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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 \u2013 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\u2010inducible factor 1 and AMP\u2010activated protein kinase, suggesting that despite being distinct phenomena, hypoxaemia and hypercapnia share mechanisms orchestrating cellular programmes regulating various skeletal muscle adaptations. Both CO\n                    <jats:sub>2<\/jats:sub>\n                    and O\n                    <jats:sub>2<\/jats:sub>\n                    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.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70412-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1113\/jp289079","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T08:12:57Z","timestamp":1772957577000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Hypoxia and hypercapnia elicit overlapping but distinct skeletal muscle toxicities"],"prefix":"10.1113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0894-2839","authenticated-orcid":false,"given":"Joseph","family":"Balnis","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Physiology Albany medical College  Albany NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4714-2260","authenticated-orcid":false,"given":"Ariel","family":"Jaitovich","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology Albany medical College  Albany NY USA"},{"name":"Division of Pulmonary and Critical Care Medicine Albany medical College  Albany NY 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