{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T15:15:57Z","timestamp":1786720557657,"version":"build-2736575974"},"reference-count":34,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T00:00:00Z","timestamp":1724716800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81770486"],"award-info":[{"award-number":["81770486"]}],"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":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Hydrogen sulfide (H<jats:sub>2<\/jats:sub>S), the third gasotransmitter discovered, regulates a variety of physiological functions. Whether H<jats:sub>2<\/jats:sub>S alleviates skeletal muscle ageing by regulating autophagy has not been reported.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mice were administered 150\u00a0mg\/kg\/day of <jats:sc>D<\/jats:sc>\u2010galactose (<jats:sc>D<\/jats:sc>\u2010gal), and C2C12 myotubes were cultured in 20\u00a0g\/L <jats:sc>D<\/jats:sc>\u2010gal to induce ageing. Sodium hydrosulfide (NaHS) was employed as an exogenous donor in the treatment group. The intracellular concentration of H<jats:sub>2<\/jats:sub>S was quantified by the 7\u2010azido\u20104\u2010methylcoumarin fluorescence probe. The proteins involved in the ubiquitin\u2010mediated degradation of AMPK\u03b11 were detected by liquid chromatography tandem mass spectrometry (LC\u2013MS\/MS) and co\u2010immunoprecipitation (Co\u2010IP). S\u2010sulfhydration of USP5 was tested by a biotin\u2010switch assay. Associated proteins were analysed by western blot.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>NaHS was found to effectively restore the H<jats:sub>2<\/jats:sub>S content in both ageing gastrocnemius (+91.89%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and C2C12 myotubes (+27.55%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). In comparison to the\u00a0D\u2010gal group, NaHS was observed to increase the mean cross\u2010sectional area of muscle fibres (+44.91%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), to decrease the collagen volume fraction of gastrocnemius (\u221281.32%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.001) and to reduce the \u03b2\u2010galactosidase\u2010positive area of C2C12 myotubes (\u221228.74%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). NaHS was also found to reverse the expression of muscle atrophy F box protein (MAFbx), muscle\u2010specific RING finger protein 1 (MuRF1), Cyclin D1 and p21 in the ageing gastrocnemius tissue (MAFbx: \u221231.73%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.008; MuRF1: \u221232.37%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.003; Cyclin D1: +45.34%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.010; p21: \u221225.53%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.022) and C2C12 myotubes (MAFbx: \u221216.38%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; MuRF1: \u221216.45%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.003; Cyclin D1: +40.23%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; p21: \u221235.85%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.026). The AMPK\u03b11\u2013ULK1 pathway was activated and autophagy was up\u2010regulated in NaHS\u2010treated gastrocnemius tissue (p\u2010AMPK\u03b11: +61.61%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.018; AMPK\u03b11: +30.64%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.010; p\u2010ULK1\/ULK1: +85.87%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.005; p62: \u221229.07%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; Beclin1: +24.75%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.007; light chain 3 II\/I [LC3 II\/I]: +55.78%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.004) and C2C12 myotubes (p\u2010AMPK\u03b11: +77.49%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.018; AMPK\u03b11: +26.18%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.022; p\u2010ULK1\/ULK1: +38.34%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.012; p62: \u22129.02%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.014; Beclin1: +13.36%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; LC3 II\/I: +79.38%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.017; autophagy flux: +24.88%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.034) compared with the <jats:sc>D<\/jats:sc>\u2010gal group. The effects of NaHS on autophagy were comparable to those of acadesine and LYN\u20101604, and chloroquine could reverse its effects on ageing. LC\u2013MS\/MS and Co\u2010IP experiments demonstrated that USP5 is a deubiquitinating enzyme of AMPK\u03b11. Following the knockdown of USP5, the activation of AMPK\u03b11 was decreased (p\u2010AMPK\u03b11: \u221242.10%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; AMPK\u03b11: \u221243.93%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), autophagy was inhibited (p\u2010ULK1\/ULK1: \u221227.51, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.001; p62: +36.00, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; Beclin1: \u221222.15%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and NaHS lost its ability to up\u2010regulate autophagy. NaHS was observed to restore the expression (gastrocnemius: +62.17%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; C2C12 myotubes: +37.51%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.003) and S\u2010sulfhydration (+53.07%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.009) of USP5 and reduce the ubiquitination of AMPK\u03b11.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>H<jats:sub>2<\/jats:sub>S promotes the deubiquitination of AMPK\u03b11 by increasing the expression and S\u2010sulfhydration of USP5, thereby up\u2010regulating autophagy and alleviating skeletal muscle ageing.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13560","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T10:35:22Z","timestamp":1724754922000},"page":"2118-2133","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Hydrogen sulfide inhibits skeletal muscle ageing by up\u2010regulating autophagy through promoting deubiquitination of adenosine 5\u2019\u2010monophosphate (AMP)\u2010activated protein kinase \u03b11 via ubiquitin specific peptidase 5"],"prefix":"10.1002","volume":"15","author":[{"given":"Jia\u2010He","family":"Yang","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine Xiamen University  Xiamen Fujian China"},{"name":"Department of Pathophysiology, School of Medicine Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine Xiangan Hospital of Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya\u2010Qi","family":"E","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine Xiamen University  Xiamen Fujian China"},{"name":"Department of Pathophysiology, School of Medicine Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li\u2010Jie","family":"Jiao","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine Xiamen University  Xiamen Fujian China"},{"name":"Department of Pathophysiology, School of Medicine Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine Xiamen University  Xiamen Fujian China"},{"name":"Department of Pathophysiology, School of Medicine Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiu\u2010Yi","family":"Yan","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine Xiamen University  Xiamen Fujian China"},{"name":"Department of Pathophysiology, School of Medicine Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi\u2010Yi","family":"Wei","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine Xiamen University  Xiamen Fujian China"},{"name":"Department of Pathophysiology, School of Medicine Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo\u2010Liang","family":"Yan","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital of 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