Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes

Hyo-Bum Kwak; Anna Thalacker-Mercer; Ethan J Anderson; Chien-Te Lin; Daniel A Kane; Nam-Sihk Lee; Ronald N Cortright; Marcas M Bamman; P. Darrell Neufer

doi:10.1016/j.freeradbiomed.2011.10.449

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Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes

Journal article

Peer reviewed

Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes

Hyo-Bum Kwak, Anna Thalacker-Mercer, Ethan J Anderson, Chien-Te Lin, Daniel A Kane, Nam-Sihk Lee, Ronald N Cortright, Marcas M Bamman and P. Darrell Neufer

Free radical biology & medicine, Vol.52(1), pp.198-207

01/01/2012

DOI: 10.1016/j.freeradbiomed.2011.10.449

PMCID: PMC3313473

PMID: 22080086

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https://www.ncbi.nlm.nih.gov/pmc/articles/3313473View

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Abstract

Statins, the widely prescribed cholesterol-lowering drugs for the treatment of cardiovascular disease, cause adverse skeletal muscle side effects ranging from fatigue to fatal rhabdomyolysis. The purpose of this study was to determine the effects of simvastatin on mitochondrial respiration, oxidative stress, and cell death in differentiated primary human skeletal muscle cells (i.e., myotubes). Simvastatin induced a dose-dependent decrease in viability of proliferating and differentiating primary human muscle precursor cells, and a similar dose-dependent effect was noted in differentiated myoblasts and myotubes. Additionally, there were decreases in myotube number and size following 48h of simvastatin treatment (5μM). In permeabilized myotubes, maximal ADP-stimulated oxygen consumption, supported by palmitoylcarnitine+malate (PCM, complex I and II substrates) and glutamate+malate (GM, complex I substrates), was 32–37% lower (P<0.05) in simvastatin-treated (5μM) vs control myotubes, providing evidence of impaired respiration at complex I. Mitochondrial superoxide and hydrogen peroxide generation were significantly greater in the simvastatin-treated human skeletal myotube cultures compared to control. In addition, simvastatin markedly increased protein levels of Bax (proapoptotic, +53%) and Bcl-2 (antiapoptotic, +100%, P<0.05), mitochondrial PTP opening (+44%, P<0.05), and TUNEL-positive nuclei in human skeletal myotubes, demonstrating up-regulation of mitochondrial-mediated myonuclear apoptotic mechanisms. These data demonstrate that simvastatin induces myotube atrophy and cell loss associated with impaired ADP-stimulated maximal mitochondrial respiratory capacity, mitochondrial oxidative stress, and apoptosis in primary human skeletal myotubes, suggesting that mitochondrial dysfunction may underlie human statin-induced myopathy. ► Statins can induce muscle weakness/myopathy. ► In culture, simvastatin induced dose dependent atrophy of human myotubes. ► Statin exposure decreased mitochondrial respiratory function and increased ROS production. ► Activation of apoptosis also evident. ► Findings suggest mitochondrial dysfunction underlies statin-induced myopathy.

Oxidative stress

Mitochondria

Hydrogen peroxide

Simvastatin

Mitochondrial respiration

Superoxide

Human skeletal muscle

Apoptosis

Details

Title: Subtitle: Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes
Creators: Hyo-Bum Kwak - Department of Kinesiology, East Carolina University, Greenville, NC 27834, USA
Anna Thalacker-Mercer - Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Ethan J Anderson - East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, USA
Chien-Te Lin - Department of Kinesiology, East Carolina University, Greenville, NC 27834, USA
Daniel A Kane - Department of Kinesiology, East Carolina University, Greenville, NC 27834, USA
Nam-Sihk Lee - Department of Internal Medicine, East Carolina University, Greenville, NC 27834, USA
Ronald N Cortright - Department of Kinesiology, East Carolina University, Greenville, NC 27834, USA
Marcas M Bamman - Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
P. Darrell Neufer - Department of Kinesiology, East Carolina University, Greenville, NC 27834, USA
Resource Type: Journal article
Publication Details: Free radical biology & medicine, Vol.52(1), pp.198-207
DOI: 10.1016/j.freeradbiomed.2011.10.449
PMID: 22080086
PMCID: PMC3313473
NLM abbreviation: Free Radic Biol Med
ISSN: 0891-5849
eISSN: 1873-4596
Publisher: Elsevier Inc
Language: English
Date published: 01/01/2012
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Fraternal Order of Eagles Diabetes Research Center; Health, Sport, and Human Physiology
Record Identifier: 9984065688902771

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