1. Slow-Myofiber Commitment by Semaphorin 3A Secreted from Myogenic Stem Cells.
- Author
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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, and Furuse, Mitsuhiro
- Abstract
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-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 (Pax7CreER
T2 -Sema3Afl °x 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. S tem C ells 2017;35:1815-1834 [ABSTRACT FROM AUTHOR]- Published
- 2017
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