HIF-1α Negatively Regulates Irisin Expression Which Involves in Muscle Atrophy Induced by Hypoxia

Int J Mol Sci. 2022 Jan 14;23(2):887. doi: 10.3390/ijms23020887.

Abstract

Exposure to high altitude environment leads to skeletal muscle atrophy. As a hormone secreted by skeletal muscles after exercise, irisin contributes to promoting muscle regeneration and ameliorating skeletal muscle atrophy, but its role in hypoxia-induced skeletal muscle atrophy is still unclear. Our results showed that 4 w of hypoxia exposure significantly reduced body weight and gastrocnemius muscle mass of mice, as well as grip strength and the duration time of treadmill exercise. Hypoxic treatment increased HIF-1α expression and decreased both the circulation level of irisin and its precursor protein FNDC5 expression in skeletal muscle. In in vitro, CoCl2-induced chemical hypoxia and 1% O2 ambient hypoxia both reduced FNDC5, along with the increase in HIF-1α. Moreover, the decline in the area and diameter of myotubes caused by hypoxia were rescued by inhibiting HIF-1α via YC-1. Collectively, our research indicated that FNDC5/irisin was negatively regulated by HIF-1α and could participate in the regulation of muscle atrophy caused by hypoxia.

Keywords: FNDC5; HIF-1α; hypoxia; irisin; muscle atrophy.

MeSH terms

  • Animals
  • Biomarkers
  • Cell Line
  • Fibronectins / genetics*
  • Fibronectins / metabolism
  • Fluorescent Antibody Technique
  • Gene Expression Regulation*
  • Hypoxia / complications*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunohistochemistry
  • Male
  • Mice
  • Muscular Atrophy / etiology*
  • Muscular Atrophy / metabolism*
  • Muscular Atrophy / pathology

Substances

  • Biomarkers
  • FNDC5 protein, mouse
  • Fibronectins
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit