-I., Tatsumi, R., Mizunoya, W., Ikeuchi, Y., and Allen, R. E., A Receptor Neuropilin-1 Mediates HGF-Induced Muscle Satellite Cell Quiescence, The American Society for Cell Biology 48th Annual Meeting, 2008.12.
43. Yamada, M., Sankoda, Y., Tatsumi, R., Mizunoya, W., Ikeuchi, Y., Sunagawa, K., and Allen, R. E., Matrix Metalloproteinase-2 Mediates Stretch-Induced Activation of Skeletal Muscle Satellite Cells in A Nitric Oxide Dependent Manner, International Journal of Biochemistry and Cell Biology, 40, 2183-2191., 2008.07.
44. Tatsumi, R. and Allen, R.E., Mechano-Biology of Resident Myogenic Stem Cells: Molecular Mechanism of Stretch-Induced Activation of Satellite Cells., Animal Science Journal, 79, 279-290; invited review, 2008.05, 筋幹細胞である衛星細胞が物理刺激を引き金として活性化・増殖し筋肥大・再生に寄与する分子メカニズムを解明した一連の研究を、招待総説論文に紹介した。本論文は2008年に掲載され、その後の論文引用回数などが評価され2011年度の優秀論文賞を受賞した。.
45. Yamada, M., Sankoda, Y., Tatsumi, R., Mizunoya, W., Ikeuchi, Y., and Allen, R. E., Matrix Metalloproteinase-2 Is Involved In Mechanical Stretch-Induced Activation of Skeletal Muscle Satellite Cells., 2007 FASEB Summer Research Conference on “Skeletal Muscle Satellite & Stem Cells, 2007.07.
46. Sato, Y., Shimizu, M., Mizunoya, W., Wariishi, H., Tatsumi, R., and Ikeuchi, Y. , Differential Expression of Sarcoplasmic and Myofibrillar Proteins of Rat Soleus Muscle during Denervation Atrophy., Adult Skeletal Muscle Symposium: Growth, Function and Motility , 2007.06.
47. Mizunoya, Y., Okamoto, S., Wakamatsu, J.-I., Sonoda, Y., Sekiguchi, T., Waga, T., Tatsumi, R., and Ikeuchi, Y. , Food Components Do Affect Skeletal Muscle Mass and Fiber Types: Effects of Beef Extract and Apple Polyphenol. , Adult Skeletal Muscle Symposium: Growth, Function and Motility , 2007.06.
48. Tatsumi, R., Yamada, M., Katsuki, Y., Okamoto, S., Ishizaki, J., Muzunoya, W., Ikeuchi, Y., Hattori, A., Shimokawa, H., and Allen, R. E., Low-pH Preparation of Skeletal Muscle Satellite Cells Can be Used to Study Activation In Vitro., International Journal of Biochemistry and Cell Biology, 38, 1678-1685, 2006.08.
49. Tatsumi, R., Liu, X., Pulido, A., Morales, M., Sakata, T., Dail, S., Hattori, A., Ikeuchi, Y., and Allen, R. E., Satellite Cell Activation in Stretched Skeletal Muscle and The Role of Nitric Oxide and Hepatocyte Growth Factor., American Journal of Physiology-Cell Physiology, 290, 1487-1494, 2006.06.
50. Yamada, M., Tatsumi, R., Kikuiri, T., Okamoto, S., Nonoshita, S., Mizunoya, W., Ikeuchi, Y., Shimokawa, H., Sunagawa, K., and Allen, R. E., Matrix Metalloproteinases are Involved in Mechanical Stretch-Induced Activation of Skeletal Muscle Satellite Cells., Muscle & Nerve, 34, 313-319, 2006.04.
51. Sakata, T., Tatsumi, R., Yamada, M., Shiratsuchi, S., Okamoto, S., Mizunoya, W., Hattori, A., and Ikeuchi, Y., Preliminary Experiments on Mechanical Stretch-Induced Activation of Skeletal Muscle Satellite Cells In Vivo., Animal Science Journal, 77, 518-525, 2006.04.
52. Yamada, M., Tatsumi, R., Okamoto, S., Nonoshita, S., Mizunoya, W., Ikeuchi, Y., and Allen, R. E., Mechanical Stretch-Induced Activation of Skeletal Muscle Satellite Cells Requires Matrix Metalloproteinase Activity., FRONTIERS IN MYOGENESIS, the meeting of the Society for Muscle Biology, 2006.04.
53. Ryuichi Tatsumi, Keitaro Yamanouchi, Toru Hosoyama, Sei-ichi Shiratsuchi, Michiko Yamada, Jun-ichiro Wakamatsu, Wataru Mizunoya, Yoshihide Ikeuchi, and Ronald E. Allen, A Possible Mechanism of Muscle Satellite Cell Quiescence: HGF Induces Myostatin Expression and Secretion., FASEB Summer Research Conference 2005, 4rd International Conference on Skeletal Muscle & Stem Cells, 2005.06.
54. Tatsumi, R. and Allen, R.E., Active Hepatocyte Growth Factor Is Present in Skeletal Muscle Extracellular Matrix, Muscle & Nerve, 10.1002/mus.20114, 30, 5, 654-658, 30, 654-658, 2004.11.
55. Mendias, C., Tatsumi, R., and Allen, R.E., Role of Cyclooxygenase-1 and -2 in Satellite Cell Proliferation, Differentiatio, and Fusion, Muscle & Nerve, 10.1002/mus.20102, 30, 4, 497-500, 30, 497-500, 2004.10.
56. Tatsumi, R., Mitsuhashi, K., Ashida, K., Haruno, A., Hattori, A., Ikeuchi, Y., and Allen, R.E., Comparative Analysis of Mechanical Stretch-Induced Activation Activity of Back and Leg Muscle Satellite Cells In Vitro, Animal Science Journal, 75, 345-351, 2004.08.
57. Tatsumi, R. and Allen, R.E., Satellite Cell Activation in Response to Muscle Stretch and Damage, FASEB Summer Research Conference 2003, 3rd International Conference on Muscle
Satellite & Stem Cells
, 2003.07.
58. Allen, R.E. and Tatsumi, R., Satellite Cell Activation in Response to Muscle Damage, Molecular Biology of Muscle Development and Regeneration, 2003.05.
59. Tatsumi, R., Hattori, A., Ikeuchi, Y., Anderson, J. E., and Allen, R. E., Release of Hepatocyte Growth Factor from Mechanical Stretched Skeletal Muscle Satellite Cells and the Role of pH and Nitric Oxide, Molecular Biology of the Cell, 10.1091/mbc.E02-01-0062, 13, 8, 2909-2918, 13, 2909-2918, 2002.12.
60. Tatsumi, R., Hattori, A., Allen, R. E., Ikeuchi Y., and Ito, T., Mechanical Stretch-Induced Activation of Skeletal Muscle Satellite Cells Is Dependent on Nitric Oxide Production, Animal Science Journal, 73, 235-239, 2002.12.
61. Tatsumi, R., Maeda, K., Hattori, A., and Takahashi, K., Calcium Binding to an Elastic Portion of Connectin/Titin Filaments, Journal of Muscle Research and Cell Motility, 22, 149-162, 2001.12.
62. Tatsumi, R., Sheehan, S. M., Iwasaki, H., Hattori, A., and Allen, R. E., Mechanical Stretch Induces Activation of Skeletal Muscle Satellite Cells In Vitro, Experimental Cell Research, 267, 107-114, 2001.12.
63. Tatsumi, R., Sakata, T., Sheehan, S.M., Hattori, A., and Allen, R.E., Mechanical Stretch-Induced Activation of Skeletal Muscle Satellite Cells: the Possible Role of HGF in the Mechanism, FASEB Summer Research Conference 2000, 2nd International Conference on Muscle Satellite & Stem Cells, 2001.07.
64. Sheehan, S. M., Tatsumi, R., Temm-Grove, C.J., and Allen, R. E., HGF is an Autocrine Growth Factor for Skeletal Muscle Satellite Cells In Vitro, Muscle & Nerve, 23, 239-245, 2000.12.
65. Tatsumi, R., Sheehan, S.M., Iwasaki, H., Hattori, A., and Allen, R.E., Mechanical Stretch Induces Activation of Skeletal Muscle Satellite Cells In Vitro., 2000 Keystone Symposia on the Molecular Biology of Muscle Development and Disease, 2000.05.
66. Tatsumi, R., Anderson, J. E., Nevoret, C. J., Halevy, O., and Allen, R. E., HGF/SF is Present in Normal Adult Skeletal Muscle and Is Capable of Activating Satellite Cells, Developmental Biology, 194, 114-128., 1998.12.
67. Allen, R.E. and Tatsumi, R., Satellite Cell Activation and the Role of Hepatocyte Growth Factor/Scatter Factor, Post-natal Myogenesis: Satellite Cells In Action, 1998.08.
68. Tatsumi, R., Shimada, K., and Hattori, A., Fluorescence Detection of Calcium-Binding Proteins with Quinoline Ca-Indicator Quin2, Analytical Biochemistry, 254, 126-131, 1997.01.
主要総説, 論評, 解説, 書評, 報告書等
1. 辰巳隆一, 水野谷航, 川口 舞, 柴田歩実, 大宅俊平, 松吉祐児, 中村真子, 抗疲労性筋線維の形成機構の解明と食品機能学的制御., 平成29年度 助成研究成果報告書 (上原記念生命科学財団), CDに個別収録のため頁数の記載なし, 2018.10, 【目的】骨格筋の主体である筋線維(筋細胞)は、収縮特性やエネルギー代謝特性の違いから、抗疲労性筋線維(遅筋型筋線維)と易疲労性筋線維(速筋型筋線維)の2つの型に分類される。動物の出生後の筋成長および筋損傷後の再生過程で形成される筋線維の型を決定する機構は不明である。代表者はこれまでに、筋幹細胞(衛星細胞)が合成・分泌する多機能性制御因子semaphorin 3A(Sema3A)によって抗疲労性筋線維の形成が誘導されることを細胞培養系を用いて示唆した。この新奇制御系をin vivoで直接検証することを本研究の目的とした。
【方法】衛星細胞特異的にSema3A発現をコンディショナルノックアウトしたマウス(Sema3A-cKO: タモキシフェン投与によって活性化したPax7CreERT2-Sema3Aflox)の後肢下腿部筋の表現型を解析した。
【結果】筋の再生および初期成長のいずれの場合でも、Sema3A発現をcKOすると抗疲労性筋線維は有意に減少し、易疲労性筋線維 (IIb型) の代替的増加が認められた(抗myosin重鎖アイソフォーム抗体による4重蛍光免疫染色;図の白黒画像参照)。この結果は、myoglobin、porin、遅筋型・速筋型myosin重鎖などの筋線維型関連因子のmRNA発現変化および後肢下腿部の筋持久力の低下とも符合した。従って、衛星細胞分泌因子Sema3Aによって作動するシグナル伝達軸は、神経支配や転写制御因子PPARδ-PGC1α系が確立する前に筋線維型を初期決定(コミット)する強力な分子機構であることが明確になった。また、Sema3Aの細胞膜受容体と同定したneuropilin2-plexinA3のアゴニスト活性を食品成分に見出したので、抗疲労性筋線維の形成を栄養機能学的に促進できると期待された。.
