{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:20:05Z","timestamp":1787746805252,"version":"build-2784847793"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001412","name":"Council of Scientific and Industrial Research, India","doi-asserted-by":"publisher","award":["MLP2028"],"award-info":[{"award-number":["MLP2028"]}],"id":[{"id":"10.13039\/501100001412","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":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Skeletal muscle atrophy is a hallmark of ageing and chronic diseases, yet effective pharmacotherapies remain unavailable. Adiponectin signalling through AdipoR1 and AdipoR2 regulates skeletal muscle metabolism, regeneration and oxidative capacity, but the therapeutic use of adiponectin is limited by its large size and complex multimeric structure. Small\u2010molecule AdipoR agonists, therefore, represent an attractive therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A PGC\u20101\u03b1 promoter\u2010luciferase assay was used to screen for AdipoR agonists in HEK\u2010293T cells overexpressing AdipoR1 or AdipoR2. Receptor specificity was validated through receptor overexpression and RNA\u2010interference. C2C12 myoblast differentiation was assessed using phase\u2010contrast microscopy and myosin heavy chain (MyHC) immunostaining followed by morphometric analyses of cross\u2010sectional area (CSA) and Feret's diameter, along with immunoblotting of MyoD and myogenin. Anti\u2010atrophy effects were examined in myotubes exposed to dexamethasone, cytokines or nutrient deprivation by evaluating CSA and diameter through morphometry, immunoblotting and qRT\u2010PCR analysis of atrogenes and myogenic markers. Oxidative metabolism and mitochondrial function were analysed using extracellular flux analysis and immunoblotting of fibre\u2010type markers, including MyHC\u2010I, MyHC\u2010IIA and MyHC\u2010IIB. In\u00a0vivo efficacy was evaluated in a dexamethasone\u2010induced and a sciatic nerve denervation\u2010induced rat models following oral administration of Med. Muscle histology, molecular signalling and functional performance were analysed. All immunoblots were analysed by densitometry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Med activated AdipoR1 and AdipoR2 with EC\n                      <jats:sub>50<\/jats:sub>\n                      values of 160 and 302\u2009pM, respectively, and stimulated canonical adiponectin signalling pathways, including AMPK, AKT and p38 MAPK. It significantly induced expression of typical adiponectin targets, PGC\u20101\u03b1, PPAR\u03b1, Glut4 and UCP3 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). AdipoR1 knockdown completely abolished Med\u2010mediated signalling, whereas AdipoR2 depletion caused partial attenuation. Med enhanced myogenic differentiation, evidenced by increasing myotube formation and expression of MyoD, myogenin and MyHC. It protected myotubes against dexamethasone\u2010, cytokine\u2010 and nutrient deprivation\u2010induced atrophy by preserving CSA and Feret's diameter (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001), which was accompanied by suppression of Atrogin\u20101 and MuRF1, and increased MyoD and myogenin expression (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Med also enhanced oxidative capacity by increasing fatty acid oxidation and Med\u2010treated cells showed elevated oxidative fibre markers. Oral administration of Med significantly attenuated muscle atrophy in both rat models, evidenced by improved muscle morphology, suppressed atrogenes, enhanced myogenic markers and increased muscle adiponectin expression and corresponding downstream signalling. Med markedly improved muscle function, including grip strength (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001), wire hanging (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) and rotarod performance (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) and toe\u2010spread ability of denervated limbs (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings identify Med as a potent small\u2010molecule orally bioavailable AdipoR agonist and provide proof\u2010of\u2010concept for AdipoR agonists as potential therapeutics for sarcopenia and muscle wasting disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70364","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T12:53:06Z","timestamp":1787575986000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Small\u2010Molecule Dual Adiponectin Receptor 1\/2 Agonist Induces Myogenesis and Ameliorates Skeletal Muscle Atrophy"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0624-3946","authenticated-orcid":false,"given":"Shubhrajyoti","family":"Das","sequence":"first","affiliation":[{"name":"Division of Biochemistry and Structural Biology CSIR\u2010Central Drug Research Institute  Lucknow Uttar Pradesh India"},{"name":"Academy of Scientific and Innovative research (AcSIR)  Ghaziabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8582-7327","authenticated-orcid":false,"given":"Pallavi","family":"Awasthi","sequence":"additional","affiliation":[{"name":"Academy of Scientific and Innovative research (AcSIR)  Ghaziabad India"},{"name":"Division of Medicinal and Process Chemistry CSIR\u2010Central Drug Research Institute  Lucknow Uttar Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1805-1515","authenticated-orcid":false,"given":"Md. 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