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Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes
Open accessAbstract
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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“Recently Kwak et al. (40) reported impaired ADP-stimulated respiration in primary human skeletal myotubes after 48 h of simvastatin treatment, and this was accompanied by increased mitochondrial oxidative stress (hydrogen peroxide emission).”
From Simvastatin Effects on Skeletal Muscle (2013) · cites this paper as [40]
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“Our findings of significantly reduced antioxidant capacity in combination with the known (3,40) elevated ROS production in the simvastatin-treated patients make it plausible that increased apoptosis could contribute to muscle pain in patients treated with statins.”
From Simvastatin Effects on Skeletal Muscle (2013) · cites this paper as [40]
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“In turn, an increased Ca 2ϩ load in the mitochondrial matrix has been linked to increased ROS production and increased permeability transition pore opening, leading to apoptosis (40,45).”
From Simvastatin Effects on Skeletal Muscle (2013) · cites this paper as [40]
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Cites
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Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes
Cannon, C. P., Braunwald, E., McCabe, C. H., Rader, D. J., Rouleau, J. L., Belder, R., Joyal, S. V., Hill, K. A., Pfeffer, M. A., & Skene, A. M. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040583 · Cited by 4,938
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Self-citationSafety of Statins: Focus on Clinical Pharmacokinetics and Drug Interactions
Bellosta, S., Paoletti, R., & Corsini, A. (2004) · Circulation · doi:10.1161/01.cir.0000131519.15067.1f · Cited by 578
Statin-associated myopathy with normal creatine kinase levels
Phillips, P. S., Haas, R. H., Bannykh, S., Hathaway, S., Gray, N. L., Kimura, B. J., Vladutiu, G. D., England, J. D. F., & and the Scripps Mercy Clinical Research Center* (2002) · Annals of Internal Medicine · doi:10.7326/0003-4819-137-7-200210010-00009 · Cited by 565
The Role of Coenzyme Q10 in Statin-Associated Myopathy
Marcoff, L., & Thompson, P. D. (2007) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.02.049 · Cited by 537
Suction applied to a muscle biopsy maximizes sample size
Evans, W. J., Phinney, S. D., & Young, V. R. (1982) · Medicine & Science in Sports & Exercise · doi:10.1249/00005768-198201000-00018 · Cited by 525
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Effects of statins on mitochondrial pathways
Mollazadeh, H., Tavana, E., Fanni, G., Bo, S., Banach, M., Pirro, M., von Haehling, S., Jamialahmadi, T., & Sahebkar, A. (2021) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12654 · Cited by 270
Simvastatin Impairs Exercise Training Adaptations
Mikus, C. R., Boyle, L. J., Borengasser, S. J., Oberlin, D. J., Naples, S. P., Fletcher, J. A., Meers, G. M.-E., Ruebel, M. L., Laughlin, M. H., Dellsperger, K. C., et al. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.02.074 · Cited by 249
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Metadata
- 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
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 52
- Issue
- 1
- Pages
- 198-207
- ISSN
- 0891-5849 (ISSN-L)
- 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
- 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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