Palmitate Induced Mitochondrial Deoxyribonucleic Acid Damage and Apoptosis in L6 Rat Skeletal Muscle Cells
Abstract
A major characteristic of type 2 diabetes mellitus (T2DM) is insulin resistance in skeletal muscle. A growing body of evidence indicates that oxidative stress that results from increased production of reactive oxygen species and/or reactive nitrogen species leads to insulin resistance, tissue damage, and other complications observed in T2DM. It has been suggested that muscular free fatty acid accumulation might be responsible for the mitochondrial dysfunction and insulin resistance seen in T2DM, although the mechanisms by which increased levels of free fatty acid lead to insulin resistance are not well understood. To help resolve this situation, we report that saturated fatty acid palmitate stimulated the expression of inducible nitric oxide (NO) synthase and the production of reactive oxygen species and NO in L6 myotubes. Additionally, palmitate caused a significant dose-dependent increase in mitochondrial DNA (mtDNA) damage and a subsequent decrease in L6 myotube viability and ATP levels at concentrations as low as 0.5 mm. Furthermore, palmitate induced apoptosis, which was detected by DNA fragmentation, caspase-3 cleavage, and cytochrome c release. N-acetyl cysteine, a precursor compound for glutathione formation, aminoguanidine, an inducible NO synthase inhibitor, and 5,10,15,20-tetrakis(4-sulphonatophenyl) porphyrinato iron (III), a peroxynitrite inhibitor, all prevented palmitate-induced mtDNA damage and diminished palmitate-induced cytotoxicity. We conclude that exposure of L6 myotubes to palmitate induced mtDNA damage and triggered mitochondrial dysfunction, which caused apoptosis. Additionally, our findings indicate that palmitate-induced mtDNA damage and cytotoxicity in skeletal muscle cells were caused by overproduction of peroxynitrite.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Palmitate induced apoptosis in C2C12 myotubes.
“Consistent with previous studies (11,35), we showed that palmitate induced apoptosis in C2C12 myotubes.”
From Increased mitochondrial fatty acid oxidation is sufficient to protect skeletal muscle cells from palmitate-induced apoptosis (2010) · cites this paper as [35]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids
Green, L. C., Wagner, D. A., Glogowski, J. A., Skipper, P. L., Wishnok, J. S., & Tannenbaum, S. R. (1982) · Analytical Biochemistry · doi:10.1016/0003-2697(82)90118-x · Cited by 12,089 · see citing works
Hydroperoxide metabolism in mammalian organs.
Chance, B., Sies, H., & Boveris, A. (1979) · Physiological Reviews · doi:10.1152/physrev.1979.59.3.527 · Cited by 5,827 · see citing works
Cellular mechanisms of insulin resistance
Shulman, G. I. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10583 · Cited by 2,714 · see citing works
Reactive oxygen species have a causal role in multiple forms of insulin resistance
Houstis, N., Rosen, E. D., & Lander, E. S. (2006) · Nature · doi:10.1038/nature04634 · Cited by 2,525 · see citing works
Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes
Kelley, D. E., He, J., Menshikova, E. V., & Ritov, V. B. (2002) · Diabetes · doi:10.2337/diabetes.51.10.2944 · Cited by 2,321 · see citing works
Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes
Petersen, K. F., Dufour, S., Befroy, D., Garcia, R., & Shulman, G. I. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa031314 · Cited by 2,193 · see citing works
Inoguchi, T., Li, P., Umeda, F., Yu, H. Y., Kakimoto, M., Imamura, M., Aoki, T., Etoh, T., Hashimoto, T., Naruse, M., et al. (2000) · Diabetes · doi:10.2337/diabetes.49.11.1939 · Cited by 1,577 · see citing works
Evans, J. L., Goldfine, I. D., Maddux, B. A., & Grodsky, G. M. (2003) · Diabetes · doi:10.2337/diabetes.52.1.1 · Cited by 1,482 · see citing works
DeFronzo, R. A., Gunnarsson, R., Björkman, O., Olsson, M., & Wahren, J. (1985) · Journal of Clinical Investigation · doi:10.1172/jci111938 · Cited by 1,167 · see citing works
The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity
Crouch, S. P. M., Kozlowski, R., Slater, K. J., & Fletcher, J. (1993) · Journal of Immunological Methods · doi:10.1016/0022-1759(93)90011-u · Cited by 926 · see citing works
Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes
Ritov, V. B., Menshikova, E. V., He, J., Ferrell, R. E., Goodpaster, B. H., & Kelley, D. E. (2005) · Diabetes · doi:10.2337/diabetes.54.1.8 · Cited by 887 · see citing works
R�sen, P., Nawroth, P., King, G. L., M�ller, W., Tritschler, H., & Packer, L. (2001) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.196 · Cited by 881 · see citing works
Rothe, G., & Valet, G. (1990) · Journal of Leukocyte Biology · doi:10.1002/jlb.47.5.440 · Cited by 870 · see citing works
