{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:32:05Z","timestamp":1791433925135,"version":"4.3.3"},"reference-count":66,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,2,1]],"date-time":"2019-02-01T00:00:00Z","timestamp":1548979200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006812","name":"Center for Integrated Healthcare, U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006812","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["5P30GM114731"],"award-info":[{"award-number":["5P30GM114731"]}],"id":[{"id":"10.13039\/100000057","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":[[2019,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Excess reactive oxygen species (ROS) and muscle weakness occur in parallel in multiple pathological conditions. However, the causative role of skeletal muscle mitochondrial ROS (mtROS) on neuromuscular junction (NMJ) morphology and function and muscle weakness has not been directly investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated mice lacking skeletal muscle\u2010specific manganese\u2010superoxide dismutase (m<jats:italic>Sod2<\/jats:italic>KO) to increase mtROS using a cre\u2010Lox approach driven by human skeletal actin. We determined primary functional parameters of skeletal muscle mitochondrial function (respiration, ROS, and calcium retention capacity) using permeabilized muscle fibres and isolated muscle mitochondria. We assessed contractile properties of isolated skeletal muscle using <jats:italic>in situ<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> preparations and whole lumbrical muscles to elucidate the mechanisms of contractile dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The m<jats:italic>Sod2<\/jats:italic>KO mice, contrary to our prediction, exhibit a 10\u201315% increase in muscle mass associated with an ~50% increase in central nuclei and ~35% increase in branched fibres (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Despite the increase in muscle mass of gastrocnemius and quadriceps, <jats:italic>in situ<\/jats:italic> sciatic nerve\u2010stimulated isometric maximum\u2010specific force (<jats:italic>N<\/jats:italic>\/cm<jats:sup>2<\/jats:sup>), force per cross\u2010sectional area, is impaired by ~60% and associated with increased NMJ fragmentation and size by ~40% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Intrinsic alterations of components of the contractile machinery show elevated markers of oxidative stress, for example, lipid peroxidation is increased by ~100%, oxidized glutathione is elevated by ~50%, and oxidative modifications of myofibrillar proteins are increased by ~30% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). We also find an approximate 20% decrease in the intracellular calcium transient that is associated with specific force deficit. Excess superoxide generation from the mitochondrial complexes causes a deficiency of succinate dehydrogenase and reduced complex\u2010II\u2010mediated respiration and adenosine triphosphate generation rates leading to severe exercise intolerance (~10\u00a0min vs. ~2\u00a0h in wild type, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Increased skeletal muscle mtROS is sufficient to elicit NMJ disruption and contractile abnormalities, but not muscle atrophy, suggesting new roles for mitochondrial oxidative stress in maintenance of muscle mass through increased fibre branching.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12375","type":"journal-article","created":{"date-parts":[[2019,2,1]],"date-time":"2019-02-01T16:17:33Z","timestamp":1549037853000},"page":"411-428","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching"],"prefix":"10.1002","volume":"10","author":[{"given":"Bumsoo","family":"Ahn","sequence":"first","affiliation":[{"name":"Aging and Metabolism Research Program Oklahoma Medical Research Foundation  Oklahoma City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rojina","family":"Ranjit","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program Oklahoma Medical Research Foundation  Oklahoma City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavithra","family":"Premkumar","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program Oklahoma Medical Research Foundation  Oklahoma City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Pharaoh","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program Oklahoma Medical Research Foundation  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Oklahoma Health Sciences Center  Oklahoma City USA"},{"name":"Reynolds Oklahoma Center on Aging University of Oklahoma Health Sciences Center  Oklahoma City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program Oklahoma Medical Research Foundation  Oklahoma City USA"},{"name":"Department of Physiology University of Oklahoma Health Sciences Center  Oklahoma City USA"},{"name":"Oklahoma Center for Neuroscience University of Oklahoma Health Sciences Center  Oklahoma City USA"},{"name":"Oklahoma City VA Medical Center  Oklahoma City USA"},{"name":"Reynolds Oklahoma Center on Aging University of Oklahoma Health Sciences Center  Oklahoma City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willard M.","family":"Freeman","sequence":"additional","affiliation":[{"name":"Department of Physiology University of Oklahoma Health Sciences Center  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