Hypoxia Inhibits Myogenic Differentiation through p53 Protein-dependent Induction of Bhlhe40 Protein

Abstract

Background: Hypoxia inhibits myogenic differentiation, but the underlying mechanisms are not well understood. Results: We used microarray analysis to identify genes and pathways affected by hypoxia. Gain-and loss-of-function studies indicate that Bhlhe40 inhibits myogenic differentiation and that hypoxia up-regulates Bhlhe40 through an HIF1␣-independent, p53-dependent mechanism. Conclusion: Hypoxia inhibits myogenesis through p53-dependent induction of Bhlhe40. Significance: Inhibition of Bhlhe40 or p53 may facilitate muscle repair after ischemic injuries.

Ascl2 inhibits myogenesis by antagonizing the transcriptional activity of myogenic regulatory factors

“…These data prove that Ascl2 inhibits myogenesis through repressing the transcriptional activities of MRFs. Our study thus identifies Ascl2 as a novel member of the repressive bHLH factors [which include MyoR, Mist1 (Bhlha15) and Bhlhe40] that compete with MRFs for heterodimerization partners and E-boxes to modulate myogenesis (Hsiao et al, 2009;Lemercier et al, 1998;Lu et al, 1999;Wang et al, 2015).…”

“…Primary myoblasts were isolated from 5-week-old female mice as described (Wang et al, 2015). Detailed procedures are provided in the supplementary Materials and Methods.…”

“…Antibody staining was performed as described (Wang et al, 2015). Further information, including details of the antibodies used, is provided in the supplementary Materials and Methods.…”

Regulation of myogenesis by environmental hypoxia

“…This is followed by the inhibition of myogenic differentiation (Wang et al, 2015). Conversely, inhibition of Bhlhe40 upregulates myogenin expression and promotes cell differentiation.…”

“…Conversely, inhibition of Bhlhe40 upregulates myogenin expression and promotes cell differentiation. Moreover, knockdown of Bhlhe40 rescues satellite cell differentiation under hypoxia (Wang et al, 2015). Finally, it is interesting to note that hypoxia induces Bhlhe40 expression independently of HIF-1α, and through a signalling pathway that involves the tetrameric transcription factor p53, which has a crucial role in cell cycle arrest and apoptosis (Wang et al, 2015).…”