Simvastatin inhibits glucose metabolism and legumain activity in human myotubes

• Published in: PloS one 2014-01, Vol.9 (1), p.e85721-e85721
• Main Authors: Smith, Robert, Solberg, Rigmor, Jacobsen, Linn Løkken, Voreland, Anette Larsen, Rustan, Arild Christian, Thoresen, G Hege, Johansen, Harald Thidemann
• Format: Article
• Language: English
• Subjects: Antilipemic agents; Apoptosis; Biology; Caspase; Cathepsin B - metabolism; Cathepsin L - metabolism; Cell Membrane - drug effects; Cell Membrane - metabolism; Cells (biology); Cholesterol; Clinical medicine; Confocal; Cysteine; Cysteine Endopeptidases - metabolism; Cysteine proteinase; Deoxyglucose; Endopeptidase; Enzymatic activity; Enzyme activity; Enzyme-linked immunosorbent assay; Glucose; Glucose - metabolism; HEK293 Cells; Humans; Hydroxymethylglutaryl-CoA reductase; Hypercholesterolemia; Immunoblotting; Insulin resistance; Kinases; Legumain; Lipids; Mammals; Mathematics; Medicine; Metabolism; Mevalonic Acid - analogs & derivatives; Mevalonic Acid - pharmacology; Mitochondria; Mitochondrial DNA; Monocytes; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - enzymology; Muscles; Musculoskeletal system; Myotubes; Nuclear fuels; Oxidation; Oxidation-Reduction - drug effects; Oxidative Phosphorylation - drug effects; Pharmaceuticals; Pharmacy; Phosphates; Polyisoprenyl Phosphates - pharmacology; Proteases; Rodents; Satellite cells; Sesquiterpenes - pharmacology; Side effects; Simvastatin; Simvastatin - pharmacology; Skeletal muscle; Statins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0085721

Simvastatin, a HMG-CoA reductase inhibitor, is prescribed worldwide to patients with hypercholesterolemia. Although simvastatin is well tolerated, side effects like myotoxicity are reported. The mechanism for statin-induced myotoxicity is still poorly understood. Reports have suggested impaired mitochondrial dysfunction as a contributor to the observed myotoxicity. In this regard, we wanted to study the effects of simvastatin on glucose metabolism and the activity of legumain, a cysteine protease. Legumain, being the only known asparaginyl endopeptidase, has caspase-like properties and is described to be involved in apoptosis. Recent evidences indicate a regulatory role of both glucose and statins on cysteine proteases in monocytes. Satellite cells were isolated from the Musculus obliquus internus abdominis of healthy human donors, proliferated and differentiated into polynuclear myotubes. Simvastatin with or without mevalonolactone, farnesyl pyrophosphate or geranylgeranyl pyrophosphate were introduced on day 5 of differentiation. After 48 h, cells were either harvested for immunoblotting, ELISA, cell viability assay, confocal imaging or enzyme activity analysis, or placed in a fuel handling system with [¹⁴C]glucose or [³H]deoxyglucose for uptake and oxidation studies. A dose-dependent decrease in both glucose uptake and oxidation were observed in mature myotubes after exposure to simvastatin in concentrations not influencing cell viability. In addition, simvastatin caused a decrease in maturation and activity of legumain. Dysregulation of glucose metabolism and decreased legumain activity by simvastatin points out new knowledge about the effects of statins on skeletal muscle, and may contribute to the understanding of the myotoxicity observed by statins.