Tags

Type your tag names separated by a space and hit enter

Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers.
Toxicol Appl Pharmacol. 2012 Sep 15; 263(3):281-6.TA

Abstract

Statin use may be limited by muscle side effects. Although incompletely understood to date, their pathophysiology may involve oxidative stress and impairments of mitochondrial function and of muscle Ca(2+) homeostasis. In order to simultaneously assess these mechanisms, 24 male healthy volunteers were randomized to receive either simvastatin for 80 mg daily or placebo for 8 weeks. Blood and urine samples and a stress test were performed at baseline and at follow-up, and mitochondrial respiration and Ca(2+) spark properties were evaluated on a muscle biopsy 4 days before the second stress test. Simvastatin-treated subjects were separated according to their median creatine kinase (CK) increase. Simvastatin treatment induced a significant elevation of aspartate amino transferase (3.38±5.68 vs -1.15±4.32 UI/L, P<0.001) and CK (-24.3±99.1±189.3 vs 48.3 UI/L, P=0.01) and a trend to an elevation of isoprostanes (193±408 vs 12±53 pmol/mmol creatinine, P=0.09) with no global change in mitochondrial respiration, lactate/pyruvate ratio or Ca(2+) sparks. However, among statin-treated subjects, those with the highest CK increase displayed a significantly lower Vmax rotenone succinate and an increase in Ca(2+) spark amplitude vs both subjects with the lowest CK increase and placebo-treated subjects. Moreover, Ca(2+) spark amplitude was positively correlated with treatment-induced CK increase in the whole group (r=0.71, P=0.0045). In conclusion, this study further supports that statin induced muscular toxicity may be related to alterations in mitochondrial respiration and muscle calcium homeostasis independently of underlying disease or concomitant medication.

Authors+Show Affiliations

CHRU Montpellier, 34295 Montpellier Cedex 5, France. f-galtier@chu-montpellier.frNo affiliation info availableNo affiliation info availableNo affiliation info availableNo 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
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22771848

Citation

Galtier, F, et al. "Effect of a High Dose of Simvastatin On Muscle Mitochondrial Metabolism and Calcium Signaling in Healthy Volunteers." Toxicology and Applied Pharmacology, vol. 263, no. 3, 2012, pp. 281-6.
Galtier F, Mura T, Raynaud de Mauverger E, et al. Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers. Toxicol Appl Pharmacol. 2012;263(3):281-6.
Galtier, F., Mura, T., Raynaud de Mauverger, E., Chevassus, H., Farret, A., Gagnol, J. P., Costa, F., Dupuy, A., Petit, P., Cristol, J. P., Mercier, J., & Lacampagne, A. (2012). Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers. Toxicology and Applied Pharmacology, 263(3), 281-6. https://doi.org/10.1016/j.taap.2012.06.020
Galtier F, et al. Effect of a High Dose of Simvastatin On Muscle Mitochondrial Metabolism and Calcium Signaling in Healthy Volunteers. Toxicol Appl Pharmacol. 2012 Sep 15;263(3):281-6. PubMed PMID: 22771848.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers. AU - Galtier,F, AU - Mura,T, AU - Raynaud de Mauverger,E, AU - Chevassus,H, AU - Farret,A, AU - Gagnol,J-P, AU - Costa,F, AU - Dupuy,A, AU - Petit,P, AU - Cristol,J P, AU - Mercier,J, AU - Lacampagne,A, Y1 - 2012/07/04/ PY - 2012/05/03/received PY - 2012/06/27/revised PY - 2012/06/28/accepted PY - 2012/7/10/entrez PY - 2012/7/10/pubmed PY - 2012/11/6/medline SP - 281 EP - 6 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 263 IS - 3 N2 - Statin use may be limited by muscle side effects. Although incompletely understood to date, their pathophysiology may involve oxidative stress and impairments of mitochondrial function and of muscle Ca(2+) homeostasis. In order to simultaneously assess these mechanisms, 24 male healthy volunteers were randomized to receive either simvastatin for 80 mg daily or placebo for 8 weeks. Blood and urine samples and a stress test were performed at baseline and at follow-up, and mitochondrial respiration and Ca(2+) spark properties were evaluated on a muscle biopsy 4 days before the second stress test. Simvastatin-treated subjects were separated according to their median creatine kinase (CK) increase. Simvastatin treatment induced a significant elevation of aspartate amino transferase (3.38±5.68 vs -1.15±4.32 UI/L, P<0.001) and CK (-24.3±99.1±189.3 vs 48.3 UI/L, P=0.01) and a trend to an elevation of isoprostanes (193±408 vs 12±53 pmol/mmol creatinine, P=0.09) with no global change in mitochondrial respiration, lactate/pyruvate ratio or Ca(2+) sparks. However, among statin-treated subjects, those with the highest CK increase displayed a significantly lower Vmax rotenone succinate and an increase in Ca(2+) spark amplitude vs both subjects with the lowest CK increase and placebo-treated subjects. Moreover, Ca(2+) spark amplitude was positively correlated with treatment-induced CK increase in the whole group (r=0.71, P=0.0045). In conclusion, this study further supports that statin induced muscular toxicity may be related to alterations in mitochondrial respiration and muscle calcium homeostasis independently of underlying disease or concomitant medication. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/22771848/Effect_of_a_high_dose_of_simvastatin_on_muscle_mitochondrial_metabolism_and_calcium_signaling_in_healthy_volunteers_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(12)00279-7 DB - PRIME DP - Unbound Medicine ER -