{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T10:43:22Z","timestamp":1768560202538,"version":"3.49.0"},"reference-count":54,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2015,6,15]],"date-time":"2015-06-15T00:00:00Z","timestamp":1434326400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL14388"],"award-info":[{"award-number":["HL14388"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Experimental Physiology"],"published-print":{"date-parts":[[2015,7]]},"abstract":"<jats:sec><jats:title>New Findings<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item>\n<jats:p><jats:bold>What is the central question of this study?<\/jats:bold><\/jats:p>\n<jats:p>Is autonomic dysregulation in a mouse model of muscular dystrophy dependent on left ventricular systolic dysfunction and\/or activation of the renin\u2013angiotensin system (RAS) and does it predict development of dilated cardiomyopathy (DCM)?<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p><jats:bold>What is the main finding and its importance?<\/jats:bold><\/jats:p>\n<jats:p>The results demonstrate that autonomic dysregulation precedes and predicts left ventricular dysfunction and DCM in sarcoglycan\u2010\u03b4\u2010deficient (<jats:italic>Sgcd<\/jats:italic>\u2212\/\u2212) mice. The autonomic dysregulation is prevented by treatment of young <jats:italic>Sgcd<\/jats:italic>\u2212\/\u2212 mice with the angiotensin\u00a0II type\u00a01 receptor blocker losartan. Measurements of RAS activation and autonomic dysregulation may predict risk of DCM, and therapies targeting the RAS and autonomic dysregulation at a young age may slow disease progression in patients.<\/jats:p>\n<\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>Sarcoglycan mutations cause muscular dystrophy. Patients with muscular dystrophy develop autonomic dysregulation and dilated cardiomyopathy (DCM), but the temporal relationship and mechanism of autonomic dysregulation are not well understood. We hypothesized that activation of the renin\u2013angiotensin system (RAS) causes autonomic dysregulation prior to development of DCM in sarcoglycan\u2010\u03b4\u2010deficient (<jats:italic>Sgcd<\/jats:italic>\u2212\/\u2212) mice and that the severity of autonomic dysfunction at a young age predicts the severity of DCM at older ages. At 10\u201312\u00a0weeks of age, when left ventricular function assessed by echocardiography remained normal, <jats:italic>Sgcd<\/jats:italic>\u2212\/\u2212 mice exhibited decreases in arterial pressure, locomotor activity, baroreflex sensitivity and cardiovagal tone and increased sympathetic tone compared with age\u2010matched C57BL\/6 control mice (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Systemic and skeletal muscle RAS were activated, and angiotensin\u00a0II type\u00a01 receptor (AT<jats:sub>1<\/jats:sub>R) expression, superoxide and fibrosis were increased in dystrophic skeletal muscle (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Treatment with the AT<jats:sub>1<\/jats:sub>R blocker losartan for 7\u20139\u00a0weeks beginning at 3\u00a0weeks of age prevented or strongly attenuated the abnormalities in <jats:italic>Sgcd<\/jats:italic>\u2212\/\u2212 mice (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Repeated assessment of phenotypes between 10 and 75\u00a0weeks of age demonstrated worsening of autonomic function, progressive cardiac dysfunction and DCM and increased mortality in <jats:italic>Sgcd<\/jats:italic>\u2212\/\u2212 mice. High sympathetic tone predicted subsequent left ventricular dysfunction. We conclude that activation of the RAS causes severe autonomic dysregulation in young <jats:italic>Sgcd<\/jats:italic>\u2212\/\u2212 mice, which portends a worse long\u2010term prognosis. Therapeutic targeting of the RAS at a young age may improve autonomic function and slow disease progression in muscular dystrophy.<\/jats:p><\/jats:sec>","DOI":"10.1113\/ep085066","type":"journal-article","created":{"date-parts":[[2015,4,29]],"date-time":"2015-04-29T10:23:18Z","timestamp":1430302998000},"page":"776-795","source":"Crossref","is-referenced-by-count":7,"title":["Angiotensin\u2010dependent autonomic dysregulation precedes dilated cardiomyopathy in a mouse model of muscular dystrophy"],"prefix":"10.1113","volume":"100","author":[{"given":"Rasna","family":"Sabharwal","sequence":"first","affiliation":[{"name":"Department of Internal Medicine University of Iowa Carver College of Medicine  Iowa City IA 52242 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert M.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Iowa Carver College of Medicine  Iowa City IA 52242 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