{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T02:19:08Z","timestamp":1790302748331,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,9,11]],"date-time":"2018-09-11T00:00:00Z","timestamp":1536624000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>A pharmacologic strategy for age\u2010related muscle weakness is desired to improve mortality and disability in the elderly. Angiotensin\u2010converting enzyme 2 (ACE2) cleaves angiotensin II into angiotensin 1\u20107, a peptide known to protect against acute and chronic skeletal muscle injury in rodents. Since physiological aging induces muscle weakness via mechanisms distinct from other muscle disorders, the role of ACE2\u2010angiotensin 1\u20107 in age\u2010related muscle weakness remains undetermined. Here, we investigated whether deletion of ACE2 alters the development of muscle weakness by aging and whether angiotensin 1\u20107 reverses muscle weakness in older mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>After periodic measurement of grip strength and running distance in male ACE2KO and wild\u2010type mice until 24\u2009months of age, we infused angiotensin 1\u20107 or vehicle for 4\u2009weeks, and measured grip strength, and excised tissues. Tissues were also excised from younger (3\u2010month\u2010old) and middle\u2010aged (15\u2010month\u2010old) mice. Microarray analysis of RNA was performed using tibialis anterior (TA) muscles from middle\u2010aged mice, and some genes were further tested using RT\u2010PCR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Grip strength of ACE2KO mice was reduced at 6\u2009months and was persistently lower than that of wild\u2010type mice (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01 at 6, 12, 18, and 24\u2010month\u2010old). Running distance of ACE2KO mice was shorter than that of wild\u2010type mice only at 24\u2009months of age [371\u2009\u00b1\u200926 vs. 479\u2009\u00b1\u200924 (m), <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01]. Angiotensin 1\u20107 improved grip strength in both types of older mice, with larger effects observed in ACE2KO mice (% increase, 3.8\u2009\u00b1\u20091.5 and 13.3\u2009\u00b1\u20093.1 in wild type and ACE2KO mice, respectively). Older, but not middle\u2010aged ACE2KO mice had higher oxygen consumption assessed by a metabolic cage than age\u2010matched wild\u2010type mice. Angiotensin 1\u20107 infusion modestly increased oxygen consumption in older mice. There was no difference in a wheel\u2010running activity or glucose tolerance between ACE2KO and wild\u2010type mice and between mice with vehicle and angiotensin 1\u20107 infusion. Analysis of TA muscles revealed that <jats:italic>p16INK4a<\/jats:italic>, a senescence\u2010associated gene, and central nuclei of myofibers increased in middle\u2010aged, but not younger ACE2KO mice. <jats:italic>p16INK4a<\/jats:italic> and central nuclei increased in TA muscles of older wild\u2010type mice, but the differences between ACE2KO and wild\u2010type mice remained significant (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). Angiotensin 1\u20107 did not alter the expression of p16INK4a or central nuclei in TA muscles of both types of mice. Muscle <jats:italic>ACE2<\/jats:italic> expression of wild\u2010type mice was the lowest at middle age (2.6 times lower than younger age, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Deletion of ACE2 induced the early manifestation of muscle weakness with signatures of muscle senescence. Angiotensin 1\u20107 improved muscle function in older mice, supporting future application of the peptide or its analogues in the treatment of muscle weakness in the elderly population.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12334","type":"journal-article","created":{"date-parts":[[2018,9,12]],"date-time":"2018-09-12T05:53:47Z","timestamp":1536731627000},"page":"975-986","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Angiotensin\u2010converting enzyme 2 deficiency accelerates and angiotensin 1\u20107 restores age\u2010related muscle weakness in mice"],"prefix":"10.1002","volume":"9","author":[{"given":"Hikari","family":"Takeshita","sequence":"first","affiliation":[{"name":"Department of Geriatric and General Medicine, Graduate School of Medicine Osaka University  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Geriatric and General Medicine, Graduate School of Medicine Osaka University  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoko","family":"Nozato","sequence":"additional","affiliation":[{"name":"Department of Geriatric and General Medicine, Graduate School of Medicine Osaka University  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masao","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Geriatric and General Medicine, Graduate School of Medicine Osaka University  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So\u2010ichiro","family":"Fukada","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences Osaka University  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadakatsu","family":"Inagaki","sequence":"additional","affiliation":[{"name":"Department of Cardiac Physiology National Cerebral and Cardiovascular Center Research Institute  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotsugu","family":"Tsuchimochi","sequence":"additional","affiliation":[{"name":"Department of Cardiac Physiology National Cerebral and Cardiovascular Center Research Institute  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikiyasu","family":"Shirai","sequence":"additional","affiliation":[{"name":"Department of Cardiac Physiology National Cerebral and Cardiovascular Center Research Institute  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichi","family":"Nozato","sequence":"additional","affiliation":[{"name":"Department of Geriatric and General Medicine, Graduate School of Medicine Osaka University  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Fujimoto","sequence":"additional","affiliation":[{"name":"Department of Geriatric and General Medicine, Graduate School of Medicine Osaka University  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Imaizumi","sequence":"additional","affiliation":[{"name":"Department of Geriatric and General Medicine, Graduate School of Medicine Osaka University  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serina","family":"Yokoyama","sequence":"additional","affiliation":[{"name":"Department of Geriatric and General Medicine, Graduate School of Medicine Osaka University  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motonori","family":"Nagasawa","sequence":"additional","affiliation":[{"name":"Department of Geriatric and General Medicine, Graduate School of Medicine Osaka University  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Go","family":"Hamano","sequence":"additional","affiliation":[{"name":"Department of Geriatric and General Medicine, Graduate School of Medicine Osaka University  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Hongyo","sequence":"additional","affiliation":[{"name":"Department of Geriatric and General Medicine, Graduate School of Medicine Osaka University  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuo","family":"Kawai","sequence":"additional","affiliation":[{"name":"Department of Geriatric and General Medicine, Graduate School of Medicine Osaka University  Suita Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Hanasaki\u2010Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Geriatric and General 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