2. 辰巳隆一, 水野谷航, 赤星眞理子, 鈴木貴弘, 松吉祐児, 宮原英生, 中村真子, 食品成分によって抗疲労性筋線維を増やせるか., デサントスポーツ科学(平成29年度 石本記念デサントスポーツ科学振興財団研究助成 研究成果報告書), 第39巻, 17-23, 2018.06, 骨格筋の疲労耐性に関わる抗疲労性筋線維(遅筋型筋線維)の形成を食品成分によって亢進できるかどうか調べた。筋幹細胞である衛星細胞の初代培養系に食事性ポリフェノールであるクロロゲン酸を添加すると(終濃度10 ng/ml)、抗疲労性筋線維の形成を誘導する新規シグナル軸(Sema3Aリガンド → 細胞膜受容体neuropilin2-plexinA3複合体 → 転写制御因子myogenin-MEF2D → 抗疲労性myosin)が活性化した。また、クロロゲン酸を主成分とするポリフェノール混合物を成熟ラットに8週間給餌すると(添加濃度0.5%)、後肢下腿部筋のmyosinアイソフォーム組成が抗疲労性方向へシフトし筋持久力が向上することが確認された。これらの実験結果より、クロロゲン酸がSema3A受容体のアゴニストとして抗疲労性筋線維の形成を促進すると考えられた。研究成果は、加齢筋医科学・健康科学・スポーツ科学への食品機能学的貢献が期待される。.
3. Anderson J. E., Do M.-K. Q., Daneshvar N., Suzuki T., Dort J., Mizunoya W., Tatsumi R., The role of semaphorin 3A in myogenic regeneration and the formation of functional neuromuscular junctions on new fibers., Biological Reviews of the Cambridge Philosophical Society, 10.1111/brv.12286, 2017.08.
4. 辰巳 隆一, Do Mai-Khoi Quy, 鈴木貴弘, 大屋雄暉, 大坪秀明, 小宮佑介, 澤野祥子, 水野谷 航, 中村 真子, 池内 義秀, 筋肥大・再生における異種細胞間コミュニケーションダイナミクス
—筋幹細胞による運動神経支配の再構築制御(仮説)を話題にして—
, 食肉の科学(日本食肉研究会)第56巻 第2号, 103–112 (2015)., 2015.11, 本稿では、骨格筋の肥大・再生過程において、分化初期特異的に浸潤する抗炎症性マクロファージ(M2マクロファージ)が産生する肝細胞増殖因子(HGF)依存的に、筋幹細胞(衛星細胞)が運動神経軸索成長ガイダンス因子semaphorin 3Aを合成・分泌し、運動神経末端が再生筋線維や新生筋線維のどこに・いつ・どのように接着するかを能動的に制御している「異種細胞間コミュニケーション仮説(機能的連関モデル)」を論述する。運動や筋損傷などの物理刺激により活性化し増殖・分化した衛星細胞が損傷筋線維に融合する、あるいは、互いに融合し新しい筋線維を形成することで筋肥大・再生に寄与することが広く知られているが、これに加えて、運動神経支配制御に対する新奇の機能を提案するものである。これは骨格筋のメカノバイオロジー(機械刺激応答生物学)の重要な要素でもあり、「筋幹細胞による筋肥大・再生制御ダイナミクス」の先駆的理解に資すると期待される。.
5. 鈴木貴弘, 大屋雄暉, 尾嶋孝一, 大坪秀明, 小宮佑介, 水野谷航, 中村真子, 池内義秀, 古瀬充宏, 辰巳隆一, 筋幹細胞が分泌するSema3Aによる筋線維型自律制御機構, 栄養生理研究会報(家畜栄養生理研究会)第58巻1号 19-25 (2014), 2014.04.
6. 辰巳隆一, 衛星細胞による運動神経支配の再構築制御仮説
(Possible implication of satellite cells in regenerative moto-neuritogenesis)
, 生体の科学 (金原一郎記念医学医療振興財団・医学書院), 特集「特殊な幹細胞としての骨格筋サテライト細胞」, 第64巻2号 122-131 (2013)., 2013.04, 骨格筋の肥大・再生は、①衛星細胞の活性化・増殖・分化・損傷部位への融合による筋細胞(細長い巨大な細胞なので“筋線維”と呼ばれる)の修復、および衛星細胞同士の融合による新しい筋線維 (新生筋線維) の形成、②運動神経末端の筋線維への接着、③疲労耐性やエネルギー代謝などの筋特性に深く関わる筋線維型(速筋型・遅筋型)の決定、④毛細血管網の再構築、の4つの現象を基盤としている。①は衛星細胞の重要な機能として古くから多くの研究対象になっており、著者らの研究グループは衛星細胞の活性化・休止化機構に関して、物理刺激で作動する時系列制御機構を明らかにした(概要は後述)。一方、これらの研究過程で、分化期に移行した衛星細胞が神経軸索成長ガイダンス因子semaphorin 3A (Sema3A) を合成・分泌することを見出し、上記②に関して、運動神経末端がいつ・どこに・どのように再生筋線維や新生筋線維に接着するかを衛星細胞が能動的に制御している可能性をはじめて提起した。本稿では、この着想に至った実験データの概略を紹介する。また、Sema3Aの発現・分泌が、衛星細胞の活性化・休止化因子である肝細胞増殖因子 (HGF)で特異的に誘導されることから、「物理刺激を引き金として、筋線維構造と運動神経支配の回復がHGFにより時系列的に協調進行する」という“プログラムド メカノバイオロジー”についても合わせて概説する。.
7. 辰巳隆一, 佐藤祐介, 筋幹細胞と運動神経末端のコミュニケーションを担う分子基盤, 平成22年度農学研究院短期集中型研究支援制度終了報告書 (2012), 2012.05.
8. 辰巳隆一, 佐藤祐介, 筋幹細胞と運動神経末端のコミュニケーションを担う分子基盤, 平成22年度農学研究院短期集中型研究支援制度中間報告書 (2010), 2011.02.
9. 辰巳 隆一, 食品機能性物質による加齢筋萎縮の抑制, 研究報告集 (上原記念生命科学財団), 第21巻, P.92-94, 2007.12.
10. 辰巳隆一, 池内義秀, 食肉増産技術の創生を目指して:衛星細胞の活性化・休止化のプログラムカスケード, 家畜栄養生理研究会報, 第49巻 第1号 P.1-19, 2005.04.
11. 辰巳隆一, 筋衛星細胞の活性化機構, 食肉の科学(日本食肉研究会), 第42巻 第2号, p.123 -133, 2001.12.
12. 辰巳隆一, 眠っていた筋細胞が目を覚ます, 化学と生物(日本農芸化学会), 第35巻 第4号 P.295-297, 1997.04.
主要学会発表等
1. 辰巳隆一, 筋幹細胞の基礎科学とその健康・医療応用., 『九州大学』産・学・官交流促進シーズ発表会 in 東京2019, 2019.03, 骨格筋幹細胞の基礎分子生理学の新奇知見から見えてききた、「筋の疲労耐性の向上(抗疲労性筋線維の形成誘導と脂肪燃焼の促進)」および「加齢性筋萎縮・再生不全(加齢に伴う筋量の低下と結合組織・脂肪組織の過剰な浸潤による筋機能の著しい低下)の主要因の全く新しい理解モデル」について紹介する。いずれも、細胞外因子とその細胞膜受容体が深く関与することから、機能性食品成分による制御および創薬の可能性についても展望する。スポーツ・健康・シルバー科学への貢献が期待される。.
2. 辰巳隆一, 筋再生における筋幹細胞のHGF-Sema3A連関:more shine to myokines., 精神・神経疾患研究開発費「ジストロフィン欠損モデル動物を基盤とした筋ジストロフィーの新しい治療法開発」班会議, 2018.12.
3. 辰巳隆一, 筋幹細胞分泌因子による筋線維型制御, 第161回 日本獣医学会学術集会, 2018.09.
4. 辰巳隆一, 筋成長・再生における筋幹細胞分泌因子Sema3Aの機能., 日本筋学会第4回学術集会, 2018.08.
5. Tatsumi R., Suzuki T., Kawaguchi M., Do M.-K. Q., Ohya S., Matsuyoshi Y., Ohya Y., Anderson J. A., Mizunoya W., Sawano S., Sakata K., Nakamura M., Allen R. E., Slow-fiber commitment by Sema3A secretion from myogenic stem satellite cells., 2018 FASEB Science Research Conference on “Skeletal Muscle Satellite Cells and Regeneration”, 2018.07.
6. Ryuichi Tatsumi, Experiments reveal a novel mechanism to regulate myofiber types and its activation by functional food ingredients, The 17th Asian-Australasian Association of Animal Production Societies Animal Science Congress, 2016.08.
7. Mai-Khoi Q. Do, 水野谷 航, 尾嶋孝一, 中村 真子, 池内 義秀, Judy E. Anderson, 辰巳 隆一, 筋芽細胞が合成・分泌するSema3Aはアセチルコリン受容体の発現と機能的凝集を制御する, 第1回日本筋学会学術集会, 2015.08.
8. 鈴木貴弘, 西松伸一郎, 寺田久美子, 片瀬直樹, 濃野勉, 大澤裕, 砂田芳秀, 水野谷 航, 池内 義秀, 辰巳 隆一, 筋幹細胞由来のSema3Aによる筋線維型制御に関する研究, 第1回日本筋学会学術集会, 2015.08.
9. ド マイコイ, 水野谷 航, 尾嶋孝一, 中村 真子, 池内 義秀, 辰巳 隆一, Sema3A ligand secreted from satellite cells promotes aneural nAChR clustering, 第119回日本畜産学会大会, 2015.03.
10. 鈴木貴弘, 西松伸一郎, 寺田久美子, 片瀬直樹, 濃野 勉, 水野谷 航, 池内 義秀, 辰巳 隆一, 筋幹細胞特異的 Sema3A cKO マウスの解析, 第119回日本畜産学会大会, 2015.03.
11. 鈴木貴弘, 大屋雄暉, 澤野祥子, 大坪秀明, 水野谷 航, 中村 真子, 池内 義秀, 辰巳 隆一, 筋幹細胞由来の分泌性因子Sema3Aによる筋線維型自律制御機構, 第37回(平成26年度)日本分子生物学会, 2014.11.
