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Muscle fibre composition switch is closely associated with chronic diseases such as muscle atrophy, obesity, type II diabetes and athletic performance. Prostaglandin D<jats:sub>2<\/jats:sub>(PGD<jats:sub>2<\/jats:sub>) is a bioactive lipid derived from arachidonic acid that aggravates muscle damage and wasting during muscle atrophy. This study aimed to investigate the precise mechanisms underlying PGD<jats:sub>2<\/jats:sub>\u2010mediated muscle homeostasis and myogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Skeletal muscle\u2010specific PGD<jats:sub>2<\/jats:sub>receptor DP2\u2010deficient mice (DP2<jats:sup>fl\/fl<\/jats:sup>HSA<jats:sup>Cre<\/jats:sup>) and their littermate controls (DP2<jats:sup>fl\/fl<\/jats:sup>) were subjected to exhaustive exercise and fed a high\u2010fat diet (HFD). X\u2010linked muscular dystrophy (MDX) mice and HFD\u2010challenged mice were treated with the selective DP2 inhibitor CAY10471. Exercise tolerance, body weight, glycometabolism and skeletal muscle fibre composition were measured to determine the role of the skeletal muscle PGD<jats:sub>2<\/jats:sub>\/DP2 signalling axis in obesity and muscle disorders. Multiple genetic and pharmacological approaches were also used to investigate the intracellular signalling cascades underlying the PGD<jats:sub>2<\/jats:sub>\/DP2\u2010mediated skeletal muscle fibre transition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PGD<jats:sub>2<\/jats:sub>generation and DP2 expression were significantly upregulated in the hindlimb muscles of HFD\u2010fed mice (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05 or<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01 vs. normal chow diet). Compared with DP2<jats:sup>fl\/fl<\/jats:sup>mice, DP2<jats:sup>fl\/fl<\/jats:sup>HSA<jats:sup>Cre<\/jats:sup>mice exhibited remarkable glycolytic\u2010to\u2010oxidative fibre\u2010type transition in hindlimb muscles and were fatigue resistant during endurance exercise (154.9\u00a0\u00b1\u00a06.0 vs. 124.2\u00a0\u00b1\u00a08.1\u00a0min,<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). DP2<jats:sup>fl\/fl<\/jats:sup>HSA<jats:sup>Cre<\/jats:sup>mice fed an HFD showed less weight gain (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and hepatic lipid accumulation (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), reduced insulin resistance and enhanced energy expenditure (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) compared with DP2<jats:sup>fl\/fl<\/jats:sup>mice. Mechanistically, DP2 deletion promoted the nuclear translocation of nuclear factor of activated T cells 1 (NFATc1) by suppressing RhoA\/Rho\u2010associated kinase 2 (ROCK2) signalling, which led to enhanced oxidative fibre\u2010specific gene transcription in muscle cells. Treatment with CAY10471 enhanced NFATc1 activity in the skeletal muscles and ameliorated HFD\u2010induced obesity (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05 vs. saline) and insulin resistance in mice. CAY10471 also enhanced exercise tolerance in MDX mice (100.8\u00a0\u00b1\u00a08.0 vs. 68.9\u00a0\u00b1\u00a011.1\u00a0min,<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05 vs. saline) by increasing the oxidative fibre\u2010type ratio in the muscles (45.1\u00a0\u00b1\u00a02.3% vs. 32.3\u00a0\u00b1\u00a02.6%,<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05 vs. saline).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>DP2 activation suppresses oxidative fibre transition via RhoA\/ROCK2\/NFATc1 signalling. The inhibition of DP2 may be a potential therapeutic approach against obesity and muscle disorders.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13136","type":"journal-article","created":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T05:30:41Z","timestamp":1671255041000},"page":"342-355","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Targeting the DP2 receptor alleviates muscle atrophy and diet\u2010induced obesity in mice through oxidative myofiber transition"],"prefix":"10.1002","volume":"14","author":[{"given":"Huying","family":"Ning","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co\u2010sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences Tianjin Medical University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiwen","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co\u2010sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences Tianjin Medical University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co\u2010sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujun","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co\u2010sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences Tianjin Medical University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co\u2010sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences Tianjin Medical University Tianjin 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