{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T15:44:51Z","timestamp":1778255091334,"version":"3.51.4"},"reference-count":74,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T00:00:00Z","timestamp":1701734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Physical activity is recommended as an alternative treatment for depression. Myokines, which are secreted from skeletal muscles during physical activity, play an important role in the skeletal muscle-brain axis. Musclin, a newly discovered myokine, exerts physical endurance, however, the effects of musclin on emotional behaviors, such as depression, have not been evaluated. This study aimed to access the anti-depressive effect of musclin and clarify the connection between depression-like behavior and hypothalamic neuropeptides in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We measured the immobility time in the forced swim (FS) test, the time spent in open arm in the elevated-plus maze (EPM) test, the mRNA levels of hypothalamic neuropeptides, and enumerated the c-Fos-positive cells in the paraventricular nucleus (PVN), arcuate nucleus (ARC), and nucleus tractus solitarii (NTS) in mice with the intraperitoneal (i.p.) administration of musclin. Next, we evaluated the effects of a selective corticotropin-releasing factor (CRF) type 1 receptor antagonist, selective CRF type 2 receptor antagonist, melanocortin receptor (MCR) agonist, and selective melanocortin 4 receptor (MC4R) agonist on changes in behaviors induced by musclin. Finally we evaluated the antidepressant effect of musclin using mice exposed to repeated water immersion (WI) stress.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that the i.p. and i.c.v. administration of musclin decreased the immobility time and relative time in the open arms (open %) in mice and increased urocortin 2 (Ucn 2) levels but decreased proopiomelanocortin levels in the hypothalamus. The numbers of c-Fos-positive cells were increased in the PVN and NTS but decreased in the ARC of mice with i.p. administration of musclin. The c-Fos-positive cells in the PVN were also found to be Ucn 2-positive. The antidepressant and anxiogenic effects of musclin were blocked by central administration of a CRF type 2 receptor antagonist and a melanocortin 4 receptor agonist, respectively. Peripheral administration of musclin also prevented depression-like behavior and the decrease in levels of hypothalamic Ucn 2 induced by repeated WI stress.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These data identify the antidepressant effects of musclin through the activation of central Ucn 2 signaling and suggest that musclin and Ucn 2 can be new therapeutic targets and endogenous peptides mediating the muscle\u2212brain axis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1288282","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T04:27:24Z","timestamp":1701750444000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Musclin prevents depression-like behavior in male mice by activating urocortin 2 signaling in the hypothalamus"],"prefix":"10.3389","volume":"14","author":[{"given":"Koji","family":"Ataka","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiro","family":"Asakawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruki","family":"Iwai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ikuo","family":"Kato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(21)00395-3","article-title":"Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019","volume":"9","year":"2022","journal-title":"Lancet Psychiatry"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02143-7","article-title":"Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic","volume":"398","year":"2021","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2018.4513","article-title":"Severity and variability of depression symptoms predicting suicide attempt in high-risk individuals","volume":"76","author":"Melhem","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.2018.27","article-title":"Depression and hopelessness as risk factors for suicide ideation, attempts and death: meta-analysis of longitudinal studies","volume":"212","author":"Ribeiro","year":"2018","journal-title":"Br J Psychiatry"},{"key":"B5","doi-asserted-by":"crossref","DOI":"10.1016\/S0140-6736(18)31948-2","article-title":"Depression","volume-title":"Lancet","author":"Malhi","year":"2018"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.20m13699","article-title":"The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States","volume":"82","author":"Zhdanava","year":"2021","journal-title":"J Clin Psychiatry"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.31083\/j.jin2105132","article-title":"Physical activity as a clinical tool against depression: opportunities and challenges","volume":"21","author":"Chen","year":"2022","journal-title":"J Integr Neurosci"},{"key":"B8","unstructured":"World Health Organization Physical activity"},{"key":"B9","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.jad.2016.03.063","article-title":"Exercise as a treatment for depression: A meta-analysis","volume":"202","author":"Kvam","year":"2016","journal-title":"J Affect Disord"},{"key":"B10","unstructured":"UK national instutute for health and clinical excellence"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1177\/0706743716659417","article-title":"Canadian network for mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3","volume":"61","author":"Kennedy","year":"2016","journal-title":"Pharmacol Treatments. 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