12. Shohei Sakaguchi, Junichi Shono, Takahiro Suzuki, Shoko Sawano, Judy E. Anderson, Mai-Khoi Q. Do, Hideaki Ohtsubo, Wataru Mizunoya, Mako Nakamura, Mitsuhiro Furuse, Yoshihide Ikeuchi, Ryuichi Tatsumi, Anti-inflammatory macrophages implicate in regenerative moto-neuritogenesis, by promoting myoblast migration and Sema3A expression., Animal Science Congress 2014 of the Asian-Australian Association of Animal Production Societies (AAAP), 2014.11.
13. Ryuichi Tatsumi, Judy E. Andeson, Ronald E. Allen, Muscle regeneration dynamics: satellite cells may do more., A Meeting-of-Minds Muscle Symposium, 2014.09.
14. Ryuichi Tatsumi, Shohei Sakaguchi, Junichi Shono, Takahiro Suzuki, Shoko Sawano, Judy E. Anderson, Mai-Khoi Q. Do, Hideaki Ohtsubo, Wataru Mizunoya, Mako Nakamura, Mitsuhiro Furuse, Yoshihide Ikeuchi, M2 macrophages may implicate in regenerative moto-neuritogenesis, by promoting myoblast migration and Sema3A expression., 2014 FASEB Science Research Conference on “Skeletal Muscle Satellite and Stem Cells”, 2014.07.
15. Takahiro Suzuki, Yuki Ohya, Koichi Ojima, Wataru Mizunoya, Shoko Sawano, Hideaki Ohtsubo, Shinichiro Nishimatsu, Judy E. Anderson, Mai-Khoi Q. Do, Mako Nakamura, Mitsuhiro Furuse, Yoshihide Ikeuchi, Tsutomu Nohno, Ryuichi Tatsumi, Sema3A secreted from satellite cells promotes slow-twitch fiber generation., 2014 FASEB Science Research Conference on “Skeletal Muscle Satellite and Stem Cells”, 2014.07.
16. 鈴木貴弘, 大屋雄暉, 尾嶋孝一, 大坪秀明, 小宮佑介, 水野谷 航, 中村 真子, 池内 義秀, 古瀬 充宏, 辰巳 隆一, 筋幹細胞が分泌するSema3Aによる筋線維型自律制御機構, 平成26年度家畜栄養生理研究会春季集談会, 2014.05.
17. 鈴木貴弘, 水野谷 航, 赤星 眞理子, 尾嶋孝一, 大坪秀明, 中村 真子, 池内 義秀, 和賀俊明, 辰巳 隆一, 筋幹細胞による筋線維型自律制御機構は食品成分によって制御できる, 第118回日本畜産学会大会, 2014.03.
18. 鈴木貴弘, 水野谷 航, 赤星 眞理子, 尾嶋孝一, 大坪秀明, 中村 真子, 池内 義秀, 和賀俊明, 辰巳 隆一, 筋幹細胞による筋線維型自律制御機構は食品成分によって制御できる, 第118回日本畜産学会大会, 2014.03.
19. ド・マイコイ, 水野谷 航, 尾嶋孝一, 中村 真子, 辰巳 隆一, 池内 義秀, Syndecan-2, 4 signal chemorepellent Sema3A expression in myogenic stem cells, 第118回日本畜産学会大会, 2014.03.
20. 辰巳 隆一, 筋肥大・再生における細胞間コミュニケーションダイナミクス, 国際食肉科学シンポジウム「「食肉をつくる細胞とその制御機構−筋肥大と脂肪蓄積のメカニズム解明に向けた新展開−」, 2014.03, 要旨:
運動や損傷に伴う骨格筋の肥大・再生は、1)筋肉の主体である筋細胞(筋線維)の肥大・修復および筋線維型(速筋・遅筋型)の決定、2)運動神経末端の筋線維への再接着(神経支配の回復)、3)筋線維を取り巻く毛細血管の再配置、の3つの現象を基盤としている。筋線維の肥大・再生は、筋幹細胞である衛星細胞の活性化・増殖に大きく依存することが知られているが、神経末端の再接着を制御する分子機構は不明である。演者らは、衛星細胞の活性化・休止化機構を調べる過程で、筋再生に伴い分化初期の衛星細胞が肝細胞増殖因子HGFを受容すると神経軸索成長ガイダンス因子Sema3Aを合成・分泌することを見出した。さらには、分化初期に浸潤する抗炎症性マクロファージ(M2)がHGFを大量に分泌し、衛星細胞のSema3A発現を誘導することを明らかにした。これらの知見に基づき本講演では、M2→衛星細胞→神経末端の異種細胞間コミュニケ−ションによって運動神経末端の筋線維への再接着が制御されていることを概説する。また、衛星細胞の活性化と休止化およびSema3Aの合成・分泌がいずれもHGFによって誘導されることから、前述の筋肥大・再生の基盤現象が物理刺激を引き金として時系列進行する自律制御モデルも併せて紹介する。この「筋肥大・再生のメカノバイオロジー」を理解することにより、食肉を効率的に生産する新規技術の開発や、ヒトの筋疾患・加齢・不活動による筋変性退行を抑制する技術開発に資すると期待される。

Abstract:
Successful regeneration and remodeling of neuromuscular connections are critical for restoring functional properties of muscle fibers. While the spatiotemporal regulatory mechanisms coordinating these processes with myogenesis remain unclear, various attractive and repulsive axon-guidance cues may be involved. Recently, we demonstrated that resident myogenic stem-satellite cells up-regulate a secreted neural-chemorepellent Sema3A during the early-differentiation period, in response to hepatocyte growth factor (HGF) elevated in injured muscle. The subsequent experiment showed that a paracrine source of the HGF release may be anti-inflammatory macrophages (M2). These findings therefore highlight a regulatory axis of “M2→satellite cells→motoneuron terminals” as an essential element of paracrine intercellular-communications that ensure the successful regenerative moto-neuritogenesis including the delay in sprouting and attachment of motoneuron terminals onto fibers. .
21. Takahiro Suzuki, Koichi Ojima, Mai-Khoi Q. Do, Minako Hara, Wataru Mizunoya, Mako Nakamura, Yoshihide Ikeuchi, Judy E. Andeson, Ryuichi Tatsumi, Semaphorin 3A secreted from myogenic stem cells promotes slow-twitch muscle fiber generation, 2013 EMBO Workshop on“Semaphorin Function and Mechanism in Action”, 2013.10, Semaphorin 3A (Sema3A), a class 3 vertebrate-secreted semaphorin originally characterized as a potent neural chemorepellent, is now recognized to play crucial roles in angiogenesis, organogenesis, osteoclastogenesis and immune responses as a multi-functional modulator. Recently, we found that resident myogenic stem cells, satellite cells, up-regulate Sema3A expression and secretion exclusively at the early-myogenic differentiation phase in response to in vivo crush injury and hepatocyte growth factor treatment in the primary cultures (Tatsumi et al., 2009); however, its physiological significance in muscle regeneration is still unknown. Here we show that Sema3A impacts slow-type myosin heavy chain (slow-MyHC) expression in mouse satellite cell cultures. Sema3A-siRNA transfection significantly reduced expression of slow-MyHC as well as the muscle-specific transcription factor myogenin, and the down-stream mediators MEF2 as revealed by qPCR and western blotting analyses. Total MyHC expression level was unchanged, likely due to compensatory up-regulation of fast-MyHC during the 72-hr transfection period. Similar responses (except for fast-MyHC) were also observed in myogenin-knockdown cultures. In addition, reduced myogenin expression induced by immunoneutralization of the receptor neuropilin1 (Npn1) was rescued by co-addition of Sema3A protein. These results therefore indicate that Sema3A may activate a slow-MyHC expression-signaling axis consisting of Npn1, myogenin and MEF2. This model is supported by our comparative observations that satellite cells from soleus muscle (abundant in slow fibers) showed higher expression of Sema3A, myogenin and a co-receptor plexinA2 than those from EDL (Suzuki et al. 2013). Overall, the findings highlight a heretofore unexplored and active role for satellite cell-derived Sema3A as a key modulator of slow fiber generation during muscle regeneration, and advance our understanding of the multi-functional contributions of Sema3A..
22. 辰巳 隆一, 筋肥大・再生における筋幹細胞・運動神経末端・マクロファージのコミュニケーションダイナミクス, 第43回日本栄養・食糧学会 北海道支部会シンポジウム「「組織の機能を支える細胞間クロストーク」, 2013.10, 要旨
 運動や損傷に伴う骨格筋の肥大・再生は、1)筋肉の主体である筋細胞(細長い巨大な細胞なので“筋線維”と呼ばれる)の肥大・修復、および筋線維型(速筋・遅筋型)の決定、2)運動神経ネットワーク(神経末端の筋線維への再接着および神経軸索の空間配置)の再構築、3)筋線維を取り巻く毛細血管の再配置、の3つの現象を基盤としている。筋線維の肥大・再生は、衛星細胞(“眠れる筋幹細胞”)の活性化・増殖活性に大きく依存することが知られているが、運動神経ネットワークの再構築(神経支配の回復)を制御する「神経軸索ガイダンス因子の発現機構」は不明である。演者らは、衛星細胞の活性化・休止化機構を調べる過程で、筋損傷に伴い分化初期の衛星細胞が肝細胞増殖因子HGFを受容すると、神経軸索成長ガイダンス因子semaphorin 3A(Sema3A)を合成・分泌することを見出した(Tatsumi et al., Am. J. Physiol. Cell Physiol. 2009; Sato et al., Anim. Sci. J. 2013)。また、TGF-β3の共添加によりHGFによるSema3Aの発現誘導はキャンセルされたことから、発現誘導因子(HGF)と抑制因子(TGF-β3)の時系列的な濃度変化によってSema3A発現が制御されていると考えられた(Do et al., Am. J. Physiol. Cell Physiol. 2011; Do et al., Anim. Sci. J. 2012)。さらには最近、筋再生の分化初期に浸潤してくる代替的活性化マクロファージ(抗炎症性Mφ、M2)がHGFを大量に分泌し、衛星細胞のSema3A発現を誘導することを明らかにした(Sakaguchi et al., PLoS ONE, 投稿中)。これらの知見から、運動神経末端の筋線維への再接着にも衛星細胞と抗炎症性Mφが積極的に関与していると予想され、抗炎症性Mφ→衛星細胞→運動神経末端の制御軸、即ち、筋組織内に存在する異種細胞群の相互連携調節(コミュニケーション)によって筋肥大・再生が巧みに制御されていると考えられた。
 衛星細胞の活性化と休止化 (Yamada et al., Am. J. Physiol. Cell Physiol. 2010)、およびSema3Aの合成・分泌がいずれもHGFによって誘導されることから、前述の筋肥大・再生の基盤現象が物理刺激を引き金として時系列的に自動進行するように巧みに制御されていると推測される。この「筋肥大・再生のプログラムド メカノバイオロジー」を理解することにより、食肉を効率的に生産する新規技術の開発や、ヒトの筋疾患および加齢・不活動による筋変性退行を抑制する技術開発に資すると期待される。.
