期刊
STEM CELLS
卷 35, 期 7, 页码 1815-1834出版社
WILEY
DOI: 10.1002/stem.2639
关键词
Resident myogenic stem satellite cells; Semaphorin 3A; Myogenin; Slow-twitch myofiber; Muscle endurance; Regeneration
资金
- NICHD
- Japan Society for the Promotion of Science (JSPS) [22380145, 25292164, 17H03908]
- Invitation Fellowship Program for Research in Japan from the Japan Society for the Promotion of Science (JSPS)
- Ito Foundation
- Uehara Memorial Foundation
- JSPS [24248045, 16H02585]
- Kyushu University Foundation
- Kawasaki Medical School [26B-29, 27B-75]
- Natural Sciences and Engineering Research Council of Canada [171302-09, 03833-15]
- JSPS
- Ministry of Education, Culture, Sports, Science and Technology-Japan (MEXT)
- Grants-in-Aid for Scientific Research [17K07807, 16K18788, 16H02585, 17H03908, 26712023, 17K15272, 17K08065, 16H01275] Funding Source: KAKEN
Recently, we found that resident myogenic stem satellite cells upregulate 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 slow myosin heavy chain. This novel axis was found by small interfering RNA-transfection experiments in myoblast cultures, which also revealed an additional element that Sema3A-neuropilinl/plexinAl, A2 may enhance slow-fiber formation by activating signals that inhibit fast myosin expression. Importantly, satellite cell-specific Sema3A conditional-knockout adult mice (Pax7CreERT2-Sema3Af 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.
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