title: Statin-Induced Increases in Atrophy Gene Expression Occur Independently of Changes in PGC1α Protein and Mitochondrial Content.
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.
authors.affiliation: Department of Physiology, University of Melbourne, Parkville, Victoria, Australia; Institute of Sport, Exercise and Active Living and the College of Health and Biomedicine, Victoria University, Victoria, Australia.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Goodman
authors.affiliation: Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Derk
authors.initials: D
authors.lastname: Pol
authors.affiliation: Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Australia.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Zacharewicz
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Division of Metabolism and Obesity, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Lee-Young
authors.affiliation: Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Australia.
authors.forename: Rod J
authors.initials: RJ
authors.lastname: Snow
authors.affiliation: Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Australia.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Russell
authors.affiliation: Department of Physiology, University of Melbourne, Parkville, Victoria, Australia; Institute of Sport, Exercise and Active Living and the College of Health and Biomedicine, Victoria University, Victoria, Australia.
authors.forename: Glenn K
authors.initials: GK
authors.lastname: McConell
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000473:pathology; D009124:Muscle Proteins / Q000096:biosynthesis*; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009124:Muscle Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; D019821:Simvastatin