mtDNA mutations increase tumorigenicity in prostate cancer
Petros, J. A., Baumann, A. K., Ruiz‐Pesini, E., Amin, M. B., Sun, C. Q., Hall, J., Lim, S.-D., Issa, M. M., Flanders, W. D., Hosseini, S. H., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408894102 · Cited by 834 · see citing works
Du, J., Wang, X., Miereles, C., Bailey, J. L., Debigaré, R., Zheng, B., Price, S. R., & Mitch, W. E. (2004) · Journal of Clinical Investigation · doi:10.1172/jci18330 · Cited by 730 · see citing works
What if Minkowski Had Been Ageusic? An Alternative Angle on Diabetes
McGarry, J. D. (1992) · Science · doi:10.1126/science.1439783 · Cited by 657 · see citing works
Schmitz-Peiffer, C., Craig, D. L., & Biden, T. J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.34.24202 · Cited by 592 · see citing works
Maedler, K., Oberholzer, J., Bucher, P., Spinas, G. A., & Donath, M. Y. (2003) · Diabetes · doi:10.2337/diabetes.52.3.726 · Cited by 552 · see citing works
Cnop, M., Hannaert, J. C., Hoorens, A., Eizirik, D. L., & PIPELEERS, D. G. (2001) · Diabetes · doi:10.2337/diabetes.50.8.1771 · Cited by 550 · see citing works
Chavez, J. A., & Summers, S. A. (2003) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2003.08.020 · Cited by 498 · see citing works
Prevention of mitochondrial oxidative damage as a therapeutic strategy in diabetes
Green, K., Brand, M. D., & Murphy, M. P. (2004) · Diabetes · doi:10.2337/diabetes.53.2007.s110 · Cited by 490 · see citing works
Oxidative Capacity, Lipotoxicity, and Mitochondrial Damage in Type 2 Diabetes
Schrauwen, P., & Hesselink, M. K. C. (2004) · Diabetes · doi:10.2337/diabetes.53.6.1412 · Cited by 408 · see citing works
Nitric oxide inhibition of mitochondrial respiration and its role in cell death
Brown, G. C., & Borutaite, V. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)01112-7 · Cited by 377 · see citing works
Mechanisms of disuse muscle atrophy: role of oxidative stress
Powers, S. K., Kavazis, A. N., & DeRuisseau, K. C. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00469.2004 · Cited by 368 · see citing works
Effect of fatty acids on energy coupling processes in mitochondria
Wojtczak, L., & Schönfeld, P. (1993) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/0005-2728(93)90004-y · Cited by 363 · see citing works
de Vries, J. E., Vork, M. M., Roemen, T. H., de Jong, Y. F., Cleutjens, J. P., van der Vusse, G. J., & van Bilsen, M. (1997) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)37421-6 · Cited by 324 · see citing works
Regulation of Muscle Protein Degradation
Lee, S. W., Dai, G., Hu, Z., Wang, X., Du, J., & Mitch, W. E. (2004) · Journal of the American Society of Nephrology · doi:10.1097/01.asn.0000127211.86206.e1 · Cited by 323 · see citing works
Saturated Fatty Acid-induced Apoptosis in MDA-MB-231 Breast Cancer Cells
Hardy, S., El-Assaad, W., Przybytkowski, E., Joly, E. C., Prentki, M., & Langelier, Y. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300190200 · Cited by 272 · see citing works
POWELL, D. J., TURBAN, S., GRAY, A., HAJDUCH, E., & HUNDAL, H. S. (2004) · Biochemical Journal · doi:10.1042/bj20040139 · Cited by 267 · see citing works
The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase
Vartanian, V. L., Lowell, B., Minko, I. G., Wood, T. G., Ceci, J. D., George, S., Ballinger, S. W., Corless, C. L., McCullough, A. K., & Lloyd, R. S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507444103 · Cited by 248 · see citing works
Mechanisms decreasing glucose oxidation in diabetes and starvation: Role of lipid fuels and hormones
Randle, P. J., Kerbey, A. L., & Espinal, J. (1988) · Diabetes/Metabolism Reviews · doi:10.1002/dmr.5610040702 · Cited by 244 · see citing works
Characterization of the Cytoprotective Action of Peroxynitrite Decomposition Catalysts
Misko, T. P., Highkin, M. K., Veenhuizen, A. W., Manning, P. T., Stern, M. K., Currie, M. G., & Salvemini, D. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.25.15646 · Cited by 232 · see citing works
Sinha, S., Perdomo, G., Brown, N. F., & O'Doherty, R. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406514200 · Cited by 215 · see citing works
Bakker, S. J. L., IJzerman, R. G., Teerlink, T., Westerhoff, H. V., Gans, R. O. B., & Heine, R. J. (2000) · Atherosclerosis · doi:10.1016/s0021-9150(99)00329-9 · Cited by 214 · see citing works
Repair of Formamidopyrimidines in DNA Involves Different Glycosylases
Hu, J., de Souza-Pinto, N. C., Haraguchi, K., Hogue, B. A., Jaruga, P., Greenberg, M. M., Dizdaroğlu, M., & Bohr, V. A. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508772200 · Cited by 197 · see citing works
Repair of oxidative damage within the mitochondrial DNA of RINr 38 cells.
