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Deletion of obscurin immunoglobulin domains Ig58/59 leads to age-dependent cardiac remodeling and arrhythmia

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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 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 Ca2+ cycling.

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Acknowledgements

The authors wish to thank Dr. Maegen Ackermann for propagating the Obscn-ΔIg58/59 mouse model and Dr. Li-Yen Rebecca Hu for propagating the Obscn-ΔIg58/59 mouse model and performing pilot studies.

Funding

This work was supported by the National Institutes of Health [Training Program in Muscle Biology, T32 AR007592-17 to A.G. and A.C., R35HL144998 to H.G, and R01AR071618 and R01AR071614 to C.W.W.]; and the American Heart Association [Grant In Aid 16GRNT31290010 to A.K.K. and AHA 19POST34450156 to H.J.].

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Alyssa Grogan & Aikaterini Kontrogianni-Konstantopoulos

  2. Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Andrew Coleman, Humberto Joca & Christopher W. Ward

  3. Department of Physiology, University of Arizona College of Medicine, Tucson, AZ, 85724, USA

    Henk Granzier

  4. Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Mark W. Russel

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  1. Alyssa Grogan
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Grogan, A., Coleman, A., Joca, H. et al. Deletion of obscurin immunoglobulin domains Ig58/59 leads to age-dependent cardiac remodeling and arrhythmia. Basic Res Cardiol 115, 60 (2020). https://doi.org/10.1007/s00395-020-00818-8

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