Abstract
Skeletal muscle has a remarkable capacity of regeneration after injury, but the regulatory network underlying this repair process remains elusive. RNA-binding proteins play key roles in the post-transcriptional regulation of gene expression and the maintenance of tissue homeostasis and plasticity. Rbm24 regulates myogenic differentiation during early development, but its implication in adult muscle is poorly understood. Here we show that it exerts multiple functions in muscle regeneration. Consistent with its dynamic subcellular localization during embryonic muscle development, Rbm24 also displays cytoplasm to nucleus translocation during C2C12 myoblast differentiation. In adult mice, Rbm24 mRNA is enriched in slow-twitch muscles along with myogenin mRNA. The protein displays nuclear localization in both slow and fast myofibers. Upon injury, Rbm24 is rapidly upregulated in regenerating myofibers and accumulates in the myonucleus of nascent myofibers. Through satellite cell transplantation, we demonstrate that Rbm24 functions sequentially to regulate myogenic differentiation and muscle regeneration. It is required for myogenin expression at early stages of muscle injury and for muscle-specific pre-mRNA alternative splicing at late stages of regeneration. These results identify Rbm24 as a multifaceted regulator of myoblast differentiation. They provide insights into the molecular pathway orchestrating the expression of myogenic factors and muscle functional proteins during regeneration.
Highlights
Skeletal muscle has a remarkable capacity of regeneration after injury, but the regulatory network underlying this repair process remains elusive
Note the higher levels of Rbm[24] and myogenin expression in the slow-twitch soleus muscle compared to the five other muscles enriched in fast-twitch myofibers. (c) Linear correlation between Rbm[24] and myogenin expression in different muscles. R2 = 0.6527. (d,e) Double immunostaining on cryosections of soleus (Sol) and gastrocnemius (Gas) muscles shows Rbm[24] nuclear localization in type I and type IIa myofibers, as well as in other fiber types devoid of myosin heavy chain (MyHC)-I or MyHC-IIa staining in the gastrocnemius
Using a mouse muscle injury model induced by cardiotoxin (CTX), we demonstrated that Rbm[24] plays a role in skeletal muscle regeneration from satellite cells through regulation of myogenin mRNA expression at early stages of muscle injury and alternative splicing of muscle-specific genes at late stages of regeneration
Summary
Skeletal muscle has a remarkable capacity of regeneration after injury, but the regulatory network underlying this repair process remains elusive. We demonstrate that Rbm[24] functions sequentially to regulate myogenic differentiation and muscle regeneration It is required for myogenin expression at early stages of muscle injury and for muscle-specific pre-mRNA alternative splicing at late stages of regeneration. Muscle regeneration involves different cellular behaviors and regulatory networks that function at each stage of the repair p rocess[3] Upon stimulation, such as muscle damage, intense exercise, or pathogenic conditions, all providing a local burst of extracellular signals, Pax7-positive quiescent satellite cells are activated to reenter the cell cycle and undergo proliferation.
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