Simvastatin triggers mitochondria-induced Ca2+ signaling alteration in skeletal muscle

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Abstract

Statin drugs represent the major improvement in the treatment of hypercholesterolemia that constitutes the main origin of atherosclerosis, leading to coronary heart disease. Besides tremendous beneficial effects of statins, various forms of muscular toxicity (myalgia, cramp, exercise intolerance, and fatigability) occur frequently. We hypothesized that the iatrogenic effects of statins could result from alterations in Ca2+ homeostasis. Acute applications of simvastatin on human skeletal muscle fibers triggered a Ca2+ wave of intra-cellular Ca2+ that mostly originates from sarcoplasmic reticulum (SR) Ca2+-release. In addition, simvastatin increased mitochondrial NADH content and induced mitochondrial membrane depolarization (EC50 = 1.96 μM) suggesting an altered mitochondrial function. Consequently on simvastatin application, a weak mitochondrial Ca2+ efflux (EC50 = 7.8μM) through permeability transient pore and Na+/Ca2+ exchanger was triggered, preceding the large SR-Ca2+ release. Increased SR Ca2+ content after acute application of statin is also suggested by the increased Ca2+ spark amplitude and by the effect of cyclopiazonic acid. We thus conclude that simvastatin induced alterations in mitochondrial function which lead to an increase in cytoplasmic Ca2+, SR-Ca2+ overload, and Ca2+ waves. Taken together, these statin-induced muscle dysregulations may contribute to myotoxicity.

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Materials and methods

Human skeletal muscle samples. Fifteen healthy voluntary men aged between 25 and 45 years without any drug therapy that could interfere with the results of the study, were recruited. Informed consent was obtained from all the subjects after explanation of the protocol. The study was approved by the local Ethic Committee and conformed to the Declaration of Helsinki regarding the use of human subject. Muscle biopsies were performed in the inferior third level of the Vastus lateralis muscle under

Effects of simvastatin on cytosolic [Ca2+]i

Acute applications of simvastatin resulted in a delayed (∼10 min) wave of [Ca2+]i characterized typically by a large transient phase followed by a sustained elevation in Ca2+ (Fig. 1A). The increase in [Ca2+]i, that was to some extent comparable to that observed under caffeine application, triggered a prolonged contraction of the fibers. This effect was also observed on non-permeabilized intact muscle fibers (not shown), indicating that simvastatin is able to diffuse through the sarcolemma.

In

Discussion

In this work, we report that an acute application of simvastatin on human muscle fibers triggers a large increase in cytoplasmic Ca2+. This effect results first from an alteration of mitochondrial function by statins leading to mitochondrial membrane depolarization and Ca2+ efflux to the cytoplasm through the PTP and NCE. Then, Ca2+ is recaptured by the SR until it reaches a level that triggers the SR release. This dysregulation of Ca2+ homeostasis, implicating several cellular compartments and

Acknowledgments

This study was supported by INSERM, the Association Française contre les Myopathies (AFM), and the Fondation pour la Recherche Médicale (FRM). We are thankful to Dr. C.W. Ward for early assistance in spark analysis and Dr. F. Joubert for preliminary experiments on NADH autofluorescence measurements.

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