Statin Administration Activates System xC - in Skeletal Muscle: A Potential Mechanism Explaining Statin-Induced Muscle Pain

Am J Physiol Cell Physiol. 2019 Nov 1;317(5):C894-C899. doi: 10.1152/ajpcell.00308.2019. Epub 2019 Sep 11.

Abstract

Statins are a cholesterol-lowering drug class that significantly reduce cardiovascular disease risk. Despite their safety and effectiveness, musculoskeletal side-effects, particularly myalgia, are prominent and the most common reason for discontinuance. The cause of statin-induced myalgia is unknown, so defining the underlying mechanism(s) and potential therapeutic strategies is of clinical importance. Here we tested the hypothesis that statin administration activates skeletal muscle system xC-, a cystine/glutamate antiporter, to increase intracellular cysteine and therefore glutathione synthesis to attenuate statin-induced oxidative stress. Increased system xC- activity would increase interstitial glutamate; an amino acid associated with peripheral nociception. Consistent with our hypothesis, atorvastatin treatment significantly increased mitochondrial reactive oxygen species (ROS; 41%) and glutamate efflux (up to 122%) in C2C12 mouse skeletal muscle myotubes. Statin-induced glutamate efflux was confirmed to be the result of system xC- activation, as cotreatment with sulfasalazine (system xC- inhibitor) negated this rise in extracellular glutamate. These findings were reproduced in primary human myotubes but, consistent with being muscle-specific, were not observed in primary human dermal fibroblasts. To further demonstrate that statin-induced increases in ROS triggered glutamate efflux, C2C12 myotubes were cotreated with atorvastatin and various antioxidants. α-Tocopherol and cysteamine bitartrate reversed the increase in statin-induced glutamate efflux, bringing glutamate levels between 50 and 92% of control-treated levels. N-acetylcysteine (a system xC- substrate) increased glutamate efflux above statin treatment alone: up to 732% greater than control treatment. Taken together, we provide a mechanistic foundation for statin-induced myalgia and offer therapeutic insights to alleviate this particular statin-associated side-effect.

Keywords: HMG-CoA reductase; glutamate; myalgia; oxidative stress; pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System y+ / metabolism*
  • Animals
  • Atorvastatin / adverse effects
  • Atorvastatin / pharmacology
  • Cell Line
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Mice
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism*
  • Myalgia / chemically induced*
  • Myalgia / metabolism*
  • Myoblasts / drug effects
  • Myoblasts / metabolism

Substances

  • Amino Acid Transport System y+
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • SLC7A11 protein, human
  • Atorvastatin