23. Ryuichi Tatsumi, Judy E. Andeson, Ronald E. Allen, Muscle regeneration dynamics mediated by resident myogenic stem cells: a possible implication in moto-neuritogenesis and fiber-type regulation, Tucson Symposium 2013 on "The Biology of Muscle Growth and Repair", 2013.09, Skeletal muscle regeneration and work-induced hypertrophy are initiated by mechanical insult or other perturbation and one of the earliest events is triggering the activation (re-entry to cell cycle from G0) of quiescent resident myogenic stem cells, satellite cells. Recent studies of satellite cells in culture and in vivo addressed the possible dual-roles of hepatocyte growth factor (HGF) in the stretch-induced activation and the re-establishing quiescence. In the proposed scenario, the time-coordinated increase in extracellular HGF is a key modulator for the two contrary pathways having low and high thresholds to impact activation and the counterpart quiescence of satellite cells, respectively. Moreover, the role of HGF in muscle repair may not be restricted to myogenesis; we demonstrated that HGF up-regulates expression of secreted axon-guidance molecule semaphorin 3A (Sema3A) in satellite cells at early-differentiation phase in primary cultures and in vivo. The results encourage a possible implication of satellite cells in the spatiotemporal regulation of extracellular Sema3A concentrations, which potentially mediates restoration or remodeling of nerve-muscle connections in muscle regeneration in synchrony with recovery of muscle-fiber integrity and types (fast and slow). Very recently, we found in satellite cell cultures that the Sema3A ligand impacts slow-twitch fiber generation through a muscle-specific transcription factor myogenin-dependent pathway; Sema3A-siRNA transfection significantly reduced expression of slow-type myosin heavy chain (slow-MyHC) as well as myogenin and its co-mediator MEF2. Total MyHC protein expression level was likely unchanged, due to compensatory up-regulation of fast-MyHC and similar responses (except for fast-MyHC) were also observed in myogenin-knockdown cultures. Overall our results highlight the “programmed mechano-biology dynamics” that successful muscle regeneration, comprised of satellite cell-driving myogenesis, intramuscular moto-neuritogenesis and fiber-type regulation (survival), may be a programmed sequence of events that respond to a mechanical perturbation in a synchronous, HGF-dependent and time-coordinated manner..
24. 鈴木貴弘, 尾嶋孝一, 大屋雄暉, 大坪秀明, 水野谷 航, 中村 真子, 池内 義秀, 辰巳 隆一, 筋幹細胞由来の分泌因子Sema3Aによる筋線維型自律制御機構の解明, 第117回日本畜産学会大会, 2013.09.
25. 安川沙也加, 水野谷 航, 中村 真子, 池内 義秀, 和賀俊明, 辰巳 隆一, リンゴポリフェノールが筋衛星細胞の活性化に及ぼす影響, 第117回日本畜産学会大会, 2013.09.
26. 坂口昇平, 生野淳一, 水野谷 航, 中村 真子, 辰巳 隆一, 池内 義秀, 活性化マクロファージは筋芽細胞の遊走性の調節に関与する, 第116回日本畜産学会大会, 2013.03.
27. ド・マイコイ, 水野谷 航, 中村 真子, 辰巳 隆一, 池内 義秀, Syndecan-3 may implicate in regulation of neural chemorepellent Sema3A expression in satellite cells, 第116回日本畜産学会大会, 2013.03.
28. 鈴木貴弘, 尾嶋孝一, 水野谷 航, 中村 真子, 辰巳 隆一, 池内 義秀, 筋幹細胞による筋線維型の自律制御機構, 第116回日本畜産学会大会, 2013.03.
29. 辰巳隆一, 筋幹細胞による筋再生制御ダイナミクス, 第245回川崎医学会講演会, 2012.12, 概要和文
骨格筋の再生は衛星細胞と呼ばれる”眠れる筋幹細胞”の増殖活性に依存している。本講演では先ず、筋の損傷や運動に伴い負荷される物理刺激を引き金として衛星細胞が活性化し、増殖した後再び休止化する時系列制御モデルを概説する。また、分化初期に至った衛星細胞が神経軸索ガイダンス因子 semaphorin 3A (Sema3A) を合成・分泌することから、運動神経末端が再生筋線維 (あるいは新生筋線維) のどこに・いつ・どのように再接着するかを能動的に調節している可能性を提起する。更には、エネルギー代謝などの筋特性に深く関わる筋線維型(速筋型・遅筋型)を決定する鍵因子でもあることを示唆する実験データを紹介する。衛星細胞の活性化と休止化、およびSema3Aの合成・分泌がいずれも肝細胞増殖因子(HGF)濃度依存的に誘導されることから、筋肥大・再生の3つの基盤である筋線維の肥大・修復と筋線維型の決定および神経支配の回復が、物理刺激を引き金として時系列的に進行するように巧みに自律制御されていると推測される。この「プログラムドメカノバイオロジー ダイナミクス」を理解することにより、ヒトの筋疾患・加齢・不活動による筋変性退行を抑制する筋医科学や健康科学に資すると期待される。.
30. 辰巳隆一, 筋幹細胞のプログラムド・メカノバイオロジー, 第35回日本分子生物学会年会、ワークショップ「骨格筋幹細胞研究の最前線」, 2012.12, 概要和文
骨格筋の肥大・再生は衛星細胞と呼ばれる”眠れる筋幹細胞”の増殖活性に依存している。本ワークショップでは先ず、筋の損傷や運動に伴い負荷される物理刺激を引き金として衛星細胞が活性化し、増殖した後再び休止化する時系列制御モデルを概説する。また、分化初期に至った衛星細胞が神経軸索ガイダンス因子semaphorin 3A (Sema3A)を合成・分泌し、運動神経末端が再生筋線維のどこに・いつ・どのように再接着(神経支配の回復)するかを能動的に調節している可能性を提起する。衛星細胞の活性化と休止化、およびSema3Aの合成・分泌がいずれも肝細胞増殖因子(HGF)濃度依存的に誘導されることから、筋肥大・再生の2つの基盤である筋線維の肥大・修復(myogenesis)と運動神経末端の再接着(moto-neuritogenesis)が、物理刺激を引き金として時系列的に進行するように巧みに自律制御されていると推測される。この「プログラムド メカノバイオロジー」を理解することにより、ヒトの筋疾患・加齢・不活動による筋変性退行を抑制する技術開発に資すると期待される。.
31. 鈴木貴弘・尾嶋孝一・Mai-Khoi Q. DO・佐藤祐介・原美菜子・大坪秀明・中村まこ・水野谷航・池内義秀・Judy E. ANDERSON・辰巳隆一, 神経軸索成長ガイダンス因子semaphorin 3Aによる筋線維型の制御, 精神・神経疾患研究開発費「筋ジストロフィーに対するトランスレーショナル・リサーチ」 の班会議(主任研究者:武田伸一, 国立精神・神経医療センター 神経研究所 遺伝子疾患治療研究部 部長), 2012.12.
32. Tatsumi, R.,* Hara, M.,* Tabata, K.,* Suzuki, T., Do, M.-K. Q., Mizunoya, W., Nakamura, M., Ikeuchi, Y., Anderson, J. E., and Allen, R. E. (*equal contributors), Mechano-Sensing Calcium-Influx Machinery that Instigates Skeletal Muscle Satellite Cell Activation, 2012 FASEB Science Research Conference on “Skeletal Muscle Satellite & Stem Cells”, 2012.08, When skeletal muscle is stretched or injured, satellite cells, resident myogenic stem cells positioned beneath the basal lamina of mature muscle fibers, are activated to enter the cell cycle. This signaling pathway is a cascade of events including calcium-calmodulin formation, nitric oxide (NO) radical production by NO synthase, matrix metalloproteinase activation, release of hepatocyte growth factor (HGF) from the extracellular matrix, and presentation of HGF to the receptor c-met, as demonstrated by assays of primary cultures and in vivo experiments. Here, we add evidence that two ion channels, the mechano-sensitive cation channel (MS-channel) and the long-lasting-type voltage-gated calcium-ion channel (L-VGC-channel), mediate the influx of extracellular calcium ions in response to cyclic stretch in satellite-cell cultures. When applied to 1-hr stretch cultures with individual inhibitors for MS- and L-VGC-channels (GsMTx-4 and nifedipine, respectively) or with a less specific inhibitor for MS-channels (gadolinium chloride, Gd), satellite cell activation and upstream HGF release were abolished, as revealed by bromodeoxyuridine-incorporation assays and western blotting of conditioned media, respectively. The inhibition was dose-dependent with a maximum at 0.1 μM (GsMTx-4), 10 μM (nifedipine) or 100 μM (Gd) and cancelled by addition of HGF to the culture media; a potent inhibitor for transient-type VGC-channels (NNC55-0396, 100 μM) did not show any significant inhibitory effect. The stretch response was also abolished when calcium-chelator EGTA (1.8 mM) was added to the medium, indicating the significance of extracellular free calcium ions in our present activation model. Finally, cation/calcium channel dependencies were further documented by calcium-imaging analyses on stretched cells; results clearly demonstrated that calcium ion influx was abolished by GsMTx-4, nifedipine and EGTA. Therefore, these results provide an additional insight that calcium ions may flow in through L-VGC-channels by possible coupling with adjacent MS-channel gating that promotes the local depolarization of cell membranes to impact the satellite cell activation cascade.

Key Words: Calcium ion influx; Mechano-sensitive channel; Muscle regeneration; Satellite cells; Stretch-activation; Voltage-gated channel.
33. Suzuki, T., Ojima, K., Do, M.Q., Hara, M., Mizunoya, W., Nakamura, M., Ikeuchi, Y., Anderson, J.E. and Tatsumi, R., Semaphorin 3A regulates the early differentiation of satellite cells, 2012 FASEB Science Research Conference on “Skeletal Muscle Satellite & Stem Cells”, 2012.08, Semaphorin 3A (Sema3A), a class 3 vertebrate-secreted semaphorin, is a potent axon-guidance molecule for sensory, sympathetic and motor neurons. Recently, we found that resident myogenic stem cells, satellite cells, up-regulate Sema3A expression and secretion exclusively at the early-myogenic differentiation phase in response to in vivo crush injury and HGF/FGF2 treatments in the primary cultures, suggesting possible implication of satellite cells in regenerative motoneuritogenesis including sprouting and attachment of motoneuron terminals onto damaged muscle fibers in synchrony with recovery of muscle-fiber structures (Tatsumi et al., Am. J. Physiol. Cell Physiol. 2009; Do et al., Am. J. Physiol. Cell Physiol. 2011). Here, we show that Sema3A also mediates post-natal myogenesis by stimulating the early differentiation of satellite cells. When recombinant Sema3A (R&D Systems) was added to satellite cell cultures for 24 hr from 48-hr post-plating, myogenin message (an early differentiation marker) was up-regulated in a dose-dependent manner with a maximum at 10 ng/ml. Sema3A-specific knock-down by RNAi technique (about 60-75% reduction efficiency) remarkably down-regulated myogenin expression at message and protein levels at the early-differentiation stage, however showed no significant effect on MyoD expression at the same phase and myosin heavy chain expression and myotube formation at the later stage. Immunofluorescence analysis revealed the presence of Sema3A membrane-receptor neuropilin1 (Npn1) at 48-hr post-plating, which is the early-differentiation time-point which siRNA was transfected to cells; immunoneutralization of Npn1 activity also reduced the myogenin expression, which can be rescued competitively by co-addition of Sema3A protein, to a level equivalent to control cultures without anti-Npn1 antibody and Sema3A. These results indicate that satellite cell-secreted Sema3A may bind to the receptor Npn1 to generate myogenin expression signaling that stimulates early differentiation of satellite cells in autocrine and/or paracrine fashions. This topic may be supported potentially by our comparative observations that rat soleus muscle satellite cells showed higher expression activities of Sema3A, myogenin, and plexinA2 (a signaling co-receptor protein for Sema3A) than EDL muscle cells at the early-differentiation stage. Overall, the data highlight again a heretofore unexplored and active role for Sema3A as a key regulator of the early myogenic differentiation of satellite cells during muscle regeneration, therefore providing a better understanding of multi-functional contributions of Sema3A..
