{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T13:14:40Z","timestamp":1790428480234,"version":"4.1.0"},"reference-count":68,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,8,2]],"date-time":"2018-08-02T00:00:00Z","timestamp":1533168000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"NIH Clinical Center","doi-asserted-by":"publisher","award":["AG051442"],"award-info":[{"award-number":["AG051442"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>We have previously shown that the deletion of the superoxide scavenger, CuZn superoxide dismutase, in mice (<jats:italic>Sod1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice) results in increased oxidative stress and an accelerated loss of skeletal muscle mass and force that mirror the changes seen in old control mice. The goal of this study is to define the effect of oxidative stress and ageing on muscle weakness and the Excitation Contraction (EC) coupling machinery in age\u2010matched adult (8\u201310\u00a0months) wild\u2010type (WT) and<jats:italic>Sod1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice in comparison with old (25\u201328\u00a0months) WT mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>In vitro<\/jats:italic>contractile assays were used to measure muscle contractile parameters. The activity of the sarcoplasmic reticulum Ca<jats:sup>2+<\/jats:sup>ATPase (SERCA) pump was measured using an NADH\u2010linked enzyme assay. Immunoblotting and immunofluorescence techniques were used to measure protein expression, and real\u2010time reverse transcription PCR was used to measure gene expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The specific force generated by the extensor digitorum longus muscle was reduced in the<jats:italic>Sod1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>and old WT mice compared with young WT mice along with significant prolongation of time to peak force, increased half relaxation time, and disruption of intracellular calcium handling. The maximal activity of the SERCA calcium uptake pump was significantly reduced in gastrocnemius muscle from both old WT (\u224814%) and adult<jats:italic>Sod1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>(\u224833%) mice compared with young WT mice along with increased expression of sarcolipin, a known inhibitor of SERCA activity. Protein levels of the voltage sensor and calcium uptake channel proteins dihydropyridine receptor \u03b11 and SERCA2 were significantly elevated (\u224845% and \u224857%, respectively), while the ratio of calstabin, a channel stabilizing protein, to ryanodine receptor was significantly reduced (\u224821%) in<jats:italic>Sod1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice compared with young WT mice. The changes in calcium handling were accompanied by substantially elevated levels of global protein carbonylation and lipid peroxidation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data suggest that the muscle weakness in<jats:italic>Sod1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>and old WT mice is in part driven by reactive oxygen species\u2010mediated EC uncoupling and supports a role for reduced SERCA pump activity in compromised muscle function. The novel quantitative mechanistic data provided here can lead to potential therapeutic interventions of SERCA dysfunction for sarcopenia and muscle diseases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12339","type":"journal-article","created":{"date-parts":[[2018,8,7]],"date-time":"2018-08-07T04:12:21Z","timestamp":1533615141000},"page":"1003-1017","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":91,"title":["Oxidative stress\u2010induced dysregulation of excitation\u2013contraction coupling contributes to muscle weakness"],"prefix":"10.1002","volume":"9","author":[{"given":"Rizwan","family":"Qaisar","sequence":"first","affiliation":[{"name":"Aging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City OK USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shylesh","family":"Bhaskaran","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program Oklahoma 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