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To elucidate the pathological impact of lipid hydroperoxides, we overexpressed glutathione peroxidase 4 (GPx4), an enzyme that targets reduction of lipid hydroperoxides in membranes, in adult CuZn superoxide dismutase knockout (<jats:italic>Sod1<\/jats:italic>KO) mice that show accelerated muscle atrophy associated with loss of innervation. The gastrocnemius muscle from <jats:italic>Sod1<\/jats:italic>KO mice shows reduced mitochondrial respiration and elevated oxidative stress (F<jats:sub>2<\/jats:sub>\u2010isoprostanes and hydroperoxides) compared to wild\u2010type (WT) mice. Overexpression of GPx4 improved mitochondrial respiration and reduced hydroperoxide generation in <jats:italic>Sod1<\/jats:italic>KO mice, but did not attenuate the muscle loss that occurs in <jats:italic>Sod1<\/jats:italic>KO mice. In contrast, contractile force generation is reduced in EDL muscle in <jats:italic>Sod1<\/jats:italic>KO mice relative to WT mice, and overexpression of GPx4 restored force generation to WT levels in <jats:italic>Sod1<\/jats:italic>KO mice. GPx4 overexpression also prevented loss of muscle contractility at the single fibre level in fast\u2010twitch fibres from <jats:italic>Sod1<\/jats:italic>KO mice. Muscle fibres from <jats:italic>Sod1<\/jats:italic>KO mice were less sensitive to both depolarization and calcium at the single fibre level and exhibited a reduced activation by <jats:italic>S<\/jats:italic>\u2010glutathionylation. GPx4 overexpression in <jats:italic>Sod1<\/jats:italic>KO mice rescued the deficits in both membrane excitability and calcium sensitivity of fast\u2010twitch muscle fibres. Overexpression of GPx4 also restored the sarco\/endoplasmic reticulum Ca<jats:sup>2+<\/jats:sup>\u2010ATPase activity in <jats:italic>Sod1<\/jats:italic>KO gastrocnemius muscles. These data suggest that GPx4 plays an important role in preserving excitation\u2013contraction coupling function and Ca<jats:sup>2+<\/jats:sup> homeostasis, and in maintaining muscle and mitochondrial function in oxidative stress\u2010induced sarcopenia.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15794-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Knockout of CuZn superoxide dismutase (<jats:italic>Sod1<\/jats:italic>KO) induces elevated oxidative stress with accelerated muscle atrophy and weakness.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Glutathione peroxidase 4 (GPx4) plays a fundamental role in the reduction of lipid hydroperoxides in membranes, and overexpression of GPx4 improves mitochondrial respiration and reduces hydroperoxide generation in <jats:italic>Sod1<\/jats:italic>KO mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Muscle contractile function deficits in <jats:italic>Sod1<\/jats:italic>KO mice are alleviated by the overexpression of GPx4.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>GPx4 overexpression in <jats:italic>Sod1<\/jats:italic>KO mice rescues the impaired muscle membrane excitability of fast\u2010twitch muscle fibres and improves their calcium sensitivity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Sarco\/endoplasmic reticulum Ca<jats:sup>2+<\/jats:sup>\u2010ATPase activity in <jats:italic>Sod1<\/jats:italic>KO muscles is decreased, and it is restored by the overexpression of GPx4.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our results confirm that GPx4 plays an important role in preserving excitation\u2013contraction coupling function and Ca<jats:sup>2+<\/jats:sup> homeostasis, and maintaining muscle and mitochondrial function in oxidative stress\u2010induced sarcopenia.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp285259","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T17:09:15Z","timestamp":1698253755000},"page":"5277-5293","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Modulation of sarcopenia phenotypes by glutathione peroxidase 4 overexpression in mice"],"prefix":"10.1113","volume":"601","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8878-0600","authenticated-orcid":false,"given":"Hongyang","family":"Xu","sequence":"first","affiliation":[{"name":"Aging and Metabolism Research Program Oklahoma Medical Research Foundation  Oklahoma City OK 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