{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T19:21:10Z","timestamp":1792264870282,"version":"4.4.0"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"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 frequent comorbidity of metabolic disorders and chronic diseases, and despite its high prevalence, no pharmacological therapy is available, representing a major unmet clinical need. Adiponectin and its receptors are key regulators of skeletal muscle metabolism, mitochondrial function and myogenesis, yet clinical translation has been hindered by the lack of receptor\u2010selective agonists with favourable pharmacological and safety profiles. Here, we report the identification and characterization of CDRI\u20101709S, the first small\u2010molecule AdipoR1\u2010selective agonist and evaluate its myogenic and anti\u2010atrophy efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A PGC\u20101\u03b1 luciferase reporter\u2010based screen in AdipoR1\/AdipoR2\u2010transfected, AdipoR\u2010low HEK293T cells identified CDRI\u20101709S as an AdipoR1 agonist. Adiponectin\u2010associated signalling events were evaluated by immunoblotting in AdipoR1\/2\u2010overexpressing HEK293T cells and AdipoR\u2010abundant C2C12 myotubes, with receptor specificity confirmed using RNA interference. Myogenic potential was assessed by morphometric analysis and immune detection of myogenic factors. Fibre\u2010type composition and metabolic capacity were evaluated using immunoblotting and extracellular flux analysis. Anti\u2010atrophy effects were examined in\u00a0vitro using various assault\u2010induced models of myotube atrophy, and in\u00a0vivo using rat models of dexamethasone (Dex) and sciatic nerve denervation\u2010induced muscle atrophy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CDRI\u20101709S selectively activated AdipoR1 with high potency (EC\n                      <jats:sub>50<\/jats:sub>\n                      : 414.7pM) and, at a pharmacologically relevant concentration (100\u2009nM), induced rapid adiponectin\u2010associated signalling, including phosphorylation of AMPK, AKT and p38\u2010MAPK, along with upregulation of its downstream skeletal muscle metabolic targets PGC\u20101\u03b1, GLUT4 and UCP3 in an AdipoR1\u2010dependent manner (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). CDRI\u20101709S promoted C2C12 myoblast differentiation into mature myotubes, accompanied by increased expression of MyoD and myogenin (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Treated myotubes were protected against cytokine\u2010, Dex\u2010 and nutrient\u2010deprivation\u2010induced atrophy through suppression of atrogenes Atrogin\u20101 and MuRF\u20101 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), restoration of myogenic markers (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and prevention of Dex\u2010induced fibre\u2010type switching toward glycolytic MyHC\u2010IIB, with concomitant induction of slow (MyHC\u2010I) and fast (MyHC\u2010IIA) oxidative fibres (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). CDRI\u20101709S also reversed Dex\u2010mediated impairments in oxidative and glycolytic capacity (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05).\n                    <\/jats:p>\n                    <jats:p>\n                      Oral administration of CDRI\u20101709S (10\u2009mg\/kg\/day) in Dex\u2010 and denervation\u2010induced rat models restored atrogene expression, myogenic markers, local adiponectin signalling and myofibrillar architecture to normalcy (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05 to\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). CDRI\u20101709S prevented Dex\u2010induced enrichment of glycolytic fibres and preserved oxidative fibre composition (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). The structural\/molecular improvements translated into significant functional enhancements, including toe\u2010spread reflex in denervated limbs (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and increased grip strength (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) plus prolonged wire\u2010hang duration (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) in Dex\u2010treated animals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>CDRI\u20101709S is the first AdipoR1\u2010selective small\u2010molecule agonist that induced myogenesis and robustly ameliorated skeletal muscle atrophy, establishing the proof\u2010of\u2010concept for AdipoR1\u2010targeting as a promising therapeutic strategy for sarcopenia and skeletal muscle atrophy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70328","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T22:26:30Z","timestamp":1784672790000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Selective Small\u2010Molecule AdipoR1 Agonist 3\u2010Hydroxy Pterocarpan Salt (CDRI\u20101709S) Ameliorates Skeletal Muscle Atrophy"],"prefix":"10.1002","volume":"17","author":[{"given":"Md. Rameez","family":"Moin","sequence":"first","affiliation":[{"name":"Division of Biochemistry and Structural Biology CSIR\u2010Central Drug Research Institute  Lucknow India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyamal","family":"Pal","sequence":"additional","affiliation":[{"name":"Division of Medicinal &amp; Process Chemistry CSIR\u2010Central Drug Research Institute  Lucknow India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  Ghaziabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubhrajyoti","family":"Das","sequence":"additional","affiliation":[{"name":"Division of Biochemistry and Structural Biology CSIR\u2010Central Drug Research Institute  Lucknow India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  Ghaziabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pallavi","family":"Awasthi","sequence":"additional","affiliation":[{"name":"Division of Medicinal &amp; Process 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