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Statin administration activates system xC- in skeletal muscle: a potential mechanism explaining statin-induced muscle pain.
Am J Physiol Cell Physiol 2019; 317(5):C894-C899AJ

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.

Authors+Show Affiliations

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31509447

Citation

Rebalka, Irena A., et al. "Statin Administration Activates System xC- in Skeletal Muscle: a Potential Mechanism Explaining Statin-induced Muscle Pain." American Journal of Physiology. Cell Physiology, vol. 317, no. 5, 2019, pp. C894-C899.
Rebalka IA, Cao AW, May LL, et al. Statin administration activates system xC- in skeletal muscle: a potential mechanism explaining statin-induced muscle pain. Am J Physiol, Cell Physiol. 2019;317(5):C894-C899.
Rebalka, I. A., Cao, A. W., May, L. L., Tarnopolsky, M. A., & Hawke, T. J. (2019). Statin administration activates system xC- in skeletal muscle: a potential mechanism explaining statin-induced muscle pain. American Journal of Physiology. Cell Physiology, 317(5), pp. C894-C899. doi:10.1152/ajpcell.00308.2019.
Rebalka IA, et al. 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. PubMed PMID: 31509447.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Statin administration activates system xC- in skeletal muscle: a potential mechanism explaining statin-induced muscle pain. AU - Rebalka,Irena A, AU - Cao,Andrew W, AU - May,Linda L, AU - Tarnopolsky,Mark A, AU - Hawke,Thomas J, Y1 - 2019/09/11/ PY - 2019/9/12/pubmed PY - 2019/9/12/medline PY - 2019/9/12/entrez KW - HMG-CoA reductase KW - glutamate KW - myalgia KW - oxidative stress KW - pain SP - C894 EP - C899 JF - American journal of physiology. Cell physiology JO - Am. J. Physiol., Cell Physiol. VL - 317 IS - 5 N2 - 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. SN - 1522-1563 UR - https://www.unboundmedicine.com/medline/citation/31509447/Statin_administration_activates_System_Xc-_in_skeletal_muscle:_a_potential_mechanism_explaining_statin-induced_muscle_pain L2 - http://www.physiology.org/doi/full/10.1152/ajpcell.00308.2019?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -