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SCS catalyses the conversion of succinyl\u2010CoA to succinate coupled with substrate\u2010level phosphorylation of either ADP or GDP in the TCA cycle. This report presents a muscle\u2010specific conditional knock\u2010out (KO) mouse model of <jats:italic>Sucla2<\/jats:italic>, the ADP\u2010specific beta subunit of SCS, generating a novel in\u00a0vivo model of mitochondrial myopathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The mouse model was generated using the Cre\u2010Lox system, with the human skeletal actin (HSA) promoter driving Cre\u2010recombination of a CRISPR\u2010Cas9\u2013generated <jats:italic>Sucla2<\/jats:italic> floxed allele within skeletal muscle. Inactivation of <jats:italic>Sucla2<\/jats:italic> was validated using RT\u2010qPCR and western blot, and both enzyme activity and serum metabolites were quantified by mass spectrometry. To characterize the model in\u00a0vivo, whole\u2010body phenotyping was conducted, with mice undergoing a panel of strength and locomotor behavioural assays. Additionally, ex\u00a0vivo contractility experiments were performed on the soleus (SOL) and extensor digitorum longus (EDL) muscles. SOL and EDL cryosections were also subject to imaging analyses to assess muscle fibre\u2010specific phenotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Molecular validation confirmed 68% reduction of <jats:italic>Sucla2<\/jats:italic> transcript within the mutant skeletal muscle (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and 95% functionally reduced SUCLA2 protein (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). By 3\u2009weeks of age, <jats:italic>Sucla2<\/jats:italic> KO mice were 44% the size of controls by body weight (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Mutant mice also exhibited 34%\u201340% reduced grip strength (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and reduced spontaneous exercise, spending about 88% less cumulative time on a running wheel (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Contractile function was also perturbed in a muscle\u2010specific manner; although no genotype\u2010specific deficiencies were seen in EDL function, SUCLA2\u2010deficient SOL muscles generated 40% less specific tetanic force (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), alongside slower contraction and relaxation rates (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). Similarly, a SOL\u2010specific threefold increase in mitochondria (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) was observed, with qualitatively increased staining for both COX and SDH, and the proportion of Type 1 myosin heavy chain expressing fibres within the SOL was nearly doubled (95% increase, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) in the <jats:italic>Sucla2<\/jats:italic> KO mice compared with that in controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>SUCLA2 loss within murine skeletal muscle yields a model of SCS\u2010deficient mitochondrial myopathy with reduced body weight, muscle weakness and exercise intolerance. Physiological and morphological analyses of hindlimb muscles showed remarkable differences in ex\u00a0vivo function and cellular consequences between the EDL and SOL muscles, with SOL muscles significantly more impacted by <jats:italic>Sucla2<\/jats:italic> inactivation. This novel model will provide an invaluable tool for investigations of muscle\u2010specific and fibre type\u2013specific pathogenic mechanisms to better understand SCS\u2010deficient myopathy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13617","type":"journal-article","created":{"date-parts":[[2024,11,1]],"date-time":"2024-11-01T06:39:20Z","timestamp":1730443160000},"page":"2729-2742","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<i>Sucla2<\/i> Knock\u2010Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type\u2013Specific Phenotypes"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8501-9282","authenticated-orcid":false,"given":"Makayla\u00a0S.","family":"Lancaster","sequence":"first","affiliation":[{"name":"Department of Medical &amp; Molecular Genetics Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Hafen","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health, Department of Anatomy, Cell Biology, &amp; Physiology Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Division of Science Indiana University Columbus  Columbus Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew\u00a0S.","family":"Law","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health, Department of Anatomy, Cell Biology, &amp; Physiology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catalina","family":"Matias","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health, Department of Anatomy, Cell Biology, &amp; Physiology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Meyer","sequence":"additional","affiliation":[{"name":"Behavioral Phenotyping Core Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Fischer","sequence":"additional","affiliation":[{"name":"Behavioral Phenotyping Core Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Medical &amp; Molecular Genetics Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhai","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Gillespie","sequence":"additional","affiliation":[{"name":"Department of Medical &amp; Molecular Genetics Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"McKinzie","sequence":"additional","affiliation":[{"name":"Behavioral Phenotyping Core Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey\u00a0J.","family":"Brault","sequence":"additional","affiliation":[{"name":"Indiana Center for Musculoskeletal Health, Department of Anatomy, Cell Biology, &amp; 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