Atonal homolog 8/Math6 regulates differentiation and maintenance of skeletal muscle

Abstract

Atonal Homolog 8 (Atoh8) belongs to a large superfamily of transcriptional regulators called basic helix-loop-helix (bHLH) transcription factors. Atoh8 (murine homolog “Math6”) has been shown to be involved in organogenesis during murine embryonic development. We have previously identified the expression of Atoh8 during skeletal myogenesis in chicken where we described its involvement in hypaxial myotome formation suggesting a regulatory role of Atoh8 in skeletal muscle development. Within the current study, we analyzed the effect of the loss of function of Atoh8 in murine primary myoblasts and during differentiation of pluripotent stem cells into myotubes, and the effect of its gain of function in C2C12 cells. Based on the observed results, we conclude that Atoh8 regulates myoblast proliferation via modulating myostatin signaling. Further, our data revealed a reduced muscle mass, strength and fiber size with significant changes to the muscle fiber type suggesting atrophy in skeletal muscle of Atoh8 mutants. We further report that Atoh8 knockout mice suffer from a condition similar to ambient hypoxia which may be the primary cause of the phenotype. Altogether, this study shows the significance of Atoh8 not only in myogenesis but also in the maintenance of skeletal muscle.

ETS1, a target gene of the EWSR1::FLI1 fusion oncoprotein, regulates the expression of the focal adhesion protein TENSIN3

“…In contrast, ETS1 may promote the expression of ATOH8 ( Fig. 4G ), which encodes a transcription factor recently implicated in the regulation of chondrogenic differentiation (36), cellular plasticity (37), and the differentiation and maintenance of skeletal muscle (38). Gene expression analysis and H3K4me3 and H3K27ac epigenetic marks all indicate that EWSR1::FLI1 suppresses the expression of ATOH8 as each mark increases following depletion of the fusion oncoprotein.…”

The temporal transcriptomic signature of cartilage formation

“…Since atonal homolog 8 ( ATOH8 ) and early B-cell factor 1 ( EBF1 ) have not yet been reported in the context of primary chondrogenesis in detail, we studied the effects of their transient knockdown at the beginning of chondrogenic differentiation. ATOH8 , a member of the basic helix-loop-helix (bHLH) transcriptional regulators ( 77 ), was also identified in our WGCNA analysis because its expression dynamics followed that of ACAN , COL2A1 and SOX9 . EBF1 belongs to the EBF family of helix loop helix transcription factors ( 78 ).…”

“…The upregulation of SOX9 , COL1A1 and COL2A1 at later time points is probably a result of a compensatory mechanism, as the effects of the siRNA diminished. In addition to bone formation, ATOH8 also regulates myogenesis and skeletal muscle maintenance ( 77 ), neurogenesis, kidney and pancreas development, and placental formation ( 80 ). ATOH8 is a direct target of the Smad-dependent TGF-ß/BMP signaling pathway, and the Alk1/Smad/ATOH8 axis regulates hypoxic response by binding to hypoxia-inducible factor 2α (HIF-2α) ( 80 ), all of which are key pathways involved in chondrogenic differentiation.…”

Identify Candidate Genes Associated with the Weight and Egg Quality Traits in Wenshui Green Shell-Laying Chickens by the Copy Number Variation-Based Genome-Wide Association Study

“…The ATOH8 gene is a transcription factor with a bHLH domain that is involved in the development of the nervous system, kidney, pancreas, retina, and muscle [ 52 ]. Studies in chickens have shown the expression of the ATOH8 gene during skeletal myogenesis in chickens [ 53 , 54 ]. In mice, it has been found that the ATOH8 gene regulates muscle cell proliferation by modulating myopeptide signaling [ 53 ].…”

“…Studies in chickens have shown the expression of the ATOH8 gene during skeletal myogenesis in chickens [ 53 , 54 ]. In mice, it has been found that the ATOH8 gene regulates muscle cell proliferation by modulating myopeptide signaling [ 53 ]. The energy metabolism status of muscles is a primary factor influencing the quality of eggs [ 55 ].…”