Statin administration activates system xC⁻ in skeletal muscle: a potential mechanism explaining statin-induced muscle pain

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.

Simvastatin improves mitochondrial respiration in peripheral blood cells

“…Importantly, we report here that increased myalgia trend with a significant increase in mitochondrial superoxide in PBMCs and platelets from statin users, while myalgia did not trend with other measures of mitochondrial respiration. This finding agrees with a recent study demonstrating a 41% increase in mitochondrial superoxide in mouse skeletal myotubes exposed to atorvastatin 50 . The study also demonstrated a statin-induced increase in glutamate efflux mediated by the xC - cysteine/glutamate antiporter, and argues that these factors could explain SAM 50 .…”

“…This finding agrees with a recent study demonstrating a 41% increase in mitochondrial superoxide in mouse skeletal myotubes exposed to atorvastatin 50 . The study also demonstrated a statin-induced increase in glutamate efflux mediated by the xC - cysteine/glutamate antiporter, and argues that these factors could explain SAM 50 .…”

Association of Metabolomic Change and Treatment Response in Patients with Non-Alcoholic Fatty Liver Disease

“…In addition, cystine levels and the sum of saturated/monounsaturated TGs were significantly altered in the S group. Cystine depletion in the S group can be explained by activation of the skeletal muscle system xC− (cystine/glutamate antiporter) induced by statin therapy, which causes myalgia [ 36 ].…”

Anti-HMGCR (Hydroxy-3-Methylglutaryl-CoA Reductase) Myopathy: A Rare Cause of Proximal Muscle Weakness

“…There has been increasing recognition of statin-associated myopathy, principally immune-mediated necrotizing myopathy (IMNM); however, it is still a relatively new entity and may not be initially considered in the differential for diffuse weakness [2,3]. The myalgia and myositis often associated with statin use have many proposed mechanisms including the inhibition of the production of CoQ 10, leading to mitochondrial dysfunction, increase in interstitial glutamate, sarcoplasmic reticulum calcium leak, and upregulation of genes involved in protein catabolism and the ubiquitinproteosome system [4][5][6][7]. While these adverse effects of statin use are unfortunate, they are often reversible upon discontinuation of the statin medication.…”