The impact of mild hypoxia exposure on myokine secretion in human obesity

Background/Objective Compelling evidence indicates that myokines act in an autocrine, paracrine and endocrine manner to alter metabolic homeostasis. The mechanisms underlying exercise-induced changes in myokine secretion remain to be elucidated. Since exercise acutely decreases oxygen partial pressure (pO 2 ) in skeletal muscle (SM), the present study was designed to test the hypothesis that (1) hypoxia exposure impacts myokine secretion in primary human myotubes and (2) exposure to mild hypoxia in vivo alters fasting and postprandial plasma myokine concentrations in humans. Methods Differentiated primary human myotubes were exposed to different physiological pO 2 levels for 24 h, and cell culture medium was harvested to determine myokine secretion. Furthermore, we performed a randomized single-blind crossover trial to investigate the impact of mild intermittent hypoxia exposure (MIH: 7-day exposure to 15% O 2 , 3x2h/day vs. normoxia: 21% O 2 ) on in vivo SM pO 2 and plasma myokine concentrations in 12 individuals with overweight and obesity (body-mass index ≥ 28 kg/m 2 ). Results Hypoxia exposure (1% O 2 ) increased secreted protein acidic and rich in cysteine (SPARC, p = 0.043) and follistatin like 1 (FSTL1, p = 0.021), and reduced leukemia inhibitory factor (LIF) secretion ( p = 0.009) compared to 3% O 2 in primary human myotubes. In addition, 1% O 2 exposure increased interleukin-6 (IL-6, p = 0.004) and SPARC secretion ( p = 0.021), whilst reducing fatty acid binding protein 3 (FABP3) secretion ( p = 0.021) compared to 21% O 2 . MIH exposure in vivo markedly decreased SM pO 2 (≈40%, p = 0.002) but did not alter plasma myokine concentrations. Conclusions Hypoxia exposure altered the secretion of several myokines in primary human myotubes, revealing hypoxia as a novel modulator of myokine secretion. However, both acute and 7-day MIH exposure did not induce alterations in plasma myokine concentrations in individuals with overweight and obesity. Clinical trials identifier: This study is registered at the Netherlands Trial Register (NL7120/NTR7325).