Lotteau, S, Ivarsson, N, Yang, Z et al. (10 more authors) (2019) A Mechanism for Statin-Induced Susceptibility to Myopathy. JACC: Basic to Translational Science, 4 (4). pp. 509-523. ISSN 2452-302X
Abstract
This study aimed to identify a mechanism for statin-induced myopathy that explains its prevalence and selectivity for skeletal muscle, and to understand its interaction with moderate exercise. Statin-associated adverse muscle symptoms reduce adherence to statin therapy; this limits the effectiveness of statins in reducing cardiovascular risk. The issue is further compounded by perceived interactions between statin treatment and exercise. This study examined muscles from individuals taking statins and rats treated with statins for 4 weeks. In skeletal muscle, statin treatment caused dissociation of the stabilizing protein FK506 binding protein (FKBP12) from the sarcoplasmic reticulum (SR) calcium (Ca2+) release channel, the ryanodine receptor 1, which was associated with pro-apoptotic signaling and reactive nitrogen species/reactive oxygen species (RNS/ROS)−dependent spontaneous SR Ca2+ release events (Ca2+ sparks). Statin treatment had no effect on Ca2+ spark frequency in cardiac myocytes. Despite potentially deleterious effects of statins on skeletal muscle, there was no impact on force production or SR Ca2+ release in electrically stimulated muscle fibers. Statin-treated rats with access to a running wheel ran further than control rats; this exercise normalized FKBP12 binding to ryanodine receptor 1, preventing the increase in Ca2+ sparks and pro-apoptotic signaling. Statin-mediated RNS/ROS−dependent destabilization of SR Ca2+ handling has the potential to initiate skeletal (but not cardiac) myopathy in susceptible individuals. Importantly, although exercise increases RNS/ROS, it did not trigger deleterious statin effects on skeletal muscle. Indeed, our results indicate that moderate exercise might benefit individuals who take statins.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 The Authors. Published By Elsevier On Behalf Of The Americancollege Of Cardiology Foundation. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
Keywords: | calcium leak; exercise; myopathy; ryanodine receptor; statin |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Biomed & Clin Sciences (LIBACS) (Leeds) > Trans Anaesthetics & Surgical Sciences (Leeds) |
Funding Information: | Funder Grant number British Heart Foundation PG/12/88/29951 |
Depositing User: | Symplectic Publications |
Date Deposited: | 29 Mar 2019 14:56 |
Last Modified: | 29 Aug 2019 15:23 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.jacbts.2019.03.012 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:144223 |