Simvastatin Inhibits Glucose Metabolism and Legumain Activity in Human Myotubes

Robert Smith,Rigmor Solberg,Linn Løkken Jacobsen,Arild Christian Rustan,Anette Larsen Voreland,G Hege Thoresen,Harald Thidemann Johansen,Matthew Bogyo

doi:10.1371/journal.pone.0085721

Robert Smith, Rigmor Solberg + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0085721

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Journal: PloS one	Publication Date: Jan 8, 2014
Citations: 71	License type: CC BY 4.0

Affiliation: University of Oslo, Oslo University Hospital

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.

Highlights

Simvastatin, a HMG-CoA reductase inhibitor, is prescribed worldwide to patients with hypercholesterolemia to prevent cardiovascular disease and death [1,2]
Since the experiments were done in absence of insulin and GLUT1 is the predominant glucose transporter in human myotubes [32], the GLUT1 expression after exposure to simvastatin was studied
Legumain was for the first time characterized in human myotubes and decreased legumain activity and expression was observed by simvastatin

Summary

Introduction

Simvastatin, a HMG-CoA reductase inhibitor (statin), is prescribed worldwide to patients with hypercholesterolemia to prevent cardiovascular disease and death [1,2]. Several hypotheses explaining the statin-induced myotoxicity have been put forward, but the underlying mechanism is still poorly understood. The mechanisms for statin-induced myotoxicity are probably multifactorial and at least partly due to a combination of impaired isoprenylation of trafficking proteins [5,6], altered Ca2+ homeostasis [7] and impaired mitochondrial respiratory function [8,9,10]. The mitochondrial respiratory dysfunction observed in statin-treated patients caused glucose intolerance [10]. Glucose intolerance was observed in tumor cells after exposure to statin, resulting in decreased glucose uptake and a higher glucose concentration in the conditioned cell medium [11]. Many biochemical processes are affected by impaired glucose oxidation and low ATP production, like the activity of the lysosomal H+-ATPase, pH of the lysosomes and processing of lysosomal proteases

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