{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:15:40Z","timestamp":1788344140563,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sarcopenia is a progressive and systemic skeletal muscle disorder characterized by the decline of muscle mass and function. Despite its early\u2010stage, \u2018possible sarcopenia\u2019 has been emphasized for prompt intervention; there are currently no specific biomarkers for the diagnosis and treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>RNA sequencing of human skeletal muscle across sarcopenia stages identified CCN5. Adeno\u2010associated virus (AAV) is intramuscularly injected into young C57BL\/6J mice to knockdown CCN5 in skeletal muscle. Phenotypic alterations are assessed through behavioural testing, body composition analysis, oil red O staining and transmission electron microscopy. Mechanisms were investigated in C2C12 myotubes using lentiviral infection, Western blotting, immunofluorescence, cellular electron microscopy and seahorse assays. Finally, aged C57BL\/6J mice received intramuscular AAV injections to overexpress CCN5 in skeletal muscle, evaluating its therapeutic efficacy against sarcopenia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Clinical samples included 56 participants (48.2% female; mean age: 63.21\u2009\u00b1\u20098.76\u2009years). By comparing gene expression in human skeletal muscle across three stages of sarcopenia, we identified CCN5 as a gene exhibiting decreased protein expression in possible sarcopenia stage (approximately 33% reduction,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0245), with this decline persisting into sarcopenia stage (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0093). In young mice, CCN5 knockdown induced a sarcopenia\u2010like phenotype, encompassing skeletal muscle dysfunction and myosteatosis (fat mass:\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01; intramyocellular triglyceride: 66.02\u2009\u00b1\u20093.798 vs. 104.5\u2009\u00b1\u20098.542\u2009\u03bcg\/mg tissue,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). CCN5 deficiency also impaired mitochondrial content and function, particularly by reducing lipid droplet\u2010mitochondrial (LD\u2010Mt) interaction (approximately 47% reduction,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). In C2C12 cells, CCN5 knockdown disrupted lipid metabolism (particularly reduced lipid oxidation, CPT1A: approximately 56% reduction,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), promoted lipid accumulation and compromised mitochondrial content and function. Mechanistically, secreted CCN5 enhanced LD\u2010Mt interaction and stimulated mitochondrial biogenesis by activating nuclear \u03b2\u2010catenin translocation to enhance FOXO3A\u2010dependent transcription, while intracellular CCN5 mitigated myosteatosis by inhibiting PPAR\u03b3 signalling. In aged mice, CCN5 overexpression improved skeletal muscle function, reduced myosteatosis (fat mass:\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001; intramyocellular triglyceride: 175.0\u2009\u00b1\u200911.18 vs. 92.18\u2009\u00b1\u200910.53\u2009\u03bcg\/mg tissue,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and restored mitochondrial function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CCN5 mitigates myosteatosis and counteracts sarcopenia by promoting mitochondrial biogenesis and enhancing LD\u2010Mt interactions through dual pathways, positioning it as a promising therapeutic target for muscle aging and sarcopenia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70282","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T18:12:14Z","timestamp":1775585534000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual Roles of CCN5\/WISP2 in Cytosol and Secretome for Maintaining Muscle Homeostasis and Preventing Sarcopenia"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4008-6016","authenticated-orcid":false,"given":"Zile","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, School of Medicine Tongji University  Shanghai China"},{"name":"Department of Gastrointestinal Surgery, Shanghai East Hospital, School of Medicine Tongji University  Shanghai 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