Driggers, W. J., LeDoux, S. P., & Wilson, G. L. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)80645-0 · Cited by 172 · see citing works
Self-citationReactive species and early manifestation of insulin resistance in type 2 diabetes
Fridlyand, L. E., & Philipson, L. H. (2005) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2005.00496.x · Cited by 166 · see citing works
Inflammation and nitric oxide production in skeletal muscle of type 2 diabetic patients
Sh, T., Sanctis, J. B. D., Briceño, L., Hernandez, N., & Finol, H. (2004) · Journal of Endocrinology · doi:10.1677/joe.0.1810419 · Cited by 163 · see citing works
Pettepher, C., LeDoux, S. P., Bohr, V. A., & Wilson, G. L. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)49961-9 · Cited by 152 · see citing works
Self-citationDobson, A. W., Xu, Y., Kelley, M. R., LeDoux, S. P., & Wilson, G. L. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000831200 · Cited by 145 · see citing works
Self-citationFatty acid—Mediated activation of vascular endothelial cells
Hennig, B., Meerarani, P., Ramadass, P., et al. (2000) · Metabolism · doi:10.1053/meta.2000.7736 · Cited by 115 · see citing works
Fatty acid–mediated effects on the glutathione redox cycle in cultured endothelial cells
Toborek, M. J., & Hennig, B. (1994) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/59.1.60 · Cited by 112 · see citing works
Burn injury impairs insulin-stimulated Akt/PKB activation in skeletal muscle
Sugita, H., Kaneki, M., Sugita, M., Yasukawa, T., Yasuhara, S., & Martyn, J. A. J. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00321.2004 · Cited by 109 · see citing works
Effects of individual fatty acids on glucose uptake and glycogen synthesis in soleus muscle in vitro
Thompson, A. L., Lim-Fraser, M. Y.-C., Kraegen, E. W., & Cooney, G. J. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.3.e577 · Cited by 107 · see citing works
Kashyap, S. R., Belfort, R., Berria, R., Suraamornkul, S., Pratipranawatr, T., Finlayson, J., Barrentine, A., Bajaj, M., Mandarino, L., DeFronzo, R., et al. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00541.2003 · Cited by 103 · see citing works
Conditional Targeting of the DNA Repair Enzyme hOGG1 into Mitochondria*
Rachek, L., Grishko, V., Musiyenko, S. I., Kelley, M., Ledoux, S., & Wilson, G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208770200 · Cited by 97 · see citing works
Self-citationProtection of INS-1 cells from free fatty acid-induced apoptosis by targeting hOGG1 to mitochondria.
