title: Simvastatin inhibits glucose metabolism and legumain activity in human myotubes.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
authors.forename: Robert
authors.initials: R
authors.lastname: Smith
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
authors.forename: Rigmor
authors.initials: R
authors.lastname: Solberg
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
authors.forename: Linn Løkken
authors.initials: LL
authors.lastname: Jacobsen
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
authors.forename: Anette Larsen
authors.initials: AL
authors.lastname: Voreland
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
authors.forename: Arild Christian
authors.initials: AC
authors.lastname: Rustan
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway ; Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: G Hege
authors.initials: GH
authors.lastname: Thoresen
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Harald Thidemann
authors.initials: HT
authors.lastname: Johansen
mesh_terms: D002401:Cathepsin B / Q000378:metabolism; D056668:Cathepsin L / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D000099240:Asparaginyl Endopeptidase
chemical_list: D002401:Cathepsin B; D056668:Cathepsin L; D003546:Cysteine Endopeptidases; D005947:Glucose; D008798:Mevalonic Acid; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D019821:Simvastatin; D000099240:Asparaginyl Endopeptidase; C015367:mevalonolactone; C004808:farnesyl pyrophosphate; C002963:geranylgeranyl pyrophosphate