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Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance.
J Am Coll Cardiol. 2013 Jan 08; 61(1):44-53.JACC

Abstract

OBJECTIVES

Glucose tolerance and skeletal muscle coenzyme Q(10) (Q(10)) content, mitochondrial density, and mitochondrial oxidative phosphorylation (OXPHOS) capacity were measured in simvastatin-treated patients (n = 10) and in well-matched control subjects (n = 9).

BACKGROUND

A prevalent side effect of statin therapy is muscle pain, and yet the basic mechanism behind it remains unknown. We hypothesize that a statin-induced reduction in muscle Q(10) may attenuate mitochondrial OXPHOS capacity, which may be an underlying mechanism.

METHODS

Plasma glucose and insulin concentrations were measured during an oral glucose tolerance test. Mitochondrial OXPHOS capacity was measured in permeabilized muscle fibers by high-resolution respirometry in a cross-sectional design. Mitochondrial content (estimated by citrate synthase [CS] activity, cardiolipin content, and voltage-dependent anion channel [VDAC] content) as well as Q(10) content was determined.

RESULTS

Simvastatin-treated patients had an impaired glucose tolerance and displayed a decreased insulin sensitivity index. Regarding mitochondrial studies, Q(10) content was reduced (p = 0.05), whereas mitochondrial content was similar between the groups. OXPHOS capacity was comparable between groups when complex I- and complex II-linked substrates were used alone, but when complex I + II-linked substrates were used (eliciting convergent electron input into the Q intersection [maximal ex vivo OXPHOS capacity]), a decreased (p < 0.01) capacity was observed in the patients compared with the control subjects.

CONCLUSIONS

These simvastatin-treated patients were glucose intolerant. A decreased Q(10) content was accompanied by a decreased maximal OXPHOS capacity in the simvastatin-treated patients. It is plausible that this finding partly explains the muscle pain and exercise intolerance that many patients experience with their statin treatment.

Authors+Show Affiliations

Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. stelar@sund.ku.dkNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23287371

Citation

Larsen, Steen, et al. "Simvastatin Effects On Skeletal Muscle: Relation to Decreased Mitochondrial Function and Glucose Intolerance." Journal of the American College of Cardiology, vol. 61, no. 1, 2013, pp. 44-53.
Larsen S, Stride N, Hey-Mogensen M, et al. Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. J Am Coll Cardiol. 2013;61(1):44-53.
Larsen, S., Stride, N., Hey-Mogensen, M., Hansen, C. N., Bang, L. E., Bundgaard, H., Nielsen, L. B., Helge, J. W., & Dela, F. (2013). Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. Journal of the American College of Cardiology, 61(1), 44-53. https://doi.org/10.1016/j.jacc.2012.09.036
Larsen S, et al. Simvastatin Effects On Skeletal Muscle: Relation to Decreased Mitochondrial Function and Glucose Intolerance. J Am Coll Cardiol. 2013 Jan 8;61(1):44-53. PubMed PMID: 23287371.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. AU - Larsen,Steen, AU - Stride,Nis, AU - Hey-Mogensen,Martin, AU - Hansen,Christina N, AU - Bang,Lia E, AU - Bundgaard,Henning, AU - Nielsen,Lars B, AU - Helge,Jørn W, AU - Dela,Flemming, PY - 2012/08/20/received PY - 2012/09/18/revised PY - 2012/09/25/accepted PY - 2013/1/5/entrez PY - 2013/1/5/pubmed PY - 2013/3/13/medline SP - 44 EP - 53 JF - Journal of the American College of Cardiology JO - J. Am. Coll. Cardiol. VL - 61 IS - 1 N2 - OBJECTIVES: Glucose tolerance and skeletal muscle coenzyme Q(10) (Q(10)) content, mitochondrial density, and mitochondrial oxidative phosphorylation (OXPHOS) capacity were measured in simvastatin-treated patients (n = 10) and in well-matched control subjects (n = 9). BACKGROUND: A prevalent side effect of statin therapy is muscle pain, and yet the basic mechanism behind it remains unknown. We hypothesize that a statin-induced reduction in muscle Q(10) may attenuate mitochondrial OXPHOS capacity, which may be an underlying mechanism. METHODS: Plasma glucose and insulin concentrations were measured during an oral glucose tolerance test. Mitochondrial OXPHOS capacity was measured in permeabilized muscle fibers by high-resolution respirometry in a cross-sectional design. Mitochondrial content (estimated by citrate synthase [CS] activity, cardiolipin content, and voltage-dependent anion channel [VDAC] content) as well as Q(10) content was determined. RESULTS: Simvastatin-treated patients had an impaired glucose tolerance and displayed a decreased insulin sensitivity index. Regarding mitochondrial studies, Q(10) content was reduced (p = 0.05), whereas mitochondrial content was similar between the groups. OXPHOS capacity was comparable between groups when complex I- and complex II-linked substrates were used alone, but when complex I + II-linked substrates were used (eliciting convergent electron input into the Q intersection [maximal ex vivo OXPHOS capacity]), a decreased (p < 0.01) capacity was observed in the patients compared with the control subjects. CONCLUSIONS: These simvastatin-treated patients were glucose intolerant. A decreased Q(10) content was accompanied by a decreased maximal OXPHOS capacity in the simvastatin-treated patients. It is plausible that this finding partly explains the muscle pain and exercise intolerance that many patients experience with their statin treatment. SN - 1558-3597 UR - https://www.unboundmedicine.com/medline/citation/23287371/Simvastatin_effects_on_skeletal_muscle:_relation_to_decreased_mitochondrial_function_and_glucose_intolerance_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0735-1097(12)05294-1 DB - PRIME DP - Unbound Medicine ER -