{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T17:01:09Z","timestamp":1789837269717,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["408289"],"award-info":[{"award-number":["408289"]}],"id":[{"id":"10.13039\/501100000024","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":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Duchenne muscular dystrophy (DMD) is a severe, life\u2010limiting neuromuscular disorder (NMD) characterized by progressive muscle wasting and mitochondrial dysfunction. Although gene therapies offer promise, even those already approved by regulatory agencies, their use remains constrained by mutation specificity, delivery challenges and durability. Pharmacologically targeting AMPK has shown potential to ameliorate dystrophic pathology, but prior strategies have been hindered by inadequate efficacy and off\u2010target effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Comparative transcriptomic analyses were conducted to assess concordance between gene expression profiles induced by direct AMPK activation and those observed in DMD patient muscle. To evaluate the therapeutic potential of sustained AMPK activation, DBA\/2J\u2010mdx (D2.mdx;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20098\u201310) mice were treated daily with MK\u20108722 (MK; 5\u2009mg\u00b7kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      ) or vehicle for 7\u2009weeks, with healthy DBA\/2J mice serving as controls. Additionally, DMD patient\u2010derived myotubes (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20094) were treated with MK (1\u2009\u03bcM, 24\u2009h) to assess AMPK\u2010mediated cellular adaptations in human cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Transcriptomic profiling revealed that MK modulated 206 DMD\u2010associated transcripts, reversing expression of 73 upregulated and 133 downregulated genes. In\u00a0vivo, MK\u2010treated D2.mdx mice showed enhanced AMPK signalling (ACC phosphorylation, +120%\u2013150%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), increased\n                      <jats:italic>Ppargc1a<\/jats:italic>\n                      expression (+60%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and reduced inflammation\u2010 and fibrosis\u2010associated transcripts (\u221225%\u201350%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Seven weeks of daily MK treatment enhanced (+95%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) whole\u2010body lipid oxidation during active periods without affecting energy expenditure or activity. Notably, we observed that repeated MK dosing did not adversely impact cardiac morphology or function (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&gt;\u20090.05). MK\u2010treated D2.mdx mice demonstrated improved grip strength fatigability (\u221235%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), inverted hang performance (+100%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and treadmill exercise capacity (+20%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Additional ex\u00a0vivo muscle assessments revealed (+30%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) greater peak isometric force and improved twitch contractile kinetics. These functional adaptations were coincident with reduced myofibre damage and fibrosis, with increased sarcolemmal expression of utrophin, \u03b3\u2010sarcoglycan and \u03b2\u2010dystroglycan (+10%\u201370%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), despite no changes in fibre size or mass. Mitochondrial assessments showed increased State III respiration (+80%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), reduced reactive oxygen species production (\u221270%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and elevated OXPHOS protein content (+25%\u201345%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). In patient\u2010derived myotubes, MK similarly activated AMPK signalling, increased mitochondrial electron transport chain proteins (+25%\u201335%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and enhanced maximal oxygen consumption (+50%\u201380%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) in DMD\u039444 and DMD\u039445 lines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings demonstrate that sustained, systemic activation of AMPK safely improves muscle function, metabolic health and dystrophic pathology in a mutation\u2010independent manner. This supports the therapeutic potential of direct AMPK agonists as a disease\u2010modifying strategy for DMD and other neuromuscular disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70200","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T01:49:35Z","timestamp":1770256175000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Direct AMPK Activation Confers Mutation\u2010Independent Therapeutic Benefit in Duchenne Muscular Dystrophy"],"prefix":"10.1002","volume":"17","author":[{"given":"Sean\u00a0Y.","family":"Ng","sequence":"first","affiliation":[{"name":"Department of Kinesiology McMaster University  Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew\u00a0I.","family":"Mikhail","sequence":"additional","affiliation":[{"name":"Department of Kinesiology McMaster University  Hamilton Ontario 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