Increase in HDAC9 suppresses myoblast differentiation via epigenetic regulation of autophagy in hypoxia

Abstract

Extremely reduced oxygen (O 2 ) levels are detrimental to myogenic differentiation and multinucleated myotube formation, and chronic exposure to high-altitude hypoxia has been reported to be an important factor in skeletal muscle atrophy. However, how chronic hypoxia causes muscle dysfunction remains unknown. In the present study, we found that severe hypoxia (1% O 2 ) significantly inhibited the function of C2C12 cells (from a myoblast cell line). Importantly, the impairment was continuously manifested even during culture under normoxic conditions for several passages. Mechanistically, we revealed that histone deacetylases 9 (HDAC9), a member of the histone deacetylase family, was significantly increased in C2C12 cells under hypoxic conditions, thereby inhibiting intracellular autophagy levels by directly binding to the promoter regions of Atg7 , Beclin1 , and LC3 . This phenomenon resulted in the sequential dephosphorylation of GSK3β and inactivation of the canonical Wnt pathway, impairing the function of the C2C12 cells. Taken together, our results suggest that hypoxia-induced myoblast dysfunction is due to aberrant epigenetic regulation of autophagy, and our experimental evidence reveals the possible molecular pathogenesis responsible for some muscle diseases caused by chronic hypoxia and suggests a potential therapeutic option.

Autophagy regulation by acetylation—implications for neurodegenerative diseases

“…Recently, the HDAC8-selective inhibitor HMC was shown to induce autophagy in MCF-7 cells 42 . In response to hypoxia in a myoblast cell line, class IIa HDAC9 was significantly increased, thereby inhibiting intracellular autophagy through direct binding to the promoter regions of Beclin 1, ATG7 and LC3 43 .…”

Hypoxia in Cell Reprogramming and the Epigenetic Regulations

“…It also suggests that the level of O2 may determine the final role of hypoxic environment. Epigenetic events are essential to establish and maintain the distinct cell lineages and have been shown to be crucial players controlling the fate and function of MSCs and MuSCs(Nakade et al, 2017 ; Zhang et al, 2019 ). More recently, a study showed MuSCs forced to express Msx1 exhibited increased proliferation index as well as promoted SSEA1 and Pax7 expression, but restricted MyoD expression and accessed osteogenic genes (Ding et al, 2017 ).…”

Quis Custodiet Ipsos Custodes (Who Controls the Controllers)? Two Decades of Studies on HDAC9

“…Hdac9 can repress the transcription of some autophagy genes by the direct binding of the relative promoters. The authors propose that through this mechanism Hdac9 regulates autophagy and muscle differentiation in hypoxic conditions [ 86 ]. In the context of cancer progression, this environmental control on HDAC9 levels could provide an important contribution to the adaptation of the cancer cells to a hostile hypoxic environment.…”