Rachek, L. I., Thornley, N. P., Grishko, V. I., LeDoux, S. P., & Wilson, G. L. (2006) · Diabetes · doi:10.2337/diabetes.55.04.06.db05-0865 · Cited by 81 · see citing works
Self-citationCytokines Induce Nitric Oxide-mediated mtDNA Damage and Apoptosis in Oligodendrocytes
Druzhyna, N., Musiyenko, S. I., Wilson, G. L., & LeDoux, S. P. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411531200 · Cited by 69 · see citing works
Self-citationInvolvement of mtDNA damage in free fatty acid-induced apoptosis
Grishko, V. I., Rachek, L. I., Musiyenko, S. I., LeDoux, S. P., & Wilson, G. L. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.11.023 · Cited by 66 · see citing works
Self-citationWassermann, K., Kohn, K. W., & Bohr, V. A. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)77434-6 · Cited by 63 · see citing works
Park, S. Y., Choi, G. H., Choi, H. I., Ryu, J., Jung, C. Y., & Lee, W. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409399200 · Cited by 61 · see citing works
Liang, P., HUGHES, V. A., & Fukagawa, N. K. (1997) · Diabetes · doi:10.2337/diab.46.5.920 · Cited by 58 · see citing works
Skeletal Muscle Proteolysis in Rats With Acute Streptozocin-Induced Diabetes
Smith, O. L. K., Wong, C., & Gelfand, R. (1989) · Diabetes · doi:10.2337/diab.38.9.1117 · Cited by 57 · see citing works
Górski, J., Nawrocki, A., & Murthy, M. (1998) · Molecular and Cellular Biochemistry · doi:10.1023/a:1006820907955 · Cited by 51 · see citing works
Contribution of Mitochondrial DNA Repair to Cell Resistance from Oxidative Stress*
Grishko, V., Rachek, L., Spitz, D., Wilson, G., & Ledoux, S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413022200 · Cited by 41 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Newsholme, P., Haber, E. P., Hirabara, S. M., Rebelato, E. L. O., Procopio, J., Morgan, D., Oliveira‐Emilio, H. C., Carpinelli, A. R., & Curi, R. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.135871 · Cited by 684 · see citing works
The Influence of Dietary Fatty Acids on Immune Responses
Radzikowska, U., Rinaldi, A. O., Çelebi Sözener, Z., Karaguzel, D., Wojcik, M., Cypryk, K., Akdis, M., Akdis, C. A., & Sokolowska, M. (2019) · Nutrients · doi:10.3390/nu11122990 · Cited by 306 · see citing works
Yuzefovych, L., Wilson, G., & Rachek, L. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00238.2010 · Cited by 280 · see citing works
Self-citationThe effects of obesity on skeletal muscle regeneration
Akhmedov, D., & Berdeaux, R. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00371 · Cited by 241 · see citing works
Peroxisome Proliferator Activator Receptor γ Coactivator-1 Expression Is Reduced in Obesity
Crunkhorn, S., Dearie, F., Mantzoros, C., Gami, H., da Silva, W. S., Espinoza, D., Faucette, R., Barry, K., Bianco, A. C., & Patti, M. E. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611214200 · Cited by 236 · see citing works
Henique, C., Mansouri, A., Fumey, G., Lenoir, V., Girard, J., Bouillaud, F., Prip-Buus, C., & Cohen, I. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.170431 · Cited by 159 · see citing works
Chavez, A. O., Kamath, S., Jani, R., Sharma, L. K., Monroy, A., Abdul-Ghani, M. A., Centonze, V. E., Sathyanarayana, P., Coletta, D. K., Jenkinson, C. P., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1387 · Cited by 52 · see citing works
- Authors
- Rachek, L. I., Musiyenko, S. I., LeDoux, S. P., & Wilson, G. L.
- Affiliations
- University of South Alabama (US)
- Corresponding author
- Rachek, L. I.
- ORCID
- Rachek, L. I.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2007-01-01
- Volume
- 148
- Issue
- 1
- Pages
- 293-299
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2043102772
- Cited by
- 137
- References
- 55
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 2 · 2020: 6 · 2019: 3 · 2018: 9 · 2017: 3 · 2015: 6 · 2014: 15 · 2013: 15 · 2012: 8
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG19602, R01AG019602)
- National Institute of Neurological Disorders and Stroke (NS 041208)
- National Institute of Environmental Health Sciences (ES05865, R01ES003456, ES 03456)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- palmitate, mitochondrial DNA damage, apoptosis, skeletal muscle, type 2 diabetes, insulin resistance, free fatty acids, inducible nitric oxide synthase, reactive oxygen species, peroxynitrite, oxidative stress, mitochondrial dysfunction, L6 myotubes, caspase-3, cytochrome c release, N-acetylcysteine, aminoguanidine
- MeSH terms
- Adenosine Triphosphate, Animals, Cell Nucleus, Cells, Cultured, Diabetes Mellitus, Type 2, DNA Damage, DNA, Mitochondrial, Mitochondria, Nitric Oxide, Palmitates, Free Radical Scavengers, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Muscle, Skeletal, Cytochromes c, Rats, Nitric Oxide Synthase Type II, Caspase 3, DNA Fragmentation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
