{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:14:57Z","timestamp":1753892097700,"version":"3.41.2"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T00:00:00Z","timestamp":1667260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K08275 21K07933 22K08072 21K19694 20H04119 21H03010 22H03527 21H03372"],"award-info":[{"award-number":["20K08275 21K07933 22K08072 21K19694 20H04119 21H03010 22H03527 21H03372"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Obesity is a risk factor for many diseases because it leads to a reduction in skeletal muscle mass and promotes insulin resistance. <jats:italic>p62\/Sqstm1<\/jats:italic>-knockout mice are a model of metabolic syndrome; show obesity, insulin resistance, and non-alcoholic fatty liver (NAFL); and develop non-alcoholic steatohepatitis (NASH) in response to the feeding of a high-fat diet (HFD). These phenotypes suggest that muscle p62 may prevent obesity-induced muscle dysfunction. In the present study, we aimed to determine the effects of muscle p62 on skeletal muscle mass, muscle strength, insulin resistance, and NASH pathology.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> We generated muscle-specific <jats:italic>p62<\/jats:italic> gene rescue mice (<jats:italic>p62<\/jats:italic>-mRes), which express p62 only in muscle and were derived from <jats:italic>p62<\/jats:italic>-knock out mice (<jats:italic>p62<\/jats:italic><jats:sup><jats:italic>KIKI<\/jats:italic><\/jats:sup>) using the <jats:italic>cre\/loxp<\/jats:italic> system. <jats:italic>p62<\/jats:italic><jats:sup><jats:italic>KIKI<\/jats:italic><\/jats:sup> and <jats:italic>p62<\/jats:italic>-mRes mice were fed an HFD for 20 weeks and their phenotypes were compared.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> HFD-feeding caused severe obesity in both <jats:italic>p62<\/jats:italic><jats:sup><jats:italic>KIKI<\/jats:italic><\/jats:sup> and <jats:italic>p62<\/jats:italic>-mRes mice, but there was no effect of muscle p62 on body mass. Limb skeletal muscle mass, grip strength, and the cross-sectional area of muscle fibers were higher in <jats:italic>p62<\/jats:italic>-mRes mice than in <jats:italic>p62<\/jats:italic><jats:sup><jats:italic>KIKI<\/jats:italic><\/jats:sup>. The glucose tolerance and insulin sensitivity of the <jats:italic>p62<\/jats:italic>-mRes mice were also superior. The protein expression of mechanistic target of rapamycin, which promotes muscle protein synthesis, and GLUT4, a glucose transporter in skeletal muscle, were higher in the <jats:italic>p62<\/jats:italic>-mRes mice. <jats:italic>p62<\/jats:italic><jats:sup><jats:italic>KIKI<\/jats:italic><\/jats:sup> mice developed severe NASH when fed an HFD, but the progression of NASH was retarded by <jats:italic>p62<\/jats:italic> gene rescue in muscle, and the expression of <jats:italic>Tgf-\u03b21<\/jats:italic>, which encodes a factor that promotes hepatic fibrosis, was reduced.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Rescue of muscle-specific <jats:italic>p62<\/jats:italic> in the whole-body <jats:italic>p62<\/jats:italic> knock-out mice ameliorates the insulin resistance and retards the progression of NASH caused by systemic <jats:italic>p62<\/jats:italic> ablation.<\/jats:p>","DOI":"10.3389\/fphys.2022.993995","type":"journal-article","created":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T06:59:07Z","timestamp":1667285947000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["p62\/Sqstm1 rescue in muscle retards the progression of steatohepatitis in p62\/Sqstm1-null mice fed a high-fat diet"],"prefix":"10.3389","volume":"13","author":[{"given":"Ikuru","family":"Miura","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kosuke","family":"Okada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akiko","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eiji","family":"Warabi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahisa","family":"Watahiki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keii","family":"To","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitoshi","family":"Shimano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shunichi","family":"Ariizumi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junichi","family":"Shoda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1016\/j.jamda.2016.04.019","article-title":"Skeletal muscle regulates metabolism via interorgan crosstalk: Roles in health and disease","volume":"17","author":"Argiles","year":"2016","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1751","DOI":"10.1002\/hep.25889","article-title":"Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients","volume":"56","author":"Bedossa","year":"2012","journal-title":"Hepatology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2055","DOI":"10.1002\/hep.29420","article-title":"Sarcopenia