Advances in myogenic differentiation: Role of stem cells, RNA-binding proteins, Molecular pathways, and Detection techniques

Abstract

The demand for effective muscle regeneration therapies has grown with the prevalence of muscle-degenerative conditions like muscular dystrophies which lack curative treatments. Although stem cells, including induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs), have great promise for muscle regeneration, their therapeutic application is constrained in the absence of a thorough comprehension of myogenic differentiation mechanisms.
A complicated network of molecular pathways, including Wnt, Notch, and Hedgehog, controls the myogenic differentiation process of the muscle progenitors. Various transcription regulators, including MyoD1, Pax 3 and 7, Myf5, and Mrf4, and the Cis-regulatory sites near the promoters, orchestrate the intricate mechanisms of gene regulation for differentiation. Activation of the signaling cascades conveys the message of muscle tissue-specific gene expression via regulating the genes at the transcriptional, epigenetic, post-transcriptional, and translational stages. Muscle-specific DNA methylation, histone acetylation and deacetylation, histone methylation, etc., and their regulators also play crucial roles in the chromatin accessibility of myogenic gene expression. In addition, The RNA-binding protein families, especially the MBNL-family, hnRNP-family, and the CELF-family, which modulate RNA-splicing, mRNA stability, and translation, are also major players in this process. Misregulation of these regulatory factors may cause muscle pathogenesis in patients. Metabolic alterations in glycolysis and OXPHOS due to changes in energy demand are crucial regulatory steps of myogenic differentiation of stem cells. Changes in mitochondrial biogenesis and metabolic pathways meet the shifting energy needs while controlling the levels of reactive oxygen species affecting the fate of the stem cells. In this review article, we discussed the advances made in the recent past of all the above aspects of myogenic differentiation of stem cells along with cutting-edge technologies, including real-time imaging, metabolic imaging, gene editing tools, and organoid cultures to study the dynamic changes at the cellular and subcellular levels during muscle differentiation.