Background: 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‐dibromo‐α‐[(phenylamino)methyl]‐9H‐carbazol‐9‐ethanol) ameliorates diabetes and muscle function.Methods: We assessed the functional, morphometric, biochemical, and molecular effects of P7C3 treatment in skeletal muscle of type 2 diabetic (db/db) mice. Nampt^+/− mice were utilized to test the specificity of P7C3.Results: Insulin resistance increased 1.6‐fold in diabetic mice compared with wild‐type mice and after 4 weeks treatment with P7C3 rescued diabetes (P < 0.05). In the db‐P7C3 mice fasting blood glucose levels decreased to 0.96‐fold compared with C57Bl/6J wild‐type naïve control mice. The insulin and glucose tolerance tests blood glucose levels were decreased to 0.6‐fold and 0.54‐folds, respectively, at 120 min along with an increase in insulin secretion (1.76‐fold) and pancreatic β‐cells (3.92‐fold) in db‐P7C3 mice. The fore‐limb and hind‐limb grip strengths were increased to 1.13‐fold and 1.17‐fold, respectively, together with a 14.2‐fold increase in voluntary running wheel distance in db‐P7C3 mice. P7C3 treatment resulted in a 1.4‐fold and 7.1‐fold increase in medium‐sized and larger‐sized myofibres cross‐sectional area, with a concomitant 0.5‐fold decrease in smaller‐sized myofibres of tibialis anterior (TA) muscle. The transmission electron microscopy images also displayed a 1.67‐fold increase in myofibre diameter of extensor digitorum longus muscle along with 2.9‐fold decrease in mitochondrial area in db‐P7C3 mice compared with db‐Veh mice. The number of SDH positive myofibres were increased to 1.74‐fold in db‐P7C3 TA muscles. The gastrocnemius and TA muscles displayed a decrease in slow oxidative myosin heavy chain type1 (MyHC1) myofibres expression (0.46‐fold) and immunostaining (6.4‐fold), respectively. qPCR analysis displayed a 2.9‐fold and 1.3‐fold increase in Pdk4 and Cpt1, and 0.55‐fold and 0.59‐fold decrease in Fgf21 and 16S in db‐P7C3 mice. There was also a 3.3‐fold and 1.9‐fold increase in Fabp1 and CD36 in db‐Veh mice. RNA‐seq differential gene expression volcano plot displayed 1415 genes to be up‐regulated and 1726 genes down‐regulated (P < 0.05) in db‐P7C3 mice. There was 1.02‐fold increase in serum HDL, and 0.9‐fold decrease in low‐density lipoprotein/very low‐density lipoprotein ratio in db‐P7C3 mice. Lipid profiling of gastrocnemius muscle displayed a decrease in inflammatory lipid mediators n‐6; AA (0.83‐fold), and n‐3; DHA (0.69‐fold) and EPA (0.81‐fold), and a 0.66‐fold decrease in endocannabinoid 2‐AG and 2.0‐fold increase in AEA in db‐P7C3 mice.Conclusions: Overall, we demonstrate that P7C3 activates Nampt, improves type 2 diabetes and skeletal muscle function in db/db mice.

Sarcopenia, a disorder marked by muscle loss and dysfunction, is a global health concern, particularly in aging populations. Sarcopenia is intricately related to various health conditions, including obesity, dysphagia, and frailty, which underscores the complexity. Despite recent advances in metabolomics and other omics data for early detection and treatment, the precise characterization and diagnosis of sarcopenia remains challenging. In the present review we provide an overview of the complex metabolic mechanisms that underlie sarcopenia, with particular emphasis on protein, lipid, carbohydrate, and bone metabolism. The review highlights the importance of leucine and other amino acids in promoting muscle protein synthesis and clarifies the critical role played by amino acid metabolism in preserving muscular health. In addition, the review provides insights regarding lipid metabolism on sarcopenia, with an emphasis on the effects of inflammation and insulin resistance. The development of sarcopenia is largely influenced by insulin resistance, especially with regard to glucose metabolism. Overall, the review emphasizes the complex relationship between bone and muscle health by highlighting the interaction between sarcopenia and bone metabolism. Furthermore, the review outlines various therapeutic approaches and potential biomarkers for diagnosing sarcopenia. These include pharmacological strategies such as hormone replacement therapy and anabolic steroids as well as lifestyle modifications such as exercise, nutrition, and dietary changes.

Diabetes is associated with increased cardiac injury and sudden death. Nicotinamide phosphoribosyltransferase (Nampt) is an essential enzyme for the NAD⁺ salvage pathway and is dysregulated in diabetes. Nampt activation results in rescued NADH/NAD⁺ ratios and provides pharmacological changes necessary for diabetic cardioprotection. Computer docking shows that 1-(3,6-Dibromo-carbazol-9-yl)-3-phenylamino-propan-2-ol (P7C3) allows for enhanced Nampt dimerization and association. To test the pharmacological application, we used male leptin receptor–deficient (db/db) mice and treated them with Nampt activator P7C3. The effects of 4-week P7C3 treatment on cardiac function were evaluated along with molecular signaling changes for phosphorylated protein kinase B (p-AKT), phosphorylated endothelial nitric oxide synthase (p-eNOS), and sirtuin 1 (SIRT1). The cardiac function evaluated by ECG and echocardiography were significantly improved after 4 weeks of P7C3 treatment. Biochemically, higher NADH/NAD⁺ ratios in diabetic hearts were rescued by P7C3 treatment. Moreover, activities of Nampt and SIRT1 were significantly increased in P7C3-treated diabetic hearts. P7C3 treatment significantly decreased the blood glucose in diabetic mice with 4-week treatment as noted by glucose tolerance test and fasting blood glucose measurements compared with vehicle-treated mice. P7C3 activated Nampt enzymatic activity both in vitro and in the 4-week diabetic mouse hearts, demonstrating the specificity of the small molecule. P7C3 treatment significantly enhanced the expression of cardioprotective signaling of p-AKT, p-eNOS, and Beclin 1 in diabetic hearts. Nampt activator P7C3 allows for decreased infarct size with decreased Troponin I and lactose dehydrogenase (LDH) release, which is beneficial to the heart. Overall, the present study shows that P7C3 activates Nampt and SIRT1 activity and decreases NADH/NAD⁺ ratio, resulting in improved biochemical signaling providing cardioprotection. SIGNIFICANCE STATEMENT This study shows that 1-(3,6-Dibromo-carbazol-9-yl)-3-phenylamino-propan-2-ol (P7C3) is effective in treating diabetes and cardiovascular diseases. The novel small molecule is antiarrhythmic and improves the ejection fraction in diabetic hearts. The study successfully demonstrated that P7C3 decreases the infarct size in hearts during myocardial infarction and ischemia-reperfusion injury. Biochemical and cellular signaling show increased NAD⁺ levels, along with Nampt activity involved in upregulating protective signaling in the diabetic heart. P7C3 has high therapeutic potential for rescuing heart disease.