| First Author | Grogan A | Year | 2020 |
| Journal | Basic Res Cardiol | Volume | 115 |
| Issue | 6 | Pages | 60 |
| PubMed ID | 32910221 | Mgi Jnum | J:302919 |
| Mgi Id | MGI:6510929 | Doi | 10.1007/s00395-020-00818-8 |
| Citation | Grogan A, et al. (2020) Deletion of obscurin immunoglobulin domains Ig58/59 leads to age-dependent cardiac remodeling and arrhythmia. Basic Res Cardiol 115(6):60 |
| abstractText | Obscurin comprises a family of giant modular proteins that play key structural and regulatory roles in striated muscles. Immunoglobulin domains 58/59 (Ig58/59) of obscurin mediate binding to essential modulators of muscle structure and function, including canonical titin, a smaller splice variant of titin, termed novex-3, and phospholamban (PLN). Importantly, missense mutations localized within the obscurin-Ig58/59 region that affect binding to titins and/or PLN have been linked to the development of myopathy in humans. To elucidate the pathophysiological role of this region, we generated a constitutive deletion mouse model, Obscn-DeltaIg58/59, that expresses obscurin lacking Ig58/59, and determined the consequences of this manipulation on cardiac morphology and function under conditions of acute stress and through the physiological process of aging. Our studies show that young Obscn-DeltaIg58/59 mice are susceptible to acute beta-adrenergic stress. Moreover, sedentary Obscn-DeltaIg58/59 mice develop left ventricular hypertrophy that progresses to dilation, contractile impairment, atrial enlargement, and arrhythmia as a function of aging with males being more affected than females. Experiments in ventricular cardiomyocytes revealed altered Ca(2+) cycling associated with changes in the expression and/or phosphorylation levels of major Ca(2+) cycling proteins, including PLN, SERCA2, and RyR2. Taken together, our work demonstrates that obscurin-Ig58/59 is an essential regulatory module in the heart and its deletion leads to age- and sex-dependent cardiac remodeling, ventricular dilation, and arrhythmia due to deregulated Ca(2+) cycling. |
