{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:52:22Z","timestamp":1791316342698,"version":"4.3.1"},"reference-count":48,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T00:00:00Z","timestamp":1642723200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Nicotinamide phosphoribosyltransferase (Nampt), a key enzyme in NAD salvage pathway is decreased in metabolic diseases, and its precise role in skeletal muscle function is not known. We tested the hypothesis, Nampt activation by P7C3 (3,6\u2010dibromo\u2010\u03b1\u2010[(phenylamino)methyl]\u20109H\u2010carbazol\u20109\u2010ethanol) ameliorates diabetes and muscle function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed the functional, morphometric, biochemical, and molecular effects of P7C3 treatment in skeletal muscle of type 2 diabetic (<jats:italic>db\/db<\/jats:italic>) mice. Nampt<jats:sup>+\/\u2212<\/jats:sup> mice were utilized to test the specificity of P7C3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Insulin resistance increased 1.6\u2010fold in diabetic mice compared with wild\u2010type mice and after 4\u00a0weeks treatment with P7C3 rescued diabetes (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). In the db\u2010P7C3 mice fasting blood glucose levels decreased to 0.96\u2010fold compared with C57Bl\/6J wild\u2010type na\u00efve control mice. The insulin and glucose tolerance tests blood glucose levels were decreased to 0.6\u2010fold and 0.54\u2010folds, respectively, at 120\u00a0min along with an increase in insulin secretion (1.76\u2010fold) and pancreatic \u03b2\u2010cells (3.92\u2010fold) in db\u2010P7C3 mice. The fore\u2010limb and hind\u2010limb grip strengths were increased to 1.13\u2010fold and 1.17\u2010fold, respectively, together with a 14.2\u2010fold increase in voluntary running wheel distance in db\u2010P7C3 mice. P7C3 treatment resulted in a 1.4\u2010fold and 7.1\u2010fold increase in medium\u2010sized and larger\u2010sized myofibres cross\u2010sectional area, with a concomitant 0.5\u2010fold decrease in smaller\u2010sized myofibres of tibialis anterior (TA) muscle. The transmission electron microscopy images also displayed a 1.67\u2010fold increase in myofibre diameter of extensor digitorum longus muscle along with 2.9\u2010fold decrease in mitochondrial area in db\u2010P7C3 mice compared with db\u2010Veh mice. The number of SDH\u00a0positive\u00a0myofibres were increased to 1.74\u2010fold in db\u2010P7C3 TA muscles. The gastrocnemius and TA muscles displayed a decrease in slow oxidative myosin heavy chain type1 (MyHC1) myofibres expression (0.46\u2010fold) and immunostaining (6.4\u2010fold), respectively. qPCR analysis displayed a 2.9\u2010fold and 1.3\u2010fold increase in <jats:italic>Pdk4<\/jats:italic> and <jats:italic>Cpt1<\/jats:italic>, and 0.55\u2010fold and 0.59\u2010fold decrease in <jats:italic>Fgf21<\/jats:italic> and 16S in db\u2010P7C3 mice. There was also a 3.3\u2010fold and 1.9\u2010fold increase in <jats:italic>Fabp1<\/jats:italic> and <jats:italic>CD36<\/jats:italic> in db\u2010Veh mice. RNA\u2010seq differential gene expression volcano plot displayed 1415 genes to be up\u2010regulated and 1726 genes down\u2010regulated (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) in db\u2010P7C3 mice. There was 1.02\u2010fold increase in serum HDL, and 0.9\u2010fold decrease in low\u2010density lipoprotein\/very low\u2010density lipoprotein ratio in db\u2010P7C3 mice. Lipid profiling of gastrocnemius muscle displayed a decrease in inflammatory lipid mediators n\u20106; AA (0.83\u2010fold), and n\u20103; DHA (0.69\u2010fold) and EPA (0.81\u2010fold), and a 0.66\u2010fold decrease in endocannabinoid 2\u2010AG and 2.0\u2010fold increase in AEA in db\u2010P7C3 mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Overall, we demonstrate that P7C3 activates Nampt, improves type 2 diabetes and skeletal muscle function in db\/db mice.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12887","type":"journal-article","created":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T09:58:14Z","timestamp":1642759094000},"page":"1177-1196","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Nampt activator P7C3 ameliorates diabetes and improves skeletal muscle function modulating cell metabolism and lipid mediators"],"prefix":"10.1002","volume":"13","author":[{"given":"Ravikumar","family":"Manickam","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Taneja College of Pharmacy University of South Florida  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared","family":"Tur","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Taneja College of Pharmacy University of South Florida  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachin L.","family":"Badole","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Taneja College of Pharmacy University of South Florida  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalyan C.","family":"Chapalamadugu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Taneja College of Pharmacy University of South Florida  Tampa FL 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