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DJ\u20101\u2010deficient mice develop gait\u2010associated progressive behavioural abnormalities and hypoactive forearm grip strength. However, underlying activity mechanisms are not fully explored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Western blotting and quantitative real\u2010time polymerase chain reaction approaches were adopted to analyse DJ\u20101 expression in skeletal muscle from aged humans or mice and compared with young subjects. Skeletal muscle\u2010specific\u2010DJ\u20101 knockout (MDKO) mice were generated, followed by an assessment of the physical activity phenotypes (grip strength, maximal load capacity, and hanging, rotarod, and exercise capacity tests) of the MDKO and control mice on the chow diet. Muscular atrophy phenotypes (cross\u2010sectional area and fibre types) were determined by imaging and quantitative real\u2010time polymerase chain reaction. Mitochondrial function and skeletal muscle morphology were evaluated by oxygen consumption rate and electron microscopy, respectively. Tail suspension was applied to address disuse atrophy. RNA\u2010seq analysis was performed to indicate molecular changes in muscles with DJ\u20101 ablation. Dual\u2010luciferase reporter assays were employed to identify the promoter region of Trim63 and Fbxo32 genes, which were indirectly regulated by DJ\u20101 via the FoxO1 pathway. Cytoplasmic and nuclear fractions of DJ\u20101\u2010deleted muscle cells were analysed by western blotting. Compound 23 was administered into the gastrocnemius muscle to mimic the of DJ\u20101 deletion effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>DJ\u20101 expression decreased in atrophied muscles of aged human (young men, <jats:italic>n<\/jats:italic>\u00a0=\u00a02; old with aged men, <jats:italic>n<\/jats:italic>\u00a0=\u00a02; young women, <jats:italic>n<\/jats:italic>\u00a0=\u00a02; old with aged women, <jats:italic>n<\/jats:italic>\u00a0=\u00a02) and immobilization mice (<jats:italic>n<\/jats:italic>\u00a0=\u00a06, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). MDKO mice exhibited no body weight difference compared with control mice on the chow diet (Flox, <jats:italic>n<\/jats:italic>\u00a0=\u00a08; MDKO, <jats:italic>n<\/jats:italic>\u00a0=\u00a09). DJ\u20101\u2010deficient muscles were slightly dystrophic (Flox, <jats:italic>n<\/jats:italic>\u00a0=\u00a07; MDKO, <jats:italic>n<\/jats:italic>\u00a0=\u00a08; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), with impaired physical activities and oxidative capacity (<jats:italic>n<\/jats:italic>\u00a0=\u00a08, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). In disuse\u2010atrophic conditions, MDKO mice showed smaller cross\u2010sectional area (<jats:italic>n<\/jats:italic>\u00a0=\u00a05, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and more central nuclei than control mice (Flox, <jats:italic>n<\/jats:italic>\u00a0=\u00a07; MDKO, <jats:italic>n<\/jats:italic>\u00a0=\u00a06; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), without alteration in muscle fibre types (Flox, <jats:italic>n<\/jats:italic>\u00a0=\u00a06; MDKO, <jats:italic>n<\/jats:italic>\u00a0=\u00a07). Biochemical analysis indicated that reduced mitochondrial function and upregulated of atrogenes induced these changes. Furthermore, RNA\u2010seq analysis revealed enhanced activity of the FoxO1 signalling pathway in DJ\u20101\u2010ablated muscles, which was responsible for the induction of atrogenes. Finally, compound 23 (an inhibitor of DJ\u20101) could mimic the effects of DJ\u20101 ablation in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results illuminate the crucial of skeletal muscle DJ\u20101 in the regulation of catabolic signals from mechanical stimulation, providing a therapeutic target for muscle wasting diseases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13290","type":"journal-article","created":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T05:42:48Z","timestamp":1689831768000},"page":"2126-2142","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Skeletal muscle\u2010specific DJ\u20101 ablation\u2010induced atrogenes expression and mitochondrial dysfunction contributing to muscular atrophy"],"prefix":"10.1002","volume":"14","author":[{"given":"Shuang","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Kinesiology, Shanghai University of Sport. 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