{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T17:00:09Z","timestamp":1789837209456,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T00:00:00Z","timestamp":1738540800000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"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","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013569","name":"Ontario Ministry of Economic Development, Job Creation and Trade","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013569","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":[[2025,2]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Spinal muscular atrophy (SMA) is a health\u2010 and life\u2010limiting neuromuscular disorder. Although varying degrees of mitochondrial abnormalities have been documented in SMA skeletal muscle, the influence of disease progression on pathways that govern organelle turnover and dynamics are poorly understood. Thus, the purpose of this study was to investigate skeletal muscle mitochondria during SMA disease progression and determine the effects of therapeutic modalities on organelle biology.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Smn<\/jats:italic>\n \n 2B\/+<\/jats:italic>\n <\/jats:sup>\n and\n Smn<\/jats:italic>\n \n 2B\/\u2212<\/jats:italic>\n <\/jats:sup>\n severe SMA\u2010like mice were used to investigate mitochondrial turnover and dynamics signalling. Muscles were analysed at postnatal day 9 (P9), P13 or P21 to address pre\u2010symptomatic, early symptomatic and late symptomatic periods of the disorder. Additionally, we utilized an acute dose of exercise and urolithin A (UA) to stimulate organelle remodelling in skeletal muscle of SMA mice in\u00a0vivo and in SMA patient\u2010derived myotubes in\u00a0vitro, respectively.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Smn<\/jats:italic>\n \n 2B\/+<\/jats:italic>\n <\/jats:sup>\n and\n Smn<\/jats:italic>\n \n 2B\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice demonstrated similar levels of muscle mitochondrial oxidative phosphorylation (OxPhos) proteins throughout disease progression. In contrast, at P21 the mRNA levels of upstream factors important for the transcription of mitochondrial genes encoded by the nuclear and mitochondrial DNA, including\n nuclear respiratory factor 2<\/jats:italic>\n ,\n sirtuin 1<\/jats:italic>\n ,\n mitochondrial transcription factor A<\/jats:italic>\n and\n tumour protein 53<\/jats:italic>\n , were upregulated (+31%\u2013195%,\n p<\/jats:italic>\n \u2009<\u20090.05) in\n Smn<\/jats:italic>\n \n 2B\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice relative to\n Smn<\/jats:italic>\n \n 2B\/+<\/jats:italic>\n <\/jats:sup>\n . Early and late symptomatic skeletal muscle from SMA\u2010like mice showed greater autophagosome formation as denoted by more phosphorylated autophagy related 16\u2010like 1 (p\u2010ATG16L1\n Ser278<\/jats:sup>\n ) puncta (+60%\u201380%,\n p<\/jats:italic>\n \u2009<\u20090.05), along with a build\u2010up of molecules indicative of damaged mitochondria such as BCL2 interacting protein 3, Parkin and PTEN\u2010induced kinase 1 (+100%\u2013195%,\n p<\/jats:italic>\n \u2009<\u20090.05). Furthermore, we observed a fragmented mitochondrial phenotype at P21 that was concomitant with abnormal splicing of\n Optic atrophy 1<\/jats:italic>\n transcripts (\u221253%,\n p<\/jats:italic>\n \u2009<\u20090.05). A single dose of exercise augmented the expression of\n citrate synthase<\/jats:italic>\n (+43%,\n p<\/jats:italic>\n \u2009<\u20090.05) and corrected the over\u2010assembly of autophagosomes (\u221264%,\n p<\/jats:italic>\n \u2009<\u20090.05). In patient muscle cells, UA treatment stimulated autophagic flux, increased the expression of OxPhos proteins (+15%\u201347%,\n p<\/jats:italic>\n \u2009<\u20090.05) and improved maximal oxygen consumption (+84%,\n p<\/jats:italic>\n \u2009<\u20090.05).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Abnormal skeletal muscle mitochondrial turnover and dynamics are associated with disease progression in\n Smn<\/jats:italic>\n \n 2B\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice despite compensatory elevations in upstream factors important for organelle synthesis and recycling. Exercise and UA enhance mitochondrial health in skeletal muscle, which indicates that lifestyle\u2010based and pharmacological interventions may be effective countermeasures targeting the organelle for therapeutic remodelling in SMA.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.13701","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T00:39:10Z","timestamp":1738629550000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Skeletal Muscle Mitochondrial and Autophagic Dysregulation Are Modifiable in Spinal Muscular Atrophy"],"prefix":"10.1002","volume":"16","author":[{"given":"Andrew\u00a0I.","family":"Mikhail","sequence":"first","affiliation":[{"name":"Department of Kinesiology McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean\u00a0Y.","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of 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Ottawa Ontario Canada"},{"name":"Canada and Centre for Neuromuscular Disease University of Ottawa Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark\u00a0A.","family":"Tarnopolsky","sequence":"additional","affiliation":[{"name":"Department of Pediatrics McMaster University Medical Center Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4592-4093","authenticated-orcid":false,"given":"Vladimir","family":"Ljubicic","sequence":"additional","affiliation":[{"name":"Department of Kinesiology McMaster University Hamilton Ontario 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