A Mechanism for Statin-Induced Susceptibility to Myopathy

Sabine Lotteau; Niklas Ivarsson; Zhaokang Yang; Damien Restagno; John Colyer; Philip Hopkins; Andrew Weightman; Koichi Himori; Takashi Yamada; Joseph Bruton; Derek Steele; Håkan Westerblad; Sarah Calaghan

doi:10.1016/j.jacbts.2019.03.012

A Mechanism for Statin-Induced Susceptibility to Myopathy

JACC Basic Transl Sci. 2019 Aug 26;4(4):509-523. doi: 10.1016/j.jacbts.2019.03.012. eCollection 2019 Aug.

Authors

Affiliations

¹ School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
² Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
³ VetAgro Sup, APCSe, Université de Lyon, Marcy l'Etoile, France.
⁴ Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom.
⁵ School of Mechanical, Aerospace and Civil Engineering, University of Manchester, Manchester, United Kingdom.
⁶ Graduate School of Health Sciences, Sapporo Medical University, Chuo-ku, Sapporo, Japan.

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.

Keywords: Ca2+, calcium; FDB, flexor digitorum brevis; FKBP12, FK506 binding protein (calstabin); GAS, gastrocnemius; HADHA, hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase; HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme A; L-NAME, N(ω)-nitro-L-arginine methyl ester; NOS, nitric oxide synthase; PGC1α, peroxisome proliferator-activated receptor γ co-activator 1α; RNS, reactive nitrogen species; ROS, reactive oxygen species; RyR, ryanodine receptor; SOD, superoxide dismutase; SR, sarcoplasmic reticulum; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; calcium leak; exercise; myopathy; ryanodine receptor; statin.