Downregulated hypoxia-inducible factor 1α improves myoblast differentiation under hypoxic condition in mouse genioglossus

Abstract

The treatment of obstructive sleep apnea-hypopnea syndrome targets the narrow anatomic structure of the upper airway (UA) and lacks an effective therapy for UA dilator muscle dysfunction. Long-term hypoxia can cause damage to UA dilator muscles and trigger a vicious cycle. We previously confirmed that hypoxia-inducible factor 1α (HIF-1α) upregulation mediates muscle fatigue in hypoxia condition, but the underlying mechanism remains to be determined. The present study investigated the intrinsic mechanisms and related pathways of HIF-1α that affect myoblast differentiation, with an aim to search for compounds that have protective effects in hypoxic condition. Differentiation of myoblasts was induced under hypoxia, and we found that hypoxia significantly inhibits the differentiation of myoblasts, damages the ultrastructure of mitochondria, and reduces the expression of myogenin, PGC-1β and pAMPKα1. HIF-1α has a negative regulation effect on AMPK. Downregulation of HIF-1α increases the expression of the abovementioned proteins, promotes the differentiation of myoblasts, and protects mitochondrial integrity. In addition, mitochondrial biogenesis occurs during myogenic differentiation. Inhibition of the AMPK pathway inhibits mitochondrial biogenesis, decreases the level of PGC-1β, and increases apoptosis. Resveratrol dimer can reverse the mitochondrial damage induced by AMPK pathway inhibition and decrease myoblast apoptosis. Our results provided a regulatory mechanism for hypoxic injury in genioglossus which may contribute to the pathogenesis and treatment of OSAHS.

Keywords: AMP-activated protein kinases; Hypoxia-inducible factor 1α; Myogenic differentiation; Peroxisome proliferator activated receptor γ coactivator-1β; Resveratrol dimer.