Abstract
Embryonic myogenesis is a temporally and spatially regulated process that generates skeletal muscle of the trunk and limbs. During this process, mononucleated myoblasts derived from myogenic progenitor cells within the somites undergo proliferation, migration and differentiation to elongate and fuse into multinucleated functional myofibers. Skeletal muscle is the most abundant tissue of the body and has the remarkable ability to self-repair by re-activating the myogenic program in muscle stem cells, known as satellite cells. Post-transcriptional regulation of gene expression mediated by RNA-binding proteins is critically required for muscle development during embryogenesis and for muscle homeostasis in the adult. Differential subcellular localization and activity of RNA-binding proteins orchestrates target gene expression at multiple levels to regulate different steps of myogenesis. Dysfunctions of these post-transcriptional regulators impair muscle development and homeostasis, but also cause defects in motor neurons or the neuromuscular junction, resulting in muscle degeneration and neuromuscular disease. Many RNA-binding proteins, such as members of the muscle blind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) families, display both overlapping and distinct targets in muscle cells. Thus they function either cooperatively or antagonistically to coordinate myoblast proliferation and differentiation. Evidence is accumulating that the dynamic interplay of their regulatory activity may control the progression of myogenic program as well as stem cell quiescence and activation. Moreover, the role of RNA-binding proteins that regulate post-transcriptional modification in the myogenic program is far less understood as compared with transcription factors involved in myogenic specification and differentiation. Here we review past achievements and recent advances in understanding the functions of RNA-binding proteins during skeletal muscle development, regeneration and disease, with the aim to identify the fundamental questions that are still open for further investigations.
Highlights
Muscle progenitor cells in vertebrates derive from the paraxial mesoderm located on both sides of the neural tube and the notochord
It is clear that RNA-binding proteins (RBPs) function sequentially to post-transcriptionally regulate gene expression at different steps of myogenesis, in much the similar manner as different myogenic transcription factors that promote myoblast proliferation, myogenic differentiation and satellite cell quiescence at the transcription level
Given the growing number of muscular disorders associated with RNAs and RBPs, understanding the functional implication of RBPs in different steps of muscle development may have the potential to use them as therapeutics (Shotwell et al, 2020)
Summary
Muscle progenitor cells in vertebrates derive from the paraxial mesoderm located on both sides of the neural tube and the notochord. Combined loss of Rbfox and Rbfox genes in adult mouse skeletal muscle disrupts a large number of alternative splicing events, resulting in the absence of muscle-specific isoforms of MEF2A and MEF2D, which are required for late stages of muscle differentiation, and leading to increased expression of an active form of the calpain 3 protease that alters proteostasis in muscle cells. Representing an adaptive response to muscle pathology, the expression of STAU1 is strongly increased in DM1 muscle cells where it interacts with CUG-expanded mutant mRNAs, resulting in their enhanced nuclear export As a consequence, this may mitigate the combined negative consequences of reduced MBNL1 function and increased CELF1 activity on the reversion of fetal splicing patterns in adult muscle (Ravel-Chapuis et al, 2012). The two proteins colocalize in discrete nuclear foci and promote myogenesis by regulating polyadenylation site selection in myogenic transcripts (Banerjee et al, 2017)
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