Statin-Induced Increases in Atrophy Gene Expression Occur Independently of Changes in PGC1α Protein and Mitochondrial Content.

Craig A Goodman,Evelyn Zacharewicz,Derk Pol,Rod J Snow,Aaron P Russell,Glenn K Mcconell,Robert S Lee-Young,Ashok Kumar

doi:10.1371/journal.pone.0128398

Abstract

One serious side effect of statin drugs is skeletal muscle myopathy. Although the mechanism(s) responsible for statin myopathy remains to be fully determined, an increase in muscle atrophy gene expression and changes in mitochondrial content and/or function have been proposed to play a role. In this study, we examined the relationship between statin-induced expression of muscle atrophy genes, regulators of mitochondrial biogenesis, and markers of mitochondrial content in slow- (ST) and fast-twitch (FT) rat skeletal muscles. Male Sprague Dawley rats were treated with simvastatin (60 or 80 mg·kg-1·day-1) or vehicle control via oral gavage for 14 days. In the absence of overt muscle damage, simvastatin treatment induced an increase in atrogin-1, MuRF1 and myostatin mRNA expression; however, these were not associated with changes in peroxisome proliferator gamma co-activator 1 alpha (PGC-1α) protein or markers of mitochondrial content. Simvastatin did, however, increase neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS) and AMPK α-subunit protein expression, and tended to increase total NOS activity, in FT but not ST muscles. Furthermore, simvastatin induced a decrease in β-hydroxyacyl CoA dehydrogenase (β-HAD) activity only in FT muscles. These findings suggest that the statin-induced activation of muscle atrophy genes occurs independent of changes in PGC-1α protein and mitochondrial content. Moreover, muscle-specific increases in NOS expression and possibly NO production, and decreases in fatty acid oxidation, could contribute to the previously reported development of overt statin-induced muscle damage in FT muscles.

Highlights

Statin drugs lower blood cholesterol, and reduce the risk of coronary heart disease and stroke, by inhibiting the rate limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
To gain a more complete understanding of the early molecular events associated with statin-induced myopathy, the purpose of this study was to determine whether statin-induced increases in muscle atrophy gene expression are associated with changes in: 1) PGC1α protein expression; 2) mitochondrial enzyme activity and mitochondrial protein expression; 3) AMPK protein expression and activation; and 4) endothelial nitric oxide synthase (NOS) (eNOS) and neuronal nitric oxide synthase (nNOS) protein expression and total NOS activity
Previous studies have shown that simvastatin at 88 mgÁkg-1Áday-1, but not at 80 mgÁkg-1Áday-1, induces significant damage in rat skeletal muscle that is accompanied by very large increases in plasma CK activity, an indirect marker of muscle damage [16]

Summary

Introduction

Statin drugs lower blood cholesterol, and reduce the risk of coronary heart disease and stroke, by inhibiting the rate limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (for review see [1]). One of the main side effects of statin medications is skeletal muscle myopathy, with clinical symptoms that include muscle pain (myalgia), inflammation (myositis), weakness, fatigue and cramping [4,5]. With an incidence of >10% of statin users in the general population [6,7], hundreds of thousands of people worldwide are likely to experience some form of statin-induced myopathy. A thorough understanding of the molecular mechanism(s) underlying statin myopathy is essential for the future identification of specific biomarkers to detect adverse statin-induced events prior to the potential onset of debilitating clinical symptoms and/or for the development of safer alternative cholesterol lowering agents

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