Cited by 114Mitochondrial Function and PathologyMuscle Physiology and DisordersCoenzyme Q10 studies and effects

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

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Kwak, Hyo-Bum, Thalacker-Mercer, Anna, Anderson, Ethan J., Lin, Chien-Te, Kane, Daniel A., Lee, Nam-Sihk, Cortright, Ronald N., Bamman, Marcas M., Neufer, P. Darrell·2012·Free Radical Biology and Medicine

DOI 10.1016/j.freeradbiomed.2011.10.449PMC PMC3313473

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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 48 h of simvastatin treatment (5 μM). 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 (5 μM) 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.

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Regulation of legumain in human cells
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Er cysteinproteaser involvert i statinindusert myotoksisitet
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Authors: Kwak, H.-B., Thalacker-Mercer, A., Anderson, E. J., Lin, C.-T., Kane, D. A., Lee, N.-S., Cortright, R. N., Bamman, M. M., & Neufer, P. D.
Affiliations: East Carolina University (US)
University of Alabama at Birmingham (US)
Corresponding author: Neufer, P. Darrell
ORCID: Kwak, Hyo-Bum
Anderson, Ethan J.
Lin, Chien-Te
Kane, Daniel A.
Bamman, Marcas M.
Neufer, P. Darrell
Venue: Free Radical Biology and Medicine
Publisher: Elsevier BV
Published: 2012-01
Volume: 52
Issue: 1
Pages: 198-207
ISSN: 0891-5849 (ISSN-L)
DOI: 10.1016/j.freeradbiomed.2011.10.449
PMC: PMC3313473
OpenAlex: W1985595789
Cited by: 114
References: 52
Citations by year: 2026: 2 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 6 · 2019: 13 · 2018: 10 · 2017: 10 · 2016: 11 · 2015: 11 · 2014: 12 · 2013: 12 · 2012: 7
FWCI: 4.03
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Free Radical Biology and Medicine (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute on Aging (R01AG017896)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK073488, R01DK075880, R01DK074825)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
Keywords: simvastatin, statin-induced myopathy, skeletal muscle, myotubes, mitochondrial respiration, complex I, mitochondrial oxidative stress, superoxide, hydrogen peroxide, apoptosis, Bax, Bcl-2, mitochondrial permeability transition, myotube atrophy, rhabdomyolysis
MeSH terms: Adenosine Diphosphate, Anticholesteremic Agents, Cell Differentiation, Dose-Response Relationship, Drug, Humans, Hydrogen Peroxide, Mitochondria, Muscular Diseases, Oxygen Consumption, Superoxides, Signal Transduction, Gene Expression, Apoptosis, Oxidative Stress, Muscle Fibers, Skeletal, Cell Respiration, Respiratory System Agents, Proto-Oncogene Proteins c-bcl-2, Simvastatin, Myoblasts, Electron Transport Complex I, Primary Cell Culture

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

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