{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T01:45:57Z","timestamp":1790214357439,"version":"4.1.0"},"reference-count":70,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,2,23]],"date-time":"2020-02-23T00:00:00Z","timestamp":1582416000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000361","name":"Diabetes UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000361","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":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Caveolin\u20103 (Cav3) is the principal structural component of caveolae in skeletal muscle. Dominant pathogenic mutations in the Cav3 gene, such as the Limb Girdle Muscular Dystrophy\u20101C (LGMD1C) P104L mutation, result in substantial loss of Cav3 and myopathic changes characterized by muscle weakness and wasting. We hypothesize such myopathy may also be associated with disturbances in mitochondrial biology. Herein, we report studies assessing the effects of Cav3 deficiency on mitochondrial form and function in skeletal muscle cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>L6 myoblasts were stably transfected with Cav3<jats:sup>P104L<\/jats:sup> or expression of native Cav3 repressed by shRNA or CRISPR\/Cas9 genome editing prior to performing fixed\/live cell imaging of mitochondrial morphology, subcellular fractionation and immunoblotting, or analysis of real time mitochondrial respiration. Skeletal muscle from wild\u2010type and Cav3<jats:sup>\u2212\/\u2212<\/jats:sup> mice was processed for analysis of mitochondrial proteins by immunoblotting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Caveolin\u20103 was detected in mitochondrial\u2010enriched membranes isolated from mouse gastrocnemius muscle and L6 myoblasts. Expression of Cav3<jats:sup>P104L<\/jats:sup> in L6 myoblasts led to its targeting to the Golgi and loss of native Cav3 (&gt;95%), including that associated with mitochondrial membranes. Cav3<jats:sup>P104L<\/jats:sup> reduced mitochondrial mass and induced fragmentation of the mitochondrial network that was associated with significant loss of proteins involved in mitochondrial biogenesis, respiration, morphology, and redox function [i.e. PGC1\u03b1, succinate dehyrdogenase (SDHA), ANT1, MFN2, OPA1, and MnSOD). Furthermore, Cav3<jats:sup>P104L<\/jats:sup> myoblasts exhibited increased mitochondrial cholesterol and loss of cardiolipin. Consistent with these changes, Cav3<jats:sup>P104L<\/jats:sup> expression reduced mitochondrial respiratory capacity and increased myocellular superoxide production. These morphological, biochemical, and functional mitochondrial changes were phenocopied in myoblasts in which Cav3 had been silenced\/knocked\u2010out using shRNA or CRISPR. Reduced mitochondrial mass, PGC1\u03b1, SDHA, ANT1, and MnSOD were also demonstrable in Cav3<jats:sup>\u2212\/\u2212<\/jats:sup> mouse gastrocnemius. Strikingly, Cav3 re\u2010expression in Cav3KO myoblasts restored its mitochondrial association and facilitated reformation of a tubular mitochondrial network. Significantly, re\u2010expression also mitigated changes in mitochondrial superoxide, cholesterol, and cardiolipin content and recovered cellular respiratory capacity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results identify Cav3 as an important regulator of mitochondrial homeostasis and reveal that Cav3 deficiency in muscle cells associated with the Cav3<jats:sup>P104L<\/jats:sup> mutation invokes major disturbances in mitochondrial respiration and energy status that may contribute to the pathology of LGMD1C.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12541","type":"journal-article","created":{"date-parts":[[2020,2,24]],"date-time":"2020-02-24T07:52:11Z","timestamp":1582530731000},"page":"838-858","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Caveolin\u20103 deficiency associated with the dystrophy P104L mutation impairs skeletal muscle mitochondrial form and function"],"prefix":"10.1002","volume":"11","author":[{"given":"Dinesh S.","family":"Shah","sequence":"first","affiliation":[{"name":"Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raid B.","family":"Nisr","sequence":"additional","affiliation":[{"name":"Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare","family":"Stretton","sequence":"additional","affiliation":[{"name":"Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Krasteva\u2010Christ","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Cell Biology, School of Medicine Saarland University  Homburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harinder S.","family":"Hundal","sequence":"additional","affiliation":[{"name":"Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences University of Dundee  Dundee 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