in hiding: The risk and consequence of underestimating muscle dysfunction in nonalcoholic steatohepatitis","volume":"66","author":"Bhanji","year":"2017","journal-title":"Hepatology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1038\/ncb1101-1014","article-title":"Akt\/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo","volume":"3","author":"Bodine","year":"2001","journal-title":"Nat. Cell Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/s00125-015-3780-8","article-title":"Resistance training improves skeletal muscle insulin sensitivity in elderly offspring of overweight and obese mothers","volume":"59","author":"Bucci","year":"2016","journal-title":"Diabetologia"},{"key":"B6","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.molcel.2011.06.038","article-title":"p62 is a key regulator of nutrient sensing in the mTORC1 pathway","volume":"44","author":"Duran","year":"2011","journal-title":"Mol. Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.ccell.2016.09.004","article-title":"p62\/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis, and liver cancer","volume":"30","author":"Duran","year":"2016","journal-title":"Cancer Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1974","DOI":"10.1016\/j.biocel.2005.04.018","article-title":"Skeletal muscle hypertrophy and atrophy signaling pathways","volume":"37","author":"Glass","year":"2005","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"T1","DOI":"10.1530\/JOE-13-0327","article-title":"Insulin signaling, resistance, and the metabolic syndrome: Insights from mouse models into disease mechanisms","volume":"220","author":"Guo","year":"2014","journal-title":"J. Endocrinol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"14767","DOI":"10.1523\/JNEUROSCI.2954-12.2013","article-title":"Deficiency of p62\/sequestosome 1 causes hyperphagia due to leptin resistance in the brain","volume":"33","author":"Harada","year":"2013","journal-title":"J. Neurosci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1016\/j.jhep.2020.01.023","article-title":"NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly","volume":"72","author":"He","year":"2020","journal-title":"J. Hepatol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e0188650","DOI":"10.1371\/journal.pone.0188650","article-title":"Relative muscle mass and the risk of incident type 2 diabetes: A cohort study","volume":"12","author":"Hong","year":"2017","journal-title":"PLos One"},{"key":"B13","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1038\/nature05482","article-title":"Mechanisms linking obesity to insulin resistance and type 2 diabetes","volume":"444","author":"Kahn","year":"2006","journal-title":"nature"},{"key":"B14","doi-asserted-by":"publisher","first-page":"4672","DOI":"10.1111\/febs.13540","article-title":"p62\/SQSTM1 functions as a signaling hub and an autophagy adaptor","volume":"282","author":"Katsuragi","year":"2015","journal-title":"FEBS J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1111\/obr.12129","article-title":"Quantitative relationship between body weight gain in adulthood and incident type 2 diabetes: A meta-analysis","volume":"15","author":"Kodama","year":"2014","journal-title":"Obes. Rev."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","article-title":"Mechanisms and disease consequences of nonalcoholic fatty liver disease","volume":"184","author":"Loomba","year":"2021","journal-title":"Cell"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e14859","DOI":"10.14814\/phy2.14859","article-title":"Prevention of non-alcoholic steatohepatitis by long-term exercise via the induction of phenotypic changes in Kupffer cells of hyperphagic obese mice","volume":"9","author":"Miura","year":"2021","journal-title":"Physiol. Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1172\/JCI64209","article-title":"p62 links \u03b2-adrenergic input to mitochondrial function and thermogenesis","volume":"123","author":"Muller","year":"2013","journal-title":"J. Clin. Invest."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1046\/j.1532-5415.2003.51534.x","article-title":"Sarcopenia: Alternative definitions and associations with lower extremity function","volume":"51","author":"Newman","year":"2003","journal-title":"J. Am. Geriatr. Soc."},{"key":"B20","doi-asserted-by":"publisher","first-page":"100253","DOI":"10.1016\/j.jhepr.2021.100253","article-title":"Weight-loss-independent benefits of exercise on liver steatosis and stiffness in Japanese men with NAFLD","volume":"3","author":"Oh","year":"2021","journal-title":"JHEP Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1111\/j.1872-034X.2008.00478.x","article-title":"The alpha-glucosidase inhibitor acarbose prevents obesity and simple steatosis in sequestosome 1\/A170\/p62 deficient mice","volume":"39","author":"Okada","year":"2009","journal-title":"Hepatol. