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

• Published in: PloS one Vol. 10; no. 5; p. e0128398
• Main Authors: Goodman, Craig A, Pol, Derk, Zacharewicz, Evelyn, Lee-Young, Robert S, Snow, Rod J, Russell, Aaron P, McConell, Glenn K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.05.2015; Public Library of Science (PLoS)
• Subjects: Animals; Atrophy; Drugs; Fatty acids; Gene expression; Gene Expression Regulation - drug effects; Genes; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Kinases; Male; Markers; Mitochondria; Mitochondria, Muscle - metabolism; Mitochondria, Muscle - pathology; Muscle Proteins - biosynthesis; Muscles; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Myopathy; Myostatin; Nitric oxide; Nitric-oxide synthase; Nutrition; Oxidation; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Rats, Sprague-Dawley; Regulators; Side effects; Simvastatin; Simvastatin - pharmacology; Skeletal muscle; Statins; Transcription activation; Transcription Factors - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0128398

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.