Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy

Kyrychenko, S.; Polakova, E.; Kang, C.; Pocsai, K.; Ullrich, Nina D.; Niggli, Ernst; Shirokova, N. (2013). Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy. Cardiovascular research, 97(4), pp. 666-675. Oxford University Press 10.1093/cvr/cvs425

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CVR-2012-983-4.pdf.pdf - Accepted Version
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AIMS:Duchenne muscular dystrophy (DMD) is a muscle disease with serious cardiac complications. Changes in Ca(2+) homeostasis and oxidative stress were recently associated with cardiac deterioration, but the cellular pathophysiological mechanisms remain elusive. We investigated whether the activity of ryanodine receptor (RyR) Ca(2+) release channels is affected, whether changes in function are cause or consequence and which post-translational modifications drive disease progression. METHODS AND RESULTS:Electrophysiological, imaging, and biochemical techniques were used to study RyRs in cardiomyocytes from mdx mice, an animal model of DMD. Young mdx mice show no changes in cardiac performance, but do so after ∼8 months. Nevertheless, myocytes from mdx pups exhibited exaggerated Ca(2+) responses to mechanical stress and 'hypersensitive' excitation-contraction coupling, hallmarks of increased RyR Ca(2+) sensitivity. Both were normalized by antioxidants, inhibitors of NAD(P)H oxidase and CaMKII, but not by NO synthases and PKA antagonists. Sarcoplasmic reticulum Ca(2+) load and leak were unchanged in young mdx mice. However, by the age of 4-5 months and in senescence, leak was increased and load was reduced, indicating disease progression. By this age, all pharmacological interventions listed above normalized Ca(2+) signals and corrected changes in ECC, Ca(2+) load, and leak. CONCLUSION:Our findings suggest that increased RyR Ca(2+) sensitivity precedes and presumably drives the progression of dystrophic cardiomyopathy, with oxidative stress initiating its development. RyR oxidation followed by phosphorylation, first by CaMKII and later by PKA, synergistically contributes to cardiac deterioration.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Physiology
09 Interdisciplinary Units > Microscopy Imaging Center (MIC)

UniBE Contributor:

Ullrich, Nina and Niggli, Ernst

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0008-6363

Publisher:

Oxford University Press

Language:

English

Submitter:

Ernst Niggli

Date Deposited:

02 Jun 2014 14:17

Last Modified:

28 Oct 2019 13:56

Publisher DOI:

10.1093/cvr/cvs425

PubMed ID:

23263329

BORIS DOI:

10.7892/boris.45841

URI:

https://boris.unibe.ch/id/eprint/45841

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