{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T07:27:52Z","timestamp":1768030072739,"version":"3.49.0"},"reference-count":58,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2015,11,2]],"date-time":"2015-11-02T00:00:00Z","timestamp":1446422400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Deficiency of dysferlin causes limb\u2010girdle muscular dystrophy 2B and Miyoshi myopathy with cardiac involvement that leads to dilated cardiomyopathy and heart failure. The pathogenesis and pathophysiology of dysferlin cardiomyopathy are not fully understood.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We studied cardiac phenotypes of young dysferlin gene knockout mice to investigate the primary pathological and pathophysiological changes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In comparison with wild\u2010type controls, dysferlin\u2010deficient cardiomyocytes showed slower Ca<jats:sup>2+<\/jats:sup> re\u2010sequestration, and dysferlin deficiency blunted the \u03b2\u2010adrenergic effect on relaxation and pumping function of <jats:italic>ex vivo<\/jats:italic> working hearts.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Dysferlin deficiency increased phosphorylation of ventricular myosin light chain 2, suggesting a compensatory response to the impaired cardiac lusitropic function.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The data suggest that delayed calcium re\u2010sequestration and post\u2010translational modification of myofilament proteins may provide potential targets to develop new treatments for dysferlin cardiomyopathy.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Dysferlin is a cell membrane bound protein with a role in the repair of skeletal and cardiac muscle cells. Deficiency of dysferlin leads to limb\u2010girdle muscular dystrophy 2B (LGMD2B) and Miyoshi myopathy. In cardiac muscle, dysferlin is located at the intercalated disc and transverse tubule membranes. Loss of dysferlin causes death of cardiomyocytes, notably in ageing hearts, leading to dilated cardiomyopathy and heart failure in LGM2B patients. To understand the primary pathogenesis and pathophysiology of dysferlin cardiomyopathy, we studied cardiac phenotypes of young adult dysferlin knockout mice and found early myocardial hypertrophy with largely compensated baseline cardiac function. Cardiomyocytes isolated from dysferlin\u2010deficient mice showed normal shortening and re\u2010lengthening velocities in the absence of external load with normal peak systolic Ca<jats:sup>2+<\/jats:sup> but slower Ca<jats:sup>2+<\/jats:sup> re\u2010sequestration than wild\u2010type controls. The effects of isoproterenol on relaxation velocity, left ventricular systolic pressure and stroke volume were blunted in dysferlin\u2010deficient mouse hearts compared with that in wild\u2010type hearts. Young dysferlin\u2010deficient mouse hearts expressed normal isoforms of myofilament proteins whereas the phosphorylation of ventricular myosin light chain 2 was significantly increased, implying a molecular response to the impaired lusitropic function. These early phenotypes of diastolic cardiac dysfunction and blunted lusitropic response of cardiac muscle to \u03b2\u2010adrenergic stimulation indicate a novel pathogenic mechanism of dysferlin cardiomyopathy.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp271225","type":"journal-article","created":{"date-parts":[[2015,9,29]],"date-time":"2015-09-29T10:14:01Z","timestamp":1443521641000},"page":"5127-5144","source":"Crossref","is-referenced-by-count":13,"title":["Dysferlin deficiency blunts \u03b2\u2010adrenergic\u2010dependent lusitropic function of mouse heart"],"prefix":"10.1113","volume":"593","author":[{"given":"Bin","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Physiology Wayne State University School of Medicine  Detroit MI 48201 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongguang","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Physiology Wayne State University School of Medicine  Detroit MI 48201 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