34. Do, M.Q., Shimizu, N., Suzuki, T., Mizunoya, W., Nakamura, M., Ikeuchi, Y., Anderson, J.E. and Tatsumi, R., Heparan/chondroitin sulfate chains may mediate HGF/FGF2-induced up-regulation of neural chemorepellent Sema3A in satellite cell cultures, 2012 FASEB Science Research Conference on “Skeletal Muscle Satellite & Stem Cells”, 2012.08, Semaphorin 3A (Sema3A, also referred to as SemaIII, SemD and collapsin), a class 3 vertebrate-secreted semaphorin, is a potent axon-guidance cue for sensory, sympathetic and motor axons. Recently, we found that satellite cells up- or down-regulate Sema3A in time-dependent responses to in vivo muscle crush-injury and in vitro treatment with recombinant HGF, FGF2 or TGF-βs. Such responses imply that satellite cells are involved in regenerative motoneuritogenesis, including sprouting and re-attachment of motoneuron terminals onto damaged muscle fibers. In order to explore the mechanism of HGF/FGF2-induced Sema3A up-regulation, the present study was designed to investigate possible membrane receptors that are present on satellite cells and could be involved in that signaling pathway. First, we tested whether c-met and FGFR1, high-affinity receptors of HGF and FGF2 respectively, are responsible for Sema3A up-regulation. Treatment with anti-c-met and anti-FGFR1 neutralizing antibodies did not diminish Sema3A up-regulation, indicating that c-met and FGFR1 may not mediate the response. In addition to such high-affinity receptors, HGF and FGF2 also bind with lower affinity to glycosaminoglycan (GAG) chains of proteoglycans - an important component of extracellular matrix- for a variety of biological functions. We therefore hypothesized that the association between HGF/FGF2 and GAG chains might mediate the Sema3A up-regulation. To test the hypothesis, satellite cell cultures were pretreated with GAG-degrading enzymes before the addition of HGF or FGF2, and the level of Sema3A expression was quantified by real-time qPCR. Results showed that treatment with heparitinase for partial removal of heparan sulfate chains significantly decreased induction of Sema3A up-regulation by HGF, but not FGF2. Similarly, treatment with chondroitinase ABC for partial removal of chondroitin sulfate chains significantly diminished the Sema3A up-regulation induced by FGF2, but not HGF. These results suggest that HGF and FGF2 bind to receptors carrying heparan and/or chondroitin sulfate chains; syndecans or other transmembrane-type proteoglycans appear to be plausible receptor candidates for signaling via growth factors to up-regulate Sema3A in satellite cells in culture. .
35. 辰巳隆一, 筋幹細胞・運動神経軸索・活性化マクロファージのクロストーク, 北海道大食肉科学セミナー, 2012.05.
36. ド・マイコイ, 清水直美, 鈴木貴弘, 水野谷航, 中村真子, 辰巳隆一, 池内義秀, Studies on signaling receptors responsible for growth factor-regulated Sema3A expression in satellite cells, 第115回日本畜産学会大会, 2012.03.
37. 鈴木貴弘, 尾嶋孝一, 佐藤祐介, 中村真子, 水野谷航, 辰巳隆一, 池内義秀, semaphorin 3Aは筋幹細胞の初期分化を制御する, 第115回日本畜産学会大会, 2012.03.
38. 辰巳隆一, 筋肥大・再生における筋幹細胞・運動神経末端・マクロファージのコミュニケーションに関する研究展開, 農業・食品産業技術総合研究機構 畜産草地研究所セミナー, 2012.03.
39. 辰巳隆一, Mai-Khoi Q. DO, 佐藤祐介, 三小田よりこ, 清水直美, 鈴木貴弘, 水野谷航, 中村まこ, 池内義秀, Judy E. ANDERSON, Ronald E. ALLEN, 筋再生の過程で筋組織幹細胞(衛星細胞)は運動神経末端の再接着制御に関与しているかもしれない:分化期の衛星細胞は神経軸索ガイダンス因子Sema3Aを合成・分泌する, 精神・神経疾患研究開発費「筋ジストロフィーに対するトランスレーショナル・リサーチ」 の班会議(主任研究者:武田伸一, 国立精神・神経医療センター 神経研究所 遺伝子疾患治療研究部 部長), 2011.12.
40. 辰巳隆一, 筋幹細胞による運動神経末端の再接着制御, 第26回日本整形外科学会基礎学術集会 パネルディスカッション「骨格筋の変性と再生」 , 2011.10.
41. 水野谷航・辰巳隆一, 骨格筋線維型の栄養機能調節への挑戦, 花王(株)生物科学研究所講演会, 2011.09.
42. 辰巳隆一・水野谷航, 筋肥大・再生における衛星細胞の役割, 花王(株)生物科学研究所講演会, 2011.09.
43. ド・マイコイ, 清水直美, 佐藤祐介, 水野谷航, 中村真子, 辰巳隆一, 池内義秀, TGF-β2, 3は衛星細胞のSema3A発現調節に関与する, 第114回日本畜産学会大会, 2011.08.
44. 佐藤祐介, 大坪秀明, 水野谷航, 辰巳隆一, 池内義秀, 筋特異的脱アミノ化酵素APOBEC2の筋細胞内局在, 第114回日本畜産学会大会, 2011.08.
45. 生野淳一, 坂口昇平, 佐藤祐介, 水野谷航, 中村真子, 辰巳隆一, 池内義秀, 活性化マクロファージは骨格筋再生に関与する, 第114回日本畜産学会大会, 2011.08.
46. 真鍋宣隆, 原美菜子, 佐藤祐介, 水野谷航, 中村真子, 辰巳隆一, 池内義秀, 伸展刺激強度の違いが筋衛星細胞の活性化に及ぼす影響, 第114回日本畜産学会大会, 2011.08.
47. 原美菜子, 田畑久仁子, 真鍋宣隆, 佐藤祐介, 水野谷航, 中村真子, 辰巳隆一, 西村正太郎, 田畑正志, 池内義秀, 筋衛星細胞の活性化における物理刺激受容機構の解明, 第114回日本畜産学会大会, 2011.08.
48. 鈴木貴弘, 尾嶋孝一, 佐藤祐介, 水野谷航, 中村真子, 辰巳隆一, 池内義秀, 筋幹細胞が分泌するsemaphorin 3Aの生理機能, 第114回日本畜産学会大会, 2011.08.
49. ド・マイコイ, 佐藤祐介, 清水直美, 水野谷航, 辰巳隆一, 池内義秀, TGF-β2とβ3は衛星細胞のSema3A発現を抑制する, 第113回日本畜産学会大会, 2011.03.
50. 鈴木貴弘, 佐藤祐介, 原美菜子, 水野谷航, 辰巳隆一, 池内義秀, 筋細胞におけるsemaphorin3Aの機能, 第113回日本畜産学会大会, 2011.03.
51. 原美菜子, 田畑久仁子, 水野谷航, 辰巳隆一, 池内義秀, 筋衛星細胞の活性化反応におけるCa2+流入機構の解明, 第113回日本畜産学会大会, 2011.03.
52. 辰巳隆一, 佐藤祐介, 筋幹細胞と運動神経末端のコミュニケーションを担う分子基盤, 平成22年度農学研究院短期集中型研究支援制度中間報告書, 2011.02.
53. 辰巳隆一, 筋肥大・再生における衛星細胞の役割, 北大食肉科学セミナー「筋細胞の謎:筋(筋原線維)形成・再生・肥大の謎を解き明かす」, 2010.12.
54. Tatsumi, R., Mizunoya, W., Ikeuchi, Y., Hattotri, A., Anderson, J.E., and Allen, R.E., Mechano-biology of resident myogenic stem cells: implication in postnatal myogenesis and intramuscular motoneuritogenesis, 14th Animal Science Congress of the Asian-Australasian Association of Animal Production Societies (AAAP)., 2010.08.
55. Tatsumi, R., Anderson, J. E., and Allen, R. E., Mechano-biology on stretch-induced activation of resident myogenic stem cells, the 6th World Congress on Biomechanics (WCB) 2010, in conjunction with the 14th International Conference on Biomedical Engineering (ICBME) 2010 and the 5th Asian Pacific Conference on Biomechanics (APBiomech) 2010.  , 2010.08, 物理刺激を引き金として肝細胞増殖因子HGF依存的に筋幹細胞(衛星細胞)が活性化する分子機構に関して招待講演を行った。.
56. Tatsumi, R., Do, M. Q., Shimizu, N., Sankoda, Y., Anderson, J. E., Sato, Y., Suzuki, T., Mizunoya, W., Ikeuchi, Y., and Allen, R. E. (*equal contributors), Possible implication of satellite cells in regenerative motoneuritogenesis: HGF and FGF2 up-regulate neural chemorepellent Sema3A expression, the 6th World Congress on Biomechanics (WCB) 2010, in conjunction with the 14th International Conference on Biomedical Engineering (ICBME) 2010 and the 5th Asian Pacific Conference on Biomechanics (APBiomech) 2010.  , 2010.08.
57. Do, M. Q.*, Shimizu, N.*, Sato, Y., Suzuki, T., Tatsumi, R., Mizunoya, W., Ikeuchi, Y., Anderson, J. E. and Allen R. E. (*equal contributors), Possible implication of satellite cells in regenerative motoneuritogenesis: Temporal coordination of HGF/FGF-2/TGF-β may regulate neural chemorepellent Sema3A expression, 2010 FASEB Summer Research Conference on “Skeletal Muscle Satellite & Stem Cells” , 2010.07.
58. Sato, Y., Probst, H. C., Mizunoya, W., Tatsumi, R., Rada, C., Neuberger, M. S., and Ikeuchi, Y., Skeletal muscle fiber-type change, diminished body mass and myopathy in APOBEC2 KO mouse, 2010 FASEB Summer Research Conference on “Skeletal Muscle Satellite & Stem Cells” , 2010.07.
