Deletion of obscurin immunoglobulin domains Ig58/59 leads to age-dependent cardiac remodeling and arrhythmia
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ORIGINAL CONTRIBUTION
Deletion of obscurin immunoglobulin domains Ig58/59 leads to age‑dependent cardiac remodeling and arrhythmia Alyssa Grogan1 · Andrew Coleman2 · Humberto Joca2 · Henk Granzier3 · Mark W. Russel4 · Christopher W. Ward2 · Aikaterini Kontrogianni‑Konstantopoulos1 Received: 16 April 2020 / Accepted: 6 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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-ΔIg58/59, 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-ΔIg58/59 mice are susceptible to acute β-adrenergic stress. Moreover, sedentary Obscn-ΔIg58/59 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 Ca2+ cycling associated with changes in the expression and/or phosphorylation levels of major Ca2+ cycling proteins, including PLN, SERCA2, and RyR2. Taken together, our work demonstrates that obscurinIg58/59 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 Ca2+ cycling. Keywords Obscurin · Hypertrophy · Dilation · Ca2+ cycling · Phospholamban · SERCA · Ryanodine receptor · Sex dimorphism
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00395-020-00818-8) contains supplementary material, which is available to authorized users. * Aikaterini Kontrogianni‑Konstantopoulos [email protected] 1
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
2
Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
3
Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85724, USA
4
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Obscurins, expressed from the single OBSCN gene, are a family of giant modular proteins (720–870 kDa) surrounding sarcomeric M-bands and Z-disks where they play key structural
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