Myostatin promotes the terminal differentiation of embryonic muscle progenitors

Abstract

Myostatin, a TGF-␤ family member, is an important regulator of adult muscle size. While extensively studied in vitro, the mechanisms by which this molecule mediates its effect in vivo are poorly understood. We addressed this question using chick and mouse embryos. We show that while myostatin overexpression in chick leads to an exhaustion of the muscle progenitor population that ultimately results in muscle hypotrophy, myostatin loss of function in chick and mouse provokes an expansion of this population. Our data demonstrate that myostatin acts in vivo to regulate the balance between proliferation and differentiation of embryonic muscle progenitors by promoting their terminal differentiation through the activation of p21 and MyoD. Previous studies have suggested that myostatin imposes quiescence on muscle progenitors. Our data suggest that myostatin's effect on muscle progenitors is more complex than previously realized and is likely to be context-dependent. We propose a novel model for myostatin mode of action in vivo, in which myostatin affects the balance between proliferation and differentiation of embryonic muscle progenitors by enhancing their differentiation.[Keywords: Myostatin; skeletal muscle; embryo; p21] Supplemental material is available at http://www.genesdev.org.

Numb-deficient satellite cells have regeneration and proliferation defects

“…Intriguingly, the cell-cycle regulator p21 and Myostatin (Mstn), both of which inhibit myoblast proliferation (4, 41-50), were significantly up-regulated in 4OH-Ttreated cells (Table S1). Myostatin is necessary for the balance between proliferation and differentiation of muscle progenitors embryonically and postnatally (41)(42)(43)(44)(45)(46)(47)(48)(49)(50). Myostatin signaling activates expression of p21, inhibiting myoblast proliferation (41)(42)(43)(48)(49)(50)).…”

“…Mstn is an important regulator of postnatal myogenesis; it is expressed in quiescent satellite cells and inhibits their activation (41,43). It also inhibits myoblast proliferation, inducing differentiation (42,44,(48)(49)(50). Mstn loss-of-function mutations in mice, cattle, and sheep result in dramatically increased muscle mass (57)(58)(59)(60)(61)(62).…”

Cripto regulates skeletal muscle regeneration and modulates satellite cell determination by antagonizing myostatin

“…Moreover, studies in chick and mouse embryos pointed to a context-dependent effect of myostatin, controlling the balance between proliferation and differentiation on muscle progenitors (46). In contrast, recent data indicate that postnatal muscle hypertrophy generated by the lack of myostatin is largely due to hypertrophy of individual fibers and not to satellite cell activity (47).…”

<b>Morphology and expression of genes related to skeletal muscle growth in juveniles of pirarucu (<i>Arapaima gigas</i>, Arapaimatidae, Teleostei)</b> - doi: 10.4025/actascianimsci.v35i3.18219

“…The myostatin expression pattern is analogous to that observed in adult mammals, where myostatin mRNA levels are higher in fast-glycolytic fibres than in slow ones (CARLSON et al, 1999;MATSAKAS et al, 2006). Based on these results and on the observation that satellite cells express myostatin and are quiescent (MCCROSKERY et al, 2003), it has been suggested that the normal function of myostatin in postnatal muscle is to maintain satellite cells in a quiescent, undifferentiated state (MANCEAU et al, 2008).…”