59. 鈴木貴弘, 清水直美, 山田路子, 辰巳隆一, 水野谷航, 池内義秀, semaphorin 3Aによる筋衛星細胞の分化促進, 第112回日本畜産学会大会, 2010.03.
60. 藤竹瑞穂, 佐藤祐介, 水野谷航, 辰巳隆一, Buchman V.L., 池内義秀, 除神経処理を施したgamma-synuclein欠損マウスの筋組織観察, 第112回日本畜産学会大会, 2010.03.
61. 佐藤祐介, 藤竹瑞穂, 水野谷航, 辰巳隆一, Buchman V.L., 池内義秀, 除神経筋中のgamma-synuclein過剰発現, 第112回日本畜産学会大会, 2010.03.
62. 宮原英生, 岡本慎平, 水野谷航, 辰巳隆一, 和賀俊明, 池内義秀, リンゴポリフェノール摂取により骨格筋の特性が変化する, 九州大学と大分県農林水産研究センター畜産試験場との試験研究連携会議, 2009.10.
63. 宮原英生, 水野谷航, 辰巳隆一, 和賀俊明, 池内義秀, リンゴポリフェノールの摂取が筋持久力に及ぼす影響, 第111回日本畜産学会大会, 2009.09.
64. 山田路子, 佐藤章子, 水野谷航, 辰巳隆一, 池内義秀, 筋衛星細胞休止化へのNpn-1の関与, 第111回日本畜産学会大会, 2009.09.
65. 鈴木貴弘, 清水直美, 山田路子, 辰巳隆一, 水野谷航, 池内義秀, semaphorin3Aが筋衛星細胞の分化に及ぼす影響, 第111回日本畜産学会大会, 2009.09.
66. 清水直美, 鈴木貴弘, 山田路子, 佐藤祐介, 水野谷航, 辰巳隆一, 池内義秀, 筋幹細胞における運動神経軸索ガイダンス因子Sema3Aの発現調節, 第111回日本畜産学会大会, 2009.09.
67. 佐藤祐介, 水野谷航, 辰巳隆一, 池内義秀, 筋特異的シチジンデアミナーゼ APOBEC-2 の発現解析, 第111回日本畜産学会大会, 2009.09.
68. 佐藤祐介, 志水元亨, 焼山 裕, 水野谷航, 辰巳隆一, 割石博之, Neuberger MS ,池内義秀, 骨格筋 APOBEC-2 は筋線維型の変化や筋萎縮に関与している, 日本農芸化学会2009 年度福岡大会, 2009.03.
69. Yamada, M., Shiratsuchi, S.-I., Tatsumi, R., Mizunoya, W., Ikeuchi, Y., and Allen, R. E., A Receptor Neuropilin-1 Mediates HGF-Induced Muscle Satellite Cell Quiescence, The American Society for Cell Biology 48th Annual Meeting, 2008.12.
70. 山田路子, 佐藤祐介, 水野谷航, 辰巳隆一, 池内義秀, 筋衛星細胞の休止化を担う複合受容体の検索, 第109回日本畜産学会大会, 2008.03.
71. 三小田より子, 山田路子, 水野谷航, 辰巳隆一, 池内義秀, 筋幹細胞は運動神経ネットワークの構築に関与する, 第109回日本畜産学会大会, 2008.03.
72. 岡本慎平, 水野谷航, 和賀俊明, 辰巳隆一, 池内義秀, リンゴポリフェノール摂食によりラットの骨格筋線維型組成は遅筋型へシフトする, 第108回日本畜産学会大会, 2007.09.
73. Yamada, M., Sankoda, Y., Tatsumi, R., Mizunoya, W., Ikeuchi, Y., and Allen, R. E., Matrix metalloproteinase-2 is involved in mechanical stretch-induced activation of skeletal muscle satellite cells, 2007 FASEB Summer Research Conference on “Skeletal Muscle Satellite & Stem Cells”, 2007.07.
74. Sato, Y., Shimizu, M., Mizunoya, W., Wariishi, H., Tatsumi, R., and Ikeuchi, Y., Differential expression of sarcoplasmic and myofibrillar proteins of rat soleus muscle during denervation atrophy, Adult Skeletal Muscle Symposium: Growth, Function and Motility, 2007.06.
75. Mizunoya, W., Okamoto, S., Wakamatsu J.-I., Sonoda Y., Sekiguchi, T., Waga, T., Tatsumi, R., and Ikeuchi, Y., Food components do affect skeletal muscle mass and fiber type: Effects of beef extract and apple polyphenol , Adult Skeletal Muscle Symposium: Growth, Function and Motility, 2007.06.
76. 辰巳隆一, 筋肥大・再生のメカノバイオロジー:筋幹細胞の活性化と休止化のHGF・NO依存的カスケード, 平成17年度文部科学省「魅力ある大学院GPプログラム」に基づく研究支援講義, 2007.02.
77. Yamada, M., Tatsumi, R., Okamoto, S., Nonoshita, S., Mizunoya, W., Ikeuchi, Y., and Allen, R. E., Mechanical Stretch-Induced Activation of Skeletal Muscle Satellite Cells Requires Matrix Metalloproteinase Activity, The meeting of the Society for Muscle Biology, Frontiers in Myogenesis, 2006.04.
78. 岡本慎平, 若松淳一郎, 水野谷航, 和賀俊明, 辰巳隆一, 池内義秀, リンゴポリフェノール摂取がラット骨格筋および体脂肪に及ぼす影響, 第106回日本畜産学会大会, 2006.03.
79. 辰巳隆一, 筋幹細胞でのミオスタチン発現機構, 日本畜産学会第106回大会企画シンポジウム, 2006.03.
80. 辰巳隆一, 筋衛星細胞のメカノバイオロジー, 第10回動物生命科学シンポジウム, 2006.03.
81. Ryuichi Tatsumi, Keitaro Yamanouchi, Toru Hosoyama, Sei-ichi Shiratsuchi, Michiko Yamada, Jun-ichiro Wakamatsu, Wataru Mizunoya, Yoshihide Ikeuchi, and Ronald E. Allen, A Possible Programmed Mechanism of Muscle Satellite Cell Quiescence: The cell Activator HGF Induces Myostatin Expression and Secretion., FASEB Summer Research Conference 2005, 2005.06.
82. 辰巳隆一, 池内義秀, 食肉増産技術の創生を目指して:衛星細胞の活性化・休止化のプログラムカスケード, 平成17年度家畜栄養生理研究会春季集談会, 2005.05.
83. 辰巳隆一, 山内啓太郎, 細山 徹, 池内義秀, 活性化因子HGFによる筋衛星細胞の休止化誘導, 第104回日本畜産学会大会, 2005.03.
84. 辰巳隆一, 池内義秀, 服部昭仁, 筋衛星細胞の活性化機構:物理刺激で作動する一酸化窒素依存的カスケード, 第137回日本獣医学会大会, 2004.04.
85. Ryuichi Tatsumi and Ronald E. Allen, Satellite Cell Activation in Response to Muscle Stretch and Damage., FASEB Summer Research Conference 2003, 2003.07.
86. Ronald E. Allen and Ryuichi Tatsumi, Satellite Cell Activation in Response to Muscle Damage, Molecular Biology of Muscle Development and Regeneration, 2003.05.
87. Takehiro Ogawa, Toshiya Hayashi, KazumasaNodake, Shohei Shiraishi, Sunao Mori, Ryuichi Tatsumi,, Yoshihide Ikeuchi and Tatsumi Ito, A Novel Muscle Cell Growth Factor, S-Myotrophin, Promotes the Expression of Fast Myosin in Myotubes Developed from C2C12 Cells., 48th International Congress of Meat Science and Technology, 2002.08.
88. Ryuichi Tatsumi, Tomowa Sakata, Shannon M. Sheehan, Akihito Hattori and Ronald E. Allen, Mechanical Stretch-Induced Activation of Skeletal Muscle Satellite Cells: the Possible Role of HGF in the Mechanism., FASEB Summer Research Conference 2000, 2001.07.
89. Ryuichi Tatsumi, Shannon M. Sheehan, Hiroyuki Iwasaki, Akihito Hattori and Ronald E. Allen, Mechanical Stretch Induces Activation of Skeletal Muscle Satellite Cells In Vitro., 2000 Keystone Symposia on the Molecular Biology of Muscle Development and Disease, 2000.05.
90. Ryuichi Tatsumi, Kenji Maeda and Koui Takahashi, Calcium-Induced Splitting of Connectin/Titin Filaments: Localization and Characterization of Calcium-Binding Sites., 45th International Congress of Meat Science and Technology, 1999.08.
91. Yukiko Ito, Ryuichi Tatsumi, Takanori Nishimura and Akihito Hattori, Solubilization of Myofibrillar Proteins of Chicken Skeletal Muscle in Water., 45th International Congress of Meat Science and Technology, 1999.08.
92. Ronald. E. Allen and Ryuichi Tatsumi, Satellite Cell Activation and the Role of Hepatocyte Growth Factor/Scatter Factor., 1998.08.
93. Ronald. E. Allen, Ryuichi Tatsumi, and Shannon M. Sheehan, HGF is the Activating Factor in Crushed Muscle Extract and Is an Autocrine Growth Factor for Satellite Cells., 1997 Keystone Symposia on Molecular and Cellular Biology, 1997.04.
特許出願・取得
特許出願件数  0件
特許登録件数  1件
その他の優れた研究業績
2017.05, 下記の論文をプレスリリースした。国内外のメディアに多数掲載された。
Tatsumi R.,† Suzuki T., Do M.-K. Q., Ohya Y., Anderson J. E., Sibata A., Kawaguchi M., Ohya S., Ohtsubo H., Mizunoya W., Sawano S., Komiya Y., Ichitsubo R., Ojima K., Nishimatsu S.-I., Nohno T., Ohsawa Y., Sunada Y., Nakamura M., Furuse M., Ikeuchi Y., Nishimura T., Yagi T., Allen R. E.
Slow-myofiber commitment by semaphorin 3A secreted from myogenic stem cells.
Stem Cells 35, 1815-1834 (2017).
IF5years = 6.281, IF2016 = 5.599
.
2014.03, 「筋生理研究会」第6回講演会の開催(Prof. Ronald E. Allen, Associate Dean for Research, School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, USA)
演題:An Historical Perspective on Satellite Cell Biology and Thoughts on Future Directions
場所:21世紀交流プラザ 第2講義室
日時:平成26年3月24日(月).
2012.01, 「筋生理研究会」第5回講演会の開催(Dr. Judy E. Anderson, Head and Prof. of Department of Biological Sciences, The University of Manitoba, Winnipeg, MB, CANADA
(Visiting Professor at Kyushu, Tokyo and Kyoto Univs. under the JSPS Invitation Fellowship Programs for Research in Japan)
演題:Muscle Regeneration from Finish to Start, and Back…
場所:九州大学農学部1号館(2階)266室
日時:平成24年1月27日(金).
