A Mechanism for Statin-Induced Susceptibility to Myopathy
| Autor: | Lotteau, S, Ivarsson, N, Yang, Z, Restagno, D, Colyer, J, Hopkins, P, Weightman, A, Himori, K, Yamada, T, Bruton, J, Steele, D, Westerblad, H, Calaghan, S |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
FKBP12
FK506 binding protein (calstabin) exercise statin HMG CoA 3-hydroxy-3-methylglutaryl coenzyme A nutritional and metabolic diseases Ca2+ calcium SR sarcoplasmic reticulum calcium leak GAS gastrocnemius RyR ryanodine receptor TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling RNS reactive nitrogen species PRECLINICAL RESEARCH FDB flexor digitorum brevis PGC1α peroxisome proliferator-activated receptor γ co-activator 1α ROS reactive oxygen species HADHA hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase SOD superoxide dismutase L-NAME N(ω)-nitro-L-arginine methyl ester ryanodine receptor lipids (amino acids peptides and proteins) cardiovascular diseases NOS nitric oxide synthase myopathy |
| Zdroj: | JACC: Basic to Translational Science |
| ISSN: | 2452-302X |
| Popis: | Visual Abstract Highlights • The authors used human and rat muscle to study the mechanism of statin myopathy and its interaction with exercise. • Statin treatment triggered loss of the modulator protein FKBP from the sarcoplasmic reticulum (SR) calcium (Ca2+) release channel, ryanodine receptor 1 (RyR1). • Loss of FKBP was associated with reactive nitrogen species/reactive oxygen species-dependent SR Ca2+ leak and pro-apoptotic signaling, but had no overt impact on muscle function. • Moderate running wheel exercise prevented the effects of statin treatment on the FKBP/RyR complex, SR Ca2+ leak, and pro-apoptotic signaling. • Our data show that statin treatment induces a potentially harmful SR Ca2+ leak that might trigger statin myopathy in susceptible individuals, but could be prevented by moderate exercise. Summary 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. |
| Databáze: | OpenAIRE |
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