Hypoxia and hypercapnia elicit overlapping but distinct skeletal muscle toxicities.

Skeletal muscle dysfunction is strongly associated with elevated mortality in acute and chronic pulmonary diseases. Hypoxaemia and hypercapnia, which are central hallmarks of respiratory failure, represent critical cellular signals regulating muscle loss, causing disruption of skeletal muscle mass, myofibre metabolic profile and oxidative capacity, and regenerative potential after injury. Both hypoxaemia and hypercapnia elicit alterations in protein synthesis and degradation, myogenesis and autophagy - key cellular processes that significantly impact skeletal muscle integrity. Recent data have also implicated epigenetic mechanisms such as microRNAs and DNA methylation as regulators of skeletal muscle phenotypes following hypoxic and hypercapnic insults. Hypoxia and hypercapnia engage overlapping pathways, including hypoxia-inducible factor 1 and AMP-activated protein kinase, suggesting that despite being distinct phenomena, hypoxaemia and hypercapnia share mechanisms orchestrating cellular programmes regulating various skeletal muscle adaptations. Both CO2 and O2 modulate key cellular hubs controlling muscle mass, including AKT, mammalian target of rapamycin complex 1 and others. Finally, in this article we outline some current gaps in knowledge in the field that we believe merit future research.