2012.01, 「筋生理研究会」第5回講演会の開催(Yasuyuki Ohkawa, Ph.D., Associate Prof., Department of Advanced Medical Initiatives, Faculty of Medicine, Kyushu University, Maidashi, Higashi-ku, Fukuoka 812-8582, JAPAN)
演題:Cell-Fate Decision by Histone Variants
場所:九州大学農学部1号館(2階)266室
日時:平成24年1月27日(金).
2011.04, 学術研究員の継続雇用(佐藤祐介氏)。特任助教の称号付与.
2011.01, 「筋生理研究会」第4回講演会の開催(Dr. Taro Toyoda, Kyoto University, iPS Cell Institute, Kyoto, Japan)
演題:Myo1c: A Novel Regulator of Glucose Transport in Skeletal Muscle
場所:農学部1号館419講義室
日時:平成23年1月28日(金).
2010.03, 下記の論文が高く評価され、2009年度BBB論文賞を受賞した。
Sato, Y., Shimizu, M., Mizunoya, W., Wariishi, H., Tatsumi, R., Buchman, V. L., and Ikeuchi, Y.
Differential Expression of Sarcoplasmic and Myofibrillar Proteins of Rat Soleus Muscle during Denervation Atrophy.
Bioscience, Biotechnology and Biochemistry 73, 1748-1756 (2009). .
2010.04, 学術研究員の雇用(佐藤祐介氏を新規雇用)。同年5月から特任助教の称号付与.
2010.03, 下記の論文が高く評価されEditorial Focusに選定された。論文内容が紹介された(Chazaud 2010, American Journal of Physiology-Cell Physiology, in press)。2010年3, 4月の"The 50 Most-Frequently Read Articles in Am. J. Physiol. Cell Physiol."にランキングされた。
Yamada, M., Tatsumi, R., Yamanouchi, K., Hosoyama, T., Shiratsuchi, S., Sato, A., Mizunoya, W., Ikeuchi, Y., Furuse, M., and Allen, R. E.
High Concentrations of HGF Inhibit Skeletal Muscle Satellite Cell Proliferation In Vitro by Inducing Expression of Myostatin: A Possible Mechanism for Re-Establishing Satellite Cell Quiescence In Vivo.
American Journal of Physiology-Cell Physiology, in press (2010)..
2009.08, 下記の論文が高く評価されEditorial Focusに選定された。論文内容が紹介された(McLoon 2009, American Journal of Physiology-Cell Physiology 297, C227-C230)。
Tatsumi, R., Sankoda, Y., Anderson, J. E., Sato, Y., Mizunoya, W., Shimizu, N., Suzuki, T., Yamada, M., Rhoads, Jr., R. P., Ikeuchi, Y., and Allen, R. E.
Possible Implication of Satellite Cells in Regenerative Motoneuritogenesis: HGF up-regulates neural chemorepellent Sema3A during myogenic differentiation.
American Journal of Physiology-Cell Physiology 297, C238-C252 (2009)..
2009.03, 「筋生理研究会」第3回講演会の開催(Dr. Atsushi Asakura, Stem Cell Institute, Paul & Sheila Wellstone Muscular Dystrophy Center, Department of Neurology, University of Minnesota Medical School, US)
演題:筋幹細胞であるサテライト細胞による骨格筋再生
場所:21世紀交流プラザ第2講義室
日時:平成21年3月30日(月).
2009.03, The American Physiological Society のregular member(2009年度から現在まで, Cell and Molecular Physiology Section)取得.
2008.04, 博士研究員の受け入れ(朱 暁琳氏を新規雇用).
2008.03, 「筋生理研究会」第2回講演会の開催(Dr. Judy E. Anderson, Head, Department of Biological Sciences,
University of Manitoba, Canada)
演題:Skeletal muscle satellite cell activation, muscle regeneration and repair
場所:21世紀交流プラザ第2講義室
日時:平成20年3月19日(水).
2008.12, The American Society for Cell Biologyのregular member(2008年度から現在まで)取得.
2007.05, 「筋生理研究会」第1回講演会の開催(Dr. 尾嶋孝一, 財団法人 東京都医学研究機構 東京都臨床医学総合研究所)
演題:骨格筋特異的カルパインp94のサルコメア内での局在変化について
場所:畜産化学演習室
日時:平成19年5月28日(月).
学会活動
所属学会名
日本暖地畜産学会
日本筋学会
日本畜産学会
西日本畜産学会
日本食肉研究会
日本農芸化学会
日本農芸化学会西日本支部会
家畜栄養生理研究会
米国細胞生物学会 (ASCB)
米国生理学会 (APS)
学協会役員等への就任
2019.04~2021.03, 日本畜産学会, 日本畜産学会大会(2020年3月開催予定)準備委員会 実行委員長.
2017.04, 日本畜産学会, 機関紙(英文雑誌・邦文雑誌)の編集委員.
2018.04, 日本食肉研究会, 評議員.
2017.10~2019.09, 日本暖地畜産学会, 幹事.
2015.01, 日本筋学会, 理事.
2014.04~2023.03, ICoMST(国際食肉技術会議), 運営委員.
2013.03~2015.03, 第17回AAAP大会(日本畜産学会が企画・運営), 運営委員.
2013.07, Science Postprint, Science Postprint査読編集委員(ゼネラルヘルスケア株式会社).
2013.04, 家畜栄養生理研究会, 幹事.
2005.04, 日本食肉研究会, 幹事.
2004.10~2006.10, 西日本畜産学会, 常任委員.
2005.04~2006.03, 日本畜産学会, 日本畜産学会第106回大会運営委員会委員.
2007.04, 日本農芸化学会西日本支部会, 評議員.
学会大会・会議・シンポジウム等における役割
2015.09.11~2015.09.12, 第120回日本畜産学会大会(北海道大会), 座長(Chairmanship).
2015.03.27~2015.03.30, 第119回日本畜産学会大会(宇都宮大会), 座長(Chairmanship).
2014.05.17~2014.05.17, 平成26年度家畜栄養生理研究会春季集談会, 座長(Chairmanship).
2014.03.26~2014.03.26, 国際食肉科学シンポジウム「「食肉をつくる細胞とその制御機構−筋肥大と脂肪蓄積のメカニズム解明に向けた新展開−」, 座長(Chairmanship).
2013.11.09~2013.11.10, 平成25年度家畜栄養生理研究会秋季集談会, 座長(Chairmanship).
2013.03.27~2013.03.30, 第116回日本畜産学会大会(広島大会), 座長(Chairmanship).
2012.03.27~2012.03.30, 第115回日本畜産学会大会(名古屋大会), 座長(Chairmanship).
2004.10, 第55回西日本畜産学会大会(宮崎大会), 座長(Chairmanship).
2005.03, 第104回日本畜産学会大会(東京大会), 座長(Chairmanship).
2006.03, 第106回日本畜産学会大会(福岡大会), 座長(Chairmanship).
2005.10, 第56回西日本畜産学会大会(鹿児島大会), 座長(Chairmanship).
2006.10, 第57回西日本畜産学会大会(熊本大会), 座長(Chairmanship).
2007.03, 第107回日本畜産学会大会(神奈川大会), 座長(Chairmanship).
2007.03, 日本食肉研究会第48回大会, 座長(Chairmanship).
2007.09.26~2007.09.27, 第108回日本畜産学会大会(岡山大会), 座長(Chairmanship).
2009.09.28~2009.09.29, 第111回日本畜産学会大会(沖縄大会), 座長(Chairmanship).
2010.08.23~2010.08.27, Animal Science Congress 2010 of the Asian-Australasian Association of Animal Production Societies (AAAP), 座長(Chairmanship).
2011.03.27~2011.03.29, 第113回日本畜産学会大会(神奈川大会), 座長(Chairmanship).
2014.03.26~2014.03.26, 食肉をつくる細胞とその制御機構 −筋肥大と脂肪蓄積のメカニズム解明に向けた新展開− シンポジウム, シンポジウム企画実行委員.
2013.09.10~2013.09.10, ミートサイエンスって面白い:科学のナイフで食肉を切る, ランチョンセミナー企画実行委員.
2006.03, 日本畜産学会第106回大会運営委員会, 運営委員会委員(編集担当).
2009.03.27~2009.03.29, 日本農芸化学会福岡大会運営委員, クローク担当.
2007.05, 筋生理学研究会第1回学術講演会, 企画運営.
2008.03, 筋生理学研究会第2回学術講演会, 企画運営.
2009.03.30~2009.03.30, 筋生理学研究会第3回学術講演会, 企画運営.
学会誌・雑誌・著書の編集への参加状況
2017.04, Animal Science Journal(日本畜産学会発行), 国内, 編集委員.
2014.04~2015.03, 食肉の科学(日本食肉研究会発行), 国内, 編集委員.
2014.03, Frontiers in Stem Cell Research, 国際, Review Editor.
2013.07, Science Postprint(ゼネラルヘルスケア株式会社), 国内, 査読編集委員.
2013.05~2015.05, 栄養生理研究会報, 国内, 編集委員長.
2004.10, 西日本畜産学会報, 国内, (常任委員).
1993.07, 食肉の科学(日本食肉研究会発行), 国内, (食肉および骨格筋に関する国内・国外論文の抄録作製、年間約20編).
2005.04, 食肉の科学(日本食肉研究会発行), 国内, 編集幹事.
学術論文等の審査
年度 外国語雑誌査読論文数 日本語雑誌査読論文数 国際会議録査読論文数 国内会議録査読論文数 合計
2003年度
2004年度
2005年度
2006年度
2007年度
2008年度
2009年度
2010年度
2011年度
2012年度
2013年度
2014年度
2015年度
その他の研究活動
海外渡航状況, 海外での教育研究歴
Steamboat Grand Resort, UnitedStatesofAmerica, 2018.07~2018.07.
inner mongolia agricultural university, Mongolia, 2016.09~2016.09.
Dr. Judy E. Anderson Lab., Department of Biological Sciences, Faculty of Science, University of Manitoba, Winnipeg, MB, Canada, 2014.09~2014.09.
Steamboat Springs, CO, UnitedStatesofAmerica, 2014.07~2014.07.
Cemay-la-Ville, France, 2013.10~2013.10.
Tucson, AZ, UnitedStatesofAmerica, 2013.09~2013.09.
Morgantown, WV, UnitedStatesofAmerica, 2013.07~2013.07.
Barga, Lucca, Italy, 2012.08~2012.08.
ライプニッツ家畜生物学研究所, Germany, 2012.02~2012.02.
National Pingtung University of Science and Technology, Taiwan, 2010.08~2010.08.
Suntec Convention and Exhibition Center, Singapore, 2010.08~2010.08.
Carefree, AZ, UnitedStatesofAmerica, 2010.07~2010.07.
