Slow‐Myofiber Commitment by Semaphorin 3A Secreted from Myogenic Stem Cells. (31st May 2017)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Stem cells. Volume 35:Number 7(2017:Jul.)
• Page Start: 1815
• Page End: 1834
• Publication Date: 2017-05-31
• Subjects: Resident myogenic stem satellite cells -- Semaphorin 3A -- Myogenin -- Slow‐twitch myofiber -- Muscle endurance -- Regeneration; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2639
• Languages: English
• ISSNs: 1066-5099

Abstract

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 ‐Sema3A fl ° 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. Stem Cells 2017;35:1815–1834 Abstract : Fiber‐type proportions are responsible for skeletal muscle properties including contractility, metabolism (glycolytic and oxidative), and fatigue resistance, as well as its susceptibility to disease conditions and its plasticity to respond to demands of exercise or disuse. The mechanism that restores the original muscle‐specific fiber‐type composition after a muscle regenerates from trauma or chemical insult is not well understood. Here we show that Sema3A ligand, which is secreted from resident myogenic stem satellite cells exclusively at the early‐differentiation phase (in a HGF/syndecan2, 4‐dependent manner), impacts slow‐fiber commitment through a signaling pathway from the cell‐membrane receptor (neuropilin2‐plexinA3) → myogenin (and MEF2D/HDAC7) → slow myosin heavy chain (MyHC). The detailed mechanistic connections between neuropilin2‐plexinA3, myogenin, and slow MyHC await further study. The model includes additional elements that Sema3A‐neuropilin2/plexinA3 and Sema3A‐neuropilin1/plexinA1, A2 coupling may enhance slow‐fiber formation by activating signals that inhibit fast‐myosin expression. At the subsequent growth phase, Sema3A expression returns to basal level and hence the motor innervation may be established on slow‐MyHC‐positive myotubes. The innervation contributes to fiber‐type maturation through a calcium/calcineurin signaling pathway, in synchrony with configuration of regenerated capillaries and transcriptional PGC1α/PPARδ‐circuitry.