{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:08:28Z","timestamp":1789517308342,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T00:00:00Z","timestamp":1678406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81900040"],"award-info":[{"award-number":["81900040"]}],"id":[{"id":"10.13039\/501100001809","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":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Skeletal muscle dysfunction is an important co\u2010morbidity in patients with chronic obstructive pulmonary disease (COPD) and is significantly associated with increased mortality. Oxidative stress has been demonstrated an important trigger for COPD\u2010related skeletal muscle dysfunction. Glycine\u2010histidine\u2010lysine (GHK) is an active tripeptide, which is a normal component of human plasma, saliva, and urine; promotes tissue regeneration; and acts as an anti\u2010inflammatory and antioxidant properties. The purpose of this study was to determine whether GHK is involved in COPD\u2010related skeletal muscle dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The plasma GHK level in patients with COPD (<jats:italic>n<\/jats:italic>\u00a0=\u00a09) and age\u2010paired healthy subjects (<jats:italic>n<\/jats:italic>\u00a0=\u00a011) were detected using reversed\u2010phase high\u2010performance liquid chromatography. The complex GHK with Cu (GHK\u2010Cu) was used in in vitro (C2C12 myotubes) and in vivo experiments (cigarette smoking [CS]\u2010exposure mouse model) to explore the involvement of GHK in CS\u2010induced skeletal muscle dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared with healthy control, plasma GHK levels were decreased in patients with COPD (70.27\u00a0\u00b1\u00a038.87\u00a0ng\/mL vs. 133.0\u00a0\u00b1\u00a054.54\u00a0ng\/mL, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.009). And plasma GHK levels in patients with COPD were associated with pectoralis muscle area (<jats:italic>R<\/jats:italic>\u00a0=\u00a00.684, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.042), inflammatory factor TNF\u2010\u03b1 (<jats:italic>R<\/jats:italic>\u00a0=\u00a0\u22120.696, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.037), and antioxidative stress factor SOD2 (<jats:italic>R<\/jats:italic>\u00a0=\u00a00.721, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.029). GHK\u2010Cu was found to rescue CSE\u2010induced skeletal muscle dysfunction in C2C12 myotubes, as evidenced by increased expression of myosin heavy chain, reduced expression of MuRF1 and atrogin\u20101, elevated mitochondrial content, and enhanced resistance to oxidative stress. In CS\u2010induced muscle dysfunction C57BL\/6 mice, GHK\u2010Cu treatment (0.2 and 2\u00a0mg\/kg) reduces CS\u2010induced muscle mass loss (skeletal muscle weight (1.19\u00a0\u00b1\u00a00.09% vs. 1.29\u00a0\u00b1\u00a00.06%, 1.40\u00a0\u00b1\u00a00.05%; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and muscle cross\u2010sectional area elevated (1055\u00a0\u00b1\u00a0552.4\u00a0\u03bcm<jats:sup>2<\/jats:sup> vs. 1797\u00a0\u00b1\u00a0620.9\u00a0\u03bcm<jats:sup>2<\/jats:sup>, 2252\u00a0\u00b1\u00a0534.0\u00a0\u03bcm<jats:sup>2<\/jats:sup>; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), and also rescues CS\u2010induced muscle weakness, indicated by improved grip strength (175.5\u00a0\u00b1\u00a036.15\u00a0g vs. 257.6\u00a0\u00b1\u00a037.98\u00a0g, 339.1\u00a0\u00b1\u00a072.22\u00a0g; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Mechanistically, GHK\u2010Cu directly binds and activates SIRT1(the binding energy was \u22126.1\u00a0kcal\/mol). Through activating SIRT1 deacetylation, GHK\u2010Cu inhibits FoxO3a transcriptional activity to reduce protein degradation, deacetylates Nrf2 and contribute to its action of reducing oxidative stress by generation of anti\u2010oxidant enzymes, increases PGC\u20101\u03b1 expression to promote mitochondrial function. Finally, GHK\u2010Cu could protect mice against CS\u2010induced skeletal muscle dysfunction via SIRT1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Plasma glycyl\u2010<jats:sc>l<\/jats:sc>\u2010histidyl\u2010<jats:sc>l<\/jats:sc>\u2010lysine level in patients with chronic obstructive pulmonary disease was significantly decreased and was significantly associated with skeletal muscle mass. Exogenous administration of glycyl\u2010<jats:sc>l<\/jats:sc>\u2010histidyl\u2010<jats:sc>l<\/jats:sc>\u2010lysine\u2010Cu<jats:sup>2+<\/jats:sup> could protect against cigarette smoking\u2010induced skeletal muscle dysfunction via sirtuin 1.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13213","type":"journal-article","created":{"date-parts":[[2023,3,11]],"date-time":"2023-03-11T06:39:10Z","timestamp":1678516750000},"page":"1365-1380","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Glycyl\u2010<scp>l<\/scp>\u2010histidyl\u2010<scp>l<\/scp>\u2010lysine\u2010Cu<sup>2+<\/sup> rescues cigarette smoking\u2010induced skeletal muscle dysfunction via a sirtuin 1\u2010dependent pathway"],"prefix":"10.1002","volume":"14","author":[{"given":"Mingming","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine China\u2010Japan Friendship 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China Medical University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiding","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine China\u2010Japan Friendship Hospital  Beijing China"},{"name":"National Center for Respiratory Medicine  Beijing China"},{"name":"Institute of Respiratory Medicine Chinese Academy of Medical Sciences  Beijing China"},{"name":"National Clinical Research Center for Respiratory Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine First Hospital of China Medical University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine First 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