Indian Wells, CA, UnitedStatesofAmerica, 2007.07~2007.07.
Pine Mountain, GA, UnitedStatesofAmerica, 2006.04~2006.05.
アリゾナ大学 Department of Animal Sciences, Muscle Biology Group, R.E. Allen Lab., UnitedStatesofAmerica, 2006.04~2006.04.
アリゾナ大学 Department of Animal Sciences, Muscle Biology Group, R.E. Allen Lab., UnitedStatesofAmerica, 2002.07~2003.08.
アリゾナ大学 Department of Animal Sciences, Muscle Biology Group, R.E. Allen Lab., UnitedStatesofAmerica, 1997.04~1997.04.
アリゾナ大学 Department of Animal Sciences, Muscle Biology Group, R.E. Allen Lab., UnitedStatesofAmerica, 1996.02~1996.11.
外国人研究者等の受入れ状況
2019.01~2019.04, 1ヶ月以上, Department of Biological Sciences, Faculty of Science, University of Manitoba, Canada, Iran, 外国政府・外国研究機関・国際機関.
2014.03~2014.03, 2週間未満, The School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, UnitedStatesofAmerica, 民間・財団.
2012.01~2012.02, 2週間以上1ヶ月未満, Department of Biological Sciences, Faculty of Science, University of Manitoba, Canada, 日本学術振興会.
受賞
2013年度 ASJ優秀論文賞, (財)日本畜産学会, 2014.03.
2011年度 ASJ優秀論文賞, (財)日本畜産学会, 2012.03.
2009年度 BBB論文賞, (財)日本農芸化学会, 2010.03.
2008年度日本畜産学会賞, (財)日本畜産学会, 2008.03.
研究資金
科学研究費補助金の採択状況(文部科学省、日本学術振興会)
2017年度~2019年度, 基盤研究(B), 代表, 筋幹細胞生物学を基盤とした筋線維型制御機構の先駆的理解と栄養機能学的調節.
2016年度~2018年度, 基盤研究(A), 分担, 骨格筋発達の統合的理解を目指す異種細胞間コミュニケーション機構の全容解明.
2014年度~2015年度, 挑戦的萌芽研究, 代表, 筋幹細胞の活性化機構の新展開:肝細胞増殖因子HGFのニトロ化による抑制的制御.
2014年度~2015年度, 挑戦的萌芽研究, 分担, 筋線タイプ変換と筋衛星細胞の関係性解明:後天的筋衛星細胞欠損マウスの利用.
2014年度~2015年度, 挑戦的萌芽研究, 代表, 筋幹細胞の活性化機構の新展開:肝細胞増殖因子HGFのニトロ化による抑制的制御.
2013年度~2015年度, 基盤研究(B), 代表, 筋肥大・再生に伴う筋線維型制御機構の新展開.
2012年度~2014年度, 基盤研究(A), 分担, 骨格筋における異種細胞間コミュニケーション機構の解明.
2012年度~2013年度, 挑戦的萌芽研究, 分担, 単離筋線維の長期培養系を用いた筋線維タイプ調節機序解明への挑戦.
2011年度~2012年度, 挑戦的萌芽研究, 代表, 筋肥大・再生における筋幹細胞とマクロファージのコミュニケーション.
2010年度~2012年度, 基盤研究(B), 代表, 筋肥大・再生に伴う運動神経ネットワーク再構築の分子基盤.
2008年度~2009年度, 萌芽研究, 代表, 筋幹細胞による運動神経ネットワークの制御.
2007年度~2009年度, 基盤研究(B), 代表, 食品機能性物質による筋肥大の超誘導.
2001年度~2003年度, 基盤研究(B), 分担, 筋原線維タンパク質の水溶化機構に関する研究.
2000年度~2001年度, 基盤研究(C), 代表, 筋衛星細胞の活性化機構の解明:in vivo伸縮モデルによる活性化シグナルの同定.
1998年度~1999年度, 奨励研究(A), 代表, 筋収縮による衛星細胞の活性化機構.
1998年度~1999年度, 萌芽研究, 分担, 食肉タンパク質の水溶化に関する基礎的研究とその応用.
1994年度~1994年度, 奨励研究(A), 代表, 熟成に伴う食肉の軟化に影響を及ぼすネブリンフィラメントの断片化に関する研究.
日本学術振興会への採択状況(科学研究費補助金以外)
2011年度~2013年度, 平成23-24年度日本学術振興会「頭脳循環を加速する若手研究者戦略的海外派遣プログラム」, 分担, 若手研究者による革新的家畜生産学術領域の構築と戦略的国際研究ネットワークの形成.
2011年度~2011年度, 平成23年度外国人研究者招聘(日本学術振興会第2回採用分, 短期), 代表, 筋肥大・再生の分子制御ダイナミクス.
競争的資金(受託研究を含む)の採択状況
2017年度~2017年度, 平成29年度(第39回)自由課題学術研究助成(石本記念デサントスポーツ科学振興財団) , 代表, 食品成分によって抗疲労性筋線維を増やせるか.
2016年度~2017年度, 平成28年度 中村奨励金(中村治四郎育英会), 代表, 筋成長・肥大・再生の筋幹細胞生物学の解明と食品機能学的制御.
2016年度~2017年度, 平成28年度研究助成(上原記念生命科学財団), 代表, 抗疲労性筋線維の形成機構の解明と食品機能学的制御.
2016年度~2016年度, 平成28年度食肉に関する助成研究調査助成(伊藤記念財団), 代表, ポリフェノール給餌による遅筋型筋線維の形成促進:筋成長期での制御による食肉特性の向上を目指して.
2015年度~2015年度, 伊藤記念財団 研究助成金, 代表, 食肉特性の向上を目指して:ポリフェノール給餌による遅筋型筋線維の形成誘導.
2014年度~2014年度, 東和食品研究振興会 学術奨励金(一般研究), 代表, ポリフェノールによる遅筋型筋線維の形成誘導.
2010年度~2010年度, (財)伊藤記念財団, 分担, 食肉由来ACE阻害ペプチドの筋肥大作用とその機構.
2010年度~2010年度, 平成22年度研究助成(不二たん白質研究振興財団), 分担, 大豆イソフラボンが骨格筋線維型に及ぼす影響.
2008年度~2008年度, (財)伊藤記念財団, 代表, 加齢筋萎縮の抑制:牛肉エキスに含まれる未知筋肥大因子の同定.
2007年度~2011年度, (独)科学技術振興機構(JST)、地域イノベーション創出総合支援事業、地域結集型研究開発プログラム, 分担, 食の高付加価値化に資する基盤技術の開発.
2007年度~2007年度, (財)伊藤記念財団, 分担, 牛肉エキスに含まれる筋肥大因子に関する研究.
2006年度~2006年度, 上原記念生命科学財団研究助成, 代表, 食品機能性物質による加齢筋萎縮の抑制.
2006年度~2006年度, (財)伊藤記念財団, 分担, 圧力利用による半調理食肉製品開発の試み:アルカリ溶液の瞬時注入.
2006年度~2006年度, 旗影会, 分担, 鶏卵中の骨格筋肥大因子のスクリーニング.
2005年度~2005年度, 伊藤記念財団食肉に関する研究調査助成, 代表, 筋肥大・再生の食品機能学的誘導に関する研究.
2004年度~2004年度, 伊藤記念財団食肉に関する研究調査助成, 代表, 筋衛星細胞の休止化誘導機構に関する研究.
2004年度~2004年度, 畜産物需給関係学術研究情報収集推進事業, 分担, 牛肉摂取と骨格筋特性の栄養応答:食肉摂取による身体能力の維持と向上を目指して.
2003年度~2003年度, 伊藤記念財団食肉に関する研究調査助成, 分担, L-カルニチン摂取による骨格筋線維型変化およびそのメカニズム.
2002年度~2002年度, 伊藤記念財団食肉に関する研究調査助成, 分担, L-カルニチン(牛肉エキス)摂取による骨格筋線維型変化.
2001年度~2001年度, 伊藤記念財団食肉に関する研究調査助成, 代表, 物理刺激による筋衛星細胞の活性化機構に関する研究.
2001年度~2001年度, 札幌同窓会海外研修助成, 代表.
2000年度~2000年度, 伊藤記念財団食肉に関する研究調査助成, 分担, L-カルニチンが培養心筋細胞の脂肪酸取り込みおよびATP産生に及ぼす影響.
1999年度~1999年度, 伊藤記念財団食肉に関する研究調査助成, 分担, 物理的伸縮を与えた筋衛星細胞の増殖活性とL-カルニチンの取り込み.
1997年度~1997年度, 伊藤記念財団食肉に関する研究調査助成, 代表, 骨格筋衛星細胞の活性化機構に関する研究.
1997年度~1997年度, 札幌同窓会海外研修助成, 代表.
1996年度~1996年度, 吉田科学技術財団国際研究集会派遣研究者助成, 代表.
1995年度~1995年度, 北海道科学産業技術振興財団研究開発支援事業助成(一般研究奨励事業),, 代表, 食肉の熟成中に起こるコネクチンフィラメントのCa2+による開裂.
1989年度~1989年度, 伊藤記念財団食肉に関する研究調査助成, 分担, 筋原線維タンパク質ネブリンの死後変化に関する研究.
1988年度~1988年度, 伊藤記念財団食肉に関する研究調査助成, 分担, 筋原線維タンパク質ネブリンの死後変化に関する研究.
1987年度~1987年度, 伊藤記念財団食肉に関する研究調査助成, 分担, 筋原線維タンパク質ネブリンの死後変化に関する研究.
共同研究、受託研究(競争的資金を除く)の受入状況
1999.04~2001.03, 分担, 単味品製造工程中の筋肉タンパク質の挙動に関する基礎的研究.
2006.05~2007.03, 代表, 筋肉特性の食品機能学的制御に関する研究.
2007.04~2008.03, 代表, 筋肉特性の食品機能学的制御に関する研究.
2008.08~2009.07, 分担, 薬剤の運動能力回復効果に関する研究.
学内資金・基金等への採択状況
2010年度~2011年度, 農学研究院短期集中型研究支援制度, 代表, 筋幹細胞と運動神経末端のコミュニケーションを担う分子基盤.
2005年度~2005年度, 九州大学後援会教職員海外派遣助成事業
(海外で開催される国際研究集会等への参加), 代表, FASEB Summer Research Conference発表演題名
A Possible Mechanism for Muscle Satellite Cell Quiescence: HGF Induces Myostatin Expression and Secretion.
2003年度~2003年度, 平成15年度九州大学大学院農学研究院教育研究特別経費, 代表, 筋衛星細胞の活性化の分子機構:物理刺激で作動するカルシウム・カルモジュリン依存的カスケード.
2001年度~2001年度, 平成13年度九州大学大学院農学研究院教育研究特別経費, 分担, 筋衛星細胞の活性化の分子機構:物理刺激で作動する一酸化窒素依存的カスケード.

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