Author + information
- Received January 24, 2019
- Revision received March 27, 2019
- Accepted March 27, 2019
- Published online August 26, 2019.
- Sabine Lotteau, PhDa,
- Niklas Ivarsson, PhDb,†,
- Zhaokang Yang, PhDa,
- Damien Restagno, PhDc,
- John Colyer, PhDa,
- Philip Hopkins, MDd,
- Andrew Weightman, PhDe,
- Koichi Himori, MScf,
- Takashi Yamada, PhDf,
- Joseph Bruton, PhDb,
- Derek Steele, PhDa,
- Håkan Westerblad, MD, PhDb,∗ and
- Sarah Calaghan, PhDa,∗∗ ()
- aSchool of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
- bDepartment of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- cVetAgro Sup, APCSe, Université de Lyon, Marcy l’Etoile, France
- dLeeds Institute of Medical Research at St James’s, University of Leeds, Leeds, United Kingdom
- eSchool of Mechanical, Aerospace and Civil Engineering, University of Manchester, Manchester, United Kingdom
- fGraduate School of Health Sciences, Sapporo Medical University, Chuo-ku, Sapporo, Japan
- ↵∗Address for correspondence:
Dr. Sarah Calaghan, School of Biomedical Sciences, Garstang Building, University of Leeds, Leeds LS2 9JT, United Kingdom.
• 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.
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.
↵∗ Prof. Westerblad and Dr. Calaghan contributed equally to this work and are joint senior authors.
↵† Dr. Ivarsson is deceased.
This work was supported by a British Heart Foundation project grant (PG/12/88/29951; 80%) and a Swedish Research Council project grant (Medicine and Health, K2014-52X-10842-21-5; 20%). Prof. Colyer is the founder and CEO of Badrilla, a life science company. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received January 24, 2019.
- Revision received March 27, 2019.
- Accepted March 27, 2019.
- 2019 The Authors