{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T23:41:21Z","timestamp":1782776481293,"version":"3.54.5"},"reference-count":40,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,10]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n \n Sarcopenia has become an urgent socioeconomic problem in rapidly aging societies. The pathogenesis of age\u2010associated sarcopenia is not fully understood and no effective therapeutic strategies have been developed to date. Recent studies have suggested the importance of the functional linkage between the brain and skeletal muscles in the pathogenesis of sarcopenia. However, the functional connections between the brain and skeletal muscles, particularly between the hypothalamus and skeletal muscles, remain unclear. In this study, we focused on the importance of nicotinamide adenine dinucleotide (NAD\n +<\/jats:sup>\n ) metabolism in the lateral hypothalamus (LH) and explored the importance of the NAD\n +<\/jats:sup>\n \u2010mediated functional connection between the LH and skeletal muscle and its involvement in the pathogenesis of sarcopenia.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n To explore the role of NAD\n +<\/jats:sup>\n in the LH, we knocked down\n nicotinamide phosphoribosyltransferase<\/jats:italic>\n (\n Nampt<\/jats:italic>\n ), a rate\u2010limiting enzyme in the NAD\n +<\/jats:sup>\n salvage pathway that is required for the maintenance of NAD\n +<\/jats:sup>\n , by stereotaxic injection of a lentivirus encoding short hairpin RNA for\n Nampt<\/jats:italic>\n into the LH.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Loss\u2010of\u2010function of\n Nampt<\/jats:italic>\n in the LH caused decreased muscle mass (mg\/cm) [tibialis anterior: 24.8\u2009\u00b1\u20090.36 vs. 22.9\u2009\u00b1\u20090.29,\n p<\/jats:italic>\n \u2009<\u20090.001; gastrocnemius: 65.7\u2009\u00b1\u20091.60 vs. 60.9\u2009\u00b1\u20090.65,\n p<\/jats:italic>\n \u2009<\u20090.05] and strength (mN) [382.0\u2009\u00b1\u200910.4 vs. 345.7\u2009\u00b1\u20095.47 at 100\u2009Hz stimulation,\n p<\/jats:italic>\n \u2009<\u20090.01], accompanied by disruption of the p70S6K\u2010S6 protein synthesis axis in skeletal muscle. Skeletal muscle of LH\u2010specific\n Nampt<\/jats:italic>\n \u2010knockdown mice exhibited decreased levels of pyruvate and lactate, the end products of glycolysis and decreased levels of glucose metabolism\u2010related genes, such as\n \u03b22 adrenergic receptor<\/jats:italic>\n (\n \u03b22\u2010AR)<\/jats:italic>\n ,\n peroxisome proliferator\u2010activated receptor delta<\/jats:italic>\n (\n PPAR\u03b4)<\/jats:italic>\n ,\n PPAR\u03b3<\/jats:italic>\n and\n pyruvate dehydrogenase kinase 4<\/jats:italic>\n (\n PDK4)<\/jats:italic>\n . We identified lactate as a mediator linking decreased glycolysis and protein synthesis. Lactate induces increases in intracellular Ca\n 2+<\/jats:sup>\n levels, which induce the activation of the p70S6K\u2010S6 protein synthesis axis.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our results indicate that\n Nampt<\/jats:italic>\n in the LH maintains skeletal muscle function by regulating lactate\u2010mediated Ca\n 2+<\/jats:sup>\n signalling in skeletal muscle. Our study highlights the essential role of\n Nampt<\/jats:italic>\n in the LH in the regulation of skeletal muscles and lactate as a mediator that links glycolysis and protein synthesis. As NAD\n +<\/jats:sup>\n levels in the LH decrease with age, our study provides new insights into the pathogenesis of sarcopenia.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.70055","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T11:31:18Z","timestamp":1758022278000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Nicotinamide phosphoribosyltransferase<\/i>\n (Nampt) in Lateral Hypothalamus Maintains Skeletal Muscle Functions Through Lactate\u2010Mediated Calcium Signalling in Male Mice"],"prefix":"10.1002","volume":"16","author":[{"given":"Takahiro","family":"Eguchi","sequence":"first","affiliation":[{"name":"Brain\u2010Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center National Center for Geriatrics and Gerontology Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Kabetani","sequence":"additional","affiliation":[{"name":"Brain\u2010Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center National Center for Geriatrics and Gerontology Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1884-8494","authenticated-orcid":false,"given":"Naoki","family":"Ito","sequence":"additional","affiliation":[{"name":"Brain\u2010Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center National Center for Geriatrics and Gerontology 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