Adaptive exhaustion during prolonged intermittent hypoxia causes dysregulated skeletal muscle protein homeostasis.

Nocturnal hypoxemia that is common in chronic obstructive pulmonary disease (COPD) patients is associated with skeletal muscle loss or sarcopenia, which contributes to adverse clinical outcomes. In COPD, we have defined this as prolonged intermittent hypoxia (PIH) because the duration of hypoxia in skeletal muscle occurs through the duration of sleep followed by normoxia during the day in contrast to recurrent brief hypoxic episodes during obstructive sleep apnea (OSA). Adaptive cellular responses to PIH are not known. Responses to PIH induced by 3-cycles of 8h hypoxia followed by 16h normoxia were compared to those during chronic hypoxia (CH) or normoxia for 72h in murine C2C12 and human inducible pluripotent stem cell-derived differentiated myotubes. RNA sequencing followed by downstream analyses were complemented by experimental validation of responses that included both unique and shared perturbations in ribosomal and mitochondrial function during PIH and CH. A sarcopenic phenotype characterized by decreased myotube diameter and protein synthesis, and increased phosphorylation of eIF2α (Ser51) by eIF2α kinase, GCN-2 (general controlled non-derepressed-2), occurred during both PIH and CH. Mitochondrial oxidative dysfunction, disrupted supercomplex assembly, lower activity of Complexes I, III, IV and V, and reduced intermediary metabolite concentrations occurred during PIH and CH. Decreased mitochondrial fission occurred during CH. Physiological relevance was established in skeletal muscle of mice with COPD that had increased phosphorylation of eIF2α, lower protein synthesis, and mitochondrial oxidative dysfunction. Molecular and metabolic responses with PIH suggests an adaptive exhaustion with failure to restore homeostasis during normoxia. Abstract figure legend Prolonged intermittent hypoxia (PIH) is commonly demonstrated in patients with COPD (chronic obstructive pulmonary disease); however, the effects of PIH on skeletal muscle are unclear. We tested the hypothesis that PIH causes skeletal muscle loss or sarcopenia in vitro by down-regulating protein synthesis and causing mitochondrial oxidative dysfunction associated with dysregulation of hypoxia inducible factors (HIF1α and HIF2α). α-ketoglutarate (αKG), a critical TCA cycle intermediate and co-factor for the degradation of HIF1α, was reduced due to PIH. Physiological relevance was established in skeletal muscle of mice with COPD. Our findings suggest that PIH causes sarcopenia through adaptive exhaustion and failure to restore homeostasis during normoxia. This article is protected by copyright. All rights reserved.