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<p>Atherosclerosis-induced oxidative stress drives skeletal muscle myopathy in peripheral artery disease, yet the combined effects of hypoxia and hypoxia sprint interval training (SIT) remain unclear. The present study was designed to evaluate how a six-week regimen of hypoxia exposure and SIT influences redox balance and myokine production in the skeletal muscle of high-fat diet (HFD) (21% fat, 1.5% (w/w) cholesterol; 43% (w/w) sucrose-free carbohydrate, 4.554&#xa0;kcal/g)-fed atherosclerotic <i>ApoE</i><sup>−/−</sup> mice. Forty male <i>ApoE</i><sup>−/−</sup> mice fed a HFD were randomly assigned to four groups: Control-Normoxia, Control-Hypoxia, SIT-Normoxia, and SIT-Hypoxia. The hypoxia protocol involved exposures to 11.2% oxygen three times (40&#xa0;min each) per week. Key assessment parameters included plasma lipid profiles, skeletal muscle reactive oxygen species (ROS), protein carbonyls, key components of the Nrf2 antioxidant pathway, glutathione metabolism, and myokine-related markers. Compared with the control group, both hypoxia and SIT-Normoxia significantly reduced levels of ROS, protein carbonyls, and <i>Vegfa165</i> mRNA expression in the skeletal muscle. Hypoxia alone enhanced the levels of GSH-synthesizing enzymes and promoted myokine production. SIT-Normoxia improved plasma lipid profiles, activated the Nrf2 pathway, enhanced the GSH system, and upregulated myokines. SIT under hypoxia further reduced ROS and <i>Vegfa165</i> while increasing plasma HDL-C and levels of SOD1 protein in the skeletal muscle, but failed to synergistically activate the Nrf2 pathway or enhance GSH production. Paradoxically, both intervention combinations suppressed the mRNA expression of myokine precursor <i>Fndc5, BAIBA-synthesizing enzyme Hadh</i> and <i>Hadha</i>. Overall, six weeks of isolated hypoxia exposure or SIT training independently reduced oxidative stress and promoted beneficial myokine responses in the skeletal muscle of <i>ApoE</i><sup>−/−</sup> mice fed a HFD. The wild-type (WT) mice fed a low-fat diet (LFD) was included to validate successful induction of hyperlipidemia, vascular remodeling, and skeletal muscle oxidative stress in <i>ApoE</i><sup><i>−/−</i></sup> mice after six weeks of HFD feeding.</p>

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Effects of six weeks of hypoxia and hypoxic SIT on oxidative stress and myokine responses in skeletal muscle of high-fat–fed ApoE−/− mice

  • 期刊论文

  • 发表日期：

    2026年7月21日

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  • Yangwenjie Wang,
  • Jessica Lavier,
  • Linjia Wang,
  • Weicheng Hua,
  • Hao Wei,
  • Changle Zhao,
  • Maxime Pellegrin,
  • Grégoire P. Millet,
  • Ying Zhang

摘要

Atherosclerosis-induced oxidative stress drives skeletal muscle myopathy in peripheral artery disease, yet the combined effects of hypoxia and hypoxia sprint interval training (SIT) remain unclear. The present study was designed to evaluate how a six-week regimen of hypoxia exposure and SIT influences redox balance and myokine production in the skeletal muscle of high-fat diet (HFD) (21% fat, 1.5% (w/w) cholesterol; 43% (w/w) sucrose-free carbohydrate, 4.554 kcal/g)-fed atherosclerotic ApoE−/− mice. Forty male ApoE−/− mice fed a HFD were randomly assigned to four groups: Control-Normoxia, Control-Hypoxia, SIT-Normoxia, and SIT-Hypoxia. The hypoxia protocol involved exposures to 11.2% oxygen three times (40 min each) per week. Key assessment parameters included plasma lipid profiles, skeletal muscle reactive oxygen species (ROS), protein carbonyls, key components of the Nrf2 antioxidant pathway, glutathione metabolism, and myokine-related markers. Compared with the control group, both hypoxia and SIT-Normoxia significantly reduced levels of ROS, protein carbonyls, and Vegfa165 mRNA expression in the skeletal muscle. Hypoxia alone enhanced the levels of GSH-synthesizing enzymes and promoted myokine production. SIT-Normoxia improved plasma lipid profiles, activated the Nrf2 pathway, enhanced the GSH system, and upregulated myokines. SIT under hypoxia further reduced ROS and Vegfa165 while increasing plasma HDL-C and levels of SOD1 protein in the skeletal muscle, but failed to synergistically activate the Nrf2 pathway or enhance GSH production. Paradoxically, both intervention combinations suppressed the mRNA expression of myokine precursor Fndc5, BAIBA-synthesizing enzyme Hadh and Hadha. Overall, six weeks of isolated hypoxia exposure or SIT training independently reduced oxidative stress and promoted beneficial myokine responses in the skeletal muscle of ApoE−/− mice fed a HFD. The wild-type (WT) mice fed a low-fat diet (LFD) was included to validate successful induction of hyperlipidemia, vascular remodeling, and skeletal muscle oxidative stress in ApoE−/− mice after six weeks of HFD feeding.