{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T01:32:28Z","timestamp":1793583148832,"version":"4.5.0"},"reference-count":66,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Duchenne muscular dystrophy (DMD) is a severe inherited muscle disorder caused by mutations that eliminate the protein, dystrophin, resulting in disrupted protein homeostasis, mitochondrial dysfunction, chronic inflammation and progressive muscle degeneration. The leucine metabolite, \u03b2\u2010hydroxy\u2010\u03b2\u2010methylbutyrate (HMB), has shown therapeutic potential in dystrophic muscle. We previously reported that HMB supplementation improves fast\u2010twitch muscle histopathology and function in juvenile\n                      <jats:italic>mdx<\/jats:italic>\n                      mice during their peak damage phase (3\u20136\u00a0weeks). However, the\n                      <jats:italic>mdx<\/jats:italic>\n                      model exhibits a relatively mild pathology compared to human DMD, limiting clinical relevance. Here, we investigated 8\u00a0weeks of HMB supplementation (1\u00a0mg\u00a0g\n                      <jats:sup>\u22121<\/jats:sup>\n                      \u00a0day\n                      <jats:sup>\u22121<\/jats:sup>\n                      via drinking water) in the more severe D2.mdx mouse model at 3 and 6\u00a0months of age, representing skeletal muscle pathologies consistent with chronic inflammation and advanced muscle fibrosis, respectively. HMB\u2010treated D2.mdx mice had improved grip strength compared to controls, whereas isolated fast\u2010twitch extensor digitorum longus (EDL) muscles displayed increased fibre size, reduced tissue infiltrate and enhanced force production\n                      <jats:italic>ex vivo<\/jats:italic>\n                      . Mechanistically, HMB increased the phospho\u2010to\u2010total ratio of direct downstream mammalian target of rapamycin complex 1 (mTORC1) targets p70S6K1 and 4EBP1, consistent with enhanced anabolic signalling. Mitochondria assessed from treated flexor digitorum brevis muscles exhibited improved respiration and ATP production, with functional improvements aligning with elevated complex II succinate dehydrogenase activity in HMB\u2010treated EDL muscles. By contrast, no significant HMB\u2010induced effects were observed in the slow\u2010twitch soleus muscle. This study is the first to demonstrate that HMB enhances\n                      <jats:italic>in vivo<\/jats:italic>\n                      and\n                      <jats:italic>ex vivo<\/jats:italic>\n                      muscle function, downstream mTORC1\u00a0signalling, and mitochondrial performance in the severe D2.mdx model, supporting its potential as a therapeutic strategy for DMD.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70848-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\u03b2\u2010Hydroxy\u2010\u03b2\u2010methylbutyrate (HMB) supplementation improves skeletal muscle function in the D2.mdx mouse model of Duchenne muscular dystrophy.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>HMB treatment increased voluntary grip strength and enhanced force production in isolated extensor digitorum longus extensor digitorum longus muscles in 3\u2010 and 6\u2010month\u2010old D2.mdx mice.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Functional improvements were accompanied by reduced tissue infiltrate, increased mean muscle fibre size, and elevated succinate dehydrogenase activity.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\u03a4\u03b7\u03b5\u03b4\u03b4 adaptations coincided with increased markers of mammalian target of rapamycin complex 1\u00a0signalling, mitochondrial respiration and ATP production, suggesting improved metabolic capacity in dystrophic muscle.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp291639","type":"journal-article","created":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T16:27:46Z","timestamp":1789835266000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["\u03b2\u2010hydroxy\u2010\u03b2\u2010methylbutyrate improves fast\u2010twitch muscle function, histopathology and mitochondrial respiration in the D2.mdx dystrophic 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