Abstract
Histone lysine demethylase 4A (KDM4A) plays a crucial role in regulating cell proliferation, cell differentiation, development and tumorigenesis. However, little is known about the function of KDM4A in muscle development and regeneration. Here, we found that the conditional ablation of KDM4A in skeletal muscle caused impairment of embryonic and postnatal muscle formation. The loss of KDM4A in satellite cells led to defective muscle regeneration and blocked the proliferation and differentiation of satellite cells. Myogenic differentiation and myotube formation in KDM4A-deficient myoblasts were inhibited. Chromatin immunoprecipitation assay revealed that KDM4A promoted myogenesis by removing the histone methylation mark H3K9me3 at MyoD, MyoG and Myf5 locus. Furthermore, inactivation of KDM4A in myoblasts suppressed myoblast differentiation and accelerated H3K9me3 level. Knockdown of KDM4A in vitro reduced myoblast proliferation through enhancing the expression of the cyclin-dependent kinase inhibitor P21 and decreasing the expression of cell cycle regulator Cyclin D1. Together, our findings identify KDM4A as an important regulator for skeletal muscle development and regeneration, orchestrating myogenic cell proliferation and differentiation.
Highlights
Skeletal muscle is an important tissue of mammalian body orchestrating metabolism and homeostasis[1], which has a robust capacity of regeneration
Hematoxylin and eosin staining and immunofluorescence staining for laminin showed that both the myofiber diameters and cross-sectional areas (CSA) of muscles in KDM4A cKO mice were significantly smaller than control mice (Fig. 1f–i)
Skeletal muscle relies on myogenic cells to maintain homeostasis
Summary
Skeletal muscle is an important tissue of mammalian body orchestrating metabolism and homeostasis[1], which has a robust capacity of regeneration. Skeletal muscle development includes embryonic development, postnatal growth and muscle regeneration after injury which require myogenesis upon myogenic cell proliferation, differentiation and fusion[2]. Muscle regeneration starts with the activation of muscle stem cells termed satellite cells (SC) in response to injury[3]. During this progress, quiescent Pax7+ SC generate Pax7+/Myf5+ SC and proliferate into Pax7+/MyoD+ committed myoblasts and subsequently differentiate into Myogenin+ myocytes, which eventually fuse to repair damaged myofibers or form new multinucleated myofibers[4,5]. Myf[5] enhances myogenesis by coordinately elevating CyclinD1 transcription and translation[15] Both Myf[5] and MyoD are essential for skeletal muscle development[16], they have distinct functions in myogenesis. Myf[5] is expressed at first among myogenic transcription factors, and MyoD is induced, while
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