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1038\/ncb1101-1009","article-title":"Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K\/Akt\/mTOR and PI(3)K\/Akt\/GSK3 pathways","volume":"3","author":"Rommel","year":"2001","journal-title":"Nat. Cell Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1002\/jcsm.12045","article-title":"p62\/SQSTM1 but not LC3 is accumulated in sarcopenic muscle of mice","volume":"7","author":"Sakuma","year":"2016","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2087","DOI":"10.1128\/mcb.7.6.2087","article-title":"Functional expression of the cre-lox site-specific recombination system in the yeast Saccharomyces cerevisiae","volume":"7","author":"Sauer","year":"1987","journal-title":"Mol. Cell. Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1007\/s00535-017-1377-3","article-title":"Skeletal muscle mass to visceral fat area ratio is an important determinant affecting hepatic conditions of non-alcoholic fatty liver disease","volume":"53","author":"Shida","year":"2018","journal-title":"J. Gastroenterol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.1172\/JCI29069","article-title":"Inflammation and insulin resistance","volume":"116","author":"Shoelson","year":"2006","journal-title":"J. Clin. Invest."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1111\/j.1478-3231.2005.01130.x","article-title":"High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogen-activated protein kinase","volume":"25","author":"Sugimoto","year":"2005","journal-title":"Liver Int."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2112","DOI":"10.1002\/jcp.25653","article-title":"p62 promotes amino acid sensitivity of mTOR pathway and hepatic differentiation in adult liver stem\/progenitor cells","volume":"232","author":"Sugiyama","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1002\/hep.510290632","article-title":"Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: Differential effects on signal transduction pathways","volume":"29","author":"Svegliati-Baroni","year":"1999","journal-title":"Hepatology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.diabres.2018.05.041","article-title":"Role of serum myostatin in the association between hyperinsulinemia and muscle atrophy in Japanese obese patients","volume":"142","author":"Tanaka","year":"2018","journal-title":"Diabetes Res. Clin. Pract."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1002\/hep.24001","article-title":"Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis","volume":"52","author":"Tilg","year":"2010","journal-title":"Hepatology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1016\/j.ccell.2016.04.006","article-title":"p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells","volume":"29","author":"Umemura","year":"2016","journal-title":"Cancer Cell"},{"key":"B33","doi-asserted-by":"publisher","first-page":"8022","DOI":"10.1096\/fj.201900133R","article-title":"p62\/SQSTM1 and Nrf2 are essential for exercise-mediated enhancement of antioxidant protein expression in oxidative muscle","volume":"33","author":"Yamada","year":"2019","journal-title":"FASEB J."},{"key":"B34","doi-asserted-by":"publisher","first-page":"788","DOI":"10.3389\/fphys.2017.00788","article-title":"mTOR as a key regulator in maintaining skeletal muscle mass","volume":"8","author":"Yoon","year":"2017","journal-title":"Front. Physiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/j.jhep.2018.10.033","article-title":"Non-alcoholic fatty liver disease - a global public health perspective","volume":"70","author":"Younossi","year":"2019","journal-title":"J. Hepatol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1007\/s001250051457","article-title":"Insulin action and insulin resistance in human skeletal muscle","volume":"43","author":"Zierath","year":"2000","journal-title":"Diabetologia"}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.993995\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T09:54:30Z","timestamp":1668160470000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.993995\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,1]]},"references-count":36,"alternative-id":["10.3389\/fphys.2022.993995"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2022.993995","relation":{},"ISSN":["1664-042X"],"issn-type":[{"type":"electronic","value":"1664-042X"}],"subject":[],"published":{"date-parts":[[2022,11,1]]},"article-number":"993995"}}