Transient systemic mtDNA damage leads to muscle wasting by reducing the satellite cell pool
Open accessAbstract
With age, muscle mass and integrity are progressively lost leaving the elderly frail, weak and unable to independently care for themselves. Defined as sarcopenia, this age-related muscle atrophy appears to be multifactorial but its definite cause is still unknown. Mitochondrial dysfunction has been implicated in this process. Using a novel transgenic mouse model of mitochondrial DNA (mtDNA) double-strand breaks (DSBs) that presents a premature aging-like phenotype, we studied the role of mtDNA damage in muscle wasting. We caused DSBs in mtDNA of adult mice using a ubiquitously expressed mitochondrial-targeted endonuclease, mito-PstI. We found that a short, transient systemic mtDNA damage led to muscle wasting and a decline in locomotor activity later in life. We found a significant decline in muscle satellite cells, which decreases the muscle's capacity to regenerate and repair during aging. This phenotype was associated with impairment in acetylcholinesterase (AChE) activity and assembly at the neuromuscular junction (NMJ), also associated with muscle aging. Our data suggests that systemic mitochondrial dysfunction plays important roles in age-related muscle wasting by preferentially affecting the myosatellite cell pool.
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?
Stress-induced damage to mitochondrial membranes contributes to sensitization of the mPTP.
“Stress-induced damage to mitochondrial membranes (40, 108, 144, 147) contributes to sensitization of the mitochondrial permeability transition pore (mPTP) (44).”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [144]
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
3 retracted
Wenz, T., Rossi, S. G., Rotundo, R. L., Spiegelman, B. M., & Moraes, C. T. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911570106 · Cited by 600 · see citing works
Self-citationRetractedSafdar, A., Bourgeois, J. M., Ogborn, D. I., Little, J. P., Hettinga, B. P., Akhtar, M., Thompson, J. E., Melov, S., Mocellin, N. J., Kujoth, G. C., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019581108 · Cited by 358 · see citing works
RetractedEndurance exercise is protective for mice with mitochondrial myopathy
Wenz, T., Diaz, F., Hernandez, D., & Moraes, C. T. (2009) · Journal of Applied Physiology · doi:10.1152/japplphysiol.91571.2008 · Cited by 78 · see citing works
Self-citationRetractedA new and rapid colorimetric determination of acetylcholinesterase activity
Ellman, G. L., Courtney, K. D., Andres, V., & Featherstone, R. M. (1961) · Biochemical Pharmacology · doi:10.1016/0006-2952(61)90145-9 · Cited by 27,221 · see citing works
Analyzing real-time PCR data by the comparative CT method
Schmittgen, T. D., & Livak, K. J. (2008) · Nature Protocols · doi:10.1038/nprot.2008.73 · Cited by 26,190 · see citing works
Sequence and organization of the human mitochondrial genome
Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., et al. (1981) · Nature · doi:10.1038/290457a0 · Cited by 9,640 · see citing works
Aging: a theory based on free radical and radiation chemistry
Harman, D. (1956) · Journal of Gerontology · doi:10.1093/geronj/11.3.298 · Cited by 8,567 · see citing works
Motor Neuron Degeneration in Mice that Express a Human Cu,Zn Superoxide Dismutase Mutation
Gurney, M. E., Pu, H., Chiu, A. Y., Dal Canto, M. C., Polchow, C. Y., Alexander, D. D., Caliendo, J., Hentati, A., Kwon, Y. W., Deng, H.-X., et al. (1994) · Science · doi:10.1126/science.8209258 · Cited by 4,143 · see citing works
Premature ageing in mice expressing defective mitochondrial DNA polymerase
Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly-Y, M., Gidlöf, S., Oldfors, A., Wibom, R., et al. (2004) · Nature · doi:10.1038/nature02517 · Cited by 2,734 · see citing works
Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging
Kujoth, G. C., Hiona, A., Pugh, T. D., Someya, S., Panzer, K., Wohlgemuth, S. E., Hofer, T., Seo, A. Y., Sullivan, R., Jobling, W. A., et al. (2005) · Science · doi:10.1126/science.1112125 · Cited by 2,165 · see citing works
Decline in skeletal muscle mitochondrial function with aging in humans
Short, K. R., Bigelow, M. L., Kahl, J., Singh, R., Coenen-Schimke, J., Raghavakaimal, S., & Nair, K. S. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501559102 · Cited by 1,333 · see citing works
Visser, M., Pahor, M., Taaffe, D. R., Goodpaster, B. H., Simonsick, E. M., Newman, A. B., Nevitt, M., & Harris, T. B. (2002) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/57.5.m326 · Cited by 1,294 · see citing works
Inflammatory markers and loss of muscle mass (sarcopenia) and strength
Schaap, L. A., Pluijm, S. M. F., Deeg, D. J. H., & Visser, M. (2006) · The American Journal of Medicine · doi:10.1016/j.amjmed.2005.10.049 · Cited by 1,047 · see citing works
Detection of a specific mitochondrial DNA deletion in tissues of older humans
Cortopassi, G. A., & Arnheim, N. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.23.6927 · Cited by 785 · see citing works
The human protein disulphide isomerase family: substrate interactions and functional properties
Ellgaard, L., & Ruddock, L. W. (2005) · EMBO Reports · doi:10.1038/sj.embor.7400311 · Cited by 757 · see citing works
Kong, J., & Xu, Z. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-09-03241.1998 · Cited by 723 · see citing works
The numbers of limb motor neurons in the human lumbosacral cord throughout life
Tomlinson, B. E., & Irving, D. (1977) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(77)90069-7 · Cited by 602 · see citing works
Review Article: Sarcopenia: Causes, Consequences, and Preventions
Marcell, T. J. (2003) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/58.10.m911 · Cited by 536 · see citing works
Satellite-cell pool size does matter: Defining the myogenic potency of aging skeletal muscle
Shefer, G., de Mark, D. P. V., Richardson, J. B., & Yablonka‐Reuveni, Z. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.02.022 · Cited by 506 · see citing works
Valdez, G., Tapia, J. C., Kang, H., Clemenson, G. D., Gage, F. H., Lichtman, J. W., & Sanes, J. R. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002220107 · Cited by 502 · see citing works
Bua, E., Johnson, J., Herbst, A., Delong, B., McKenzie, D., Salamat, S., & Aiken, J. M. (2006) · The American Journal of Human Genetics · doi:10.1086/507132 · Cited by 442 · see citing works
Belteki, G., Haigh, J., Kabacs, N., Haigh, K., Sison, K., Costantini, F., Whitsett, J., Quaggin, S., & Nagy, A. (2005) · Nucleic Acids Research · doi:10.1093/nar/gni051 · Cited by 423 · see citing works
Cellular and molecular mechanisms underlying age-related skeletal muscle wasting and weakness
Ryall, J. G., Schertzer, J. D., & Lynch, G. S. (2008) · Biogerontology · doi:10.1007/s10522-008-9131-0 · Cited by 423 · see citing works
Kayo, T., Allison, D. B., Weindruch, R., & Prolla, T. A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.081061898 · Cited by 384 · see citing works
Transcriptional profiling of aging in human muscle reveals a common aging signature
Zahn, J. M., Sonu, R., Vogel, H., Crane, E., Mazan-Mamczarz, K., Rabkin, R., Davis, R. W., Becker, K. G., Owen, A. B., & Kim, S. K. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020115 · Cited by 351 · see citing works
Molecular inflammation hypothesis of aging based on the anti‐aging mechanism of calorie restriction
Chung, H. Y., Kim, H. J., Kim, K. W., Choi, J. S., & Yu, B. P. (2002) · Microscopy Research and Technique · doi:10.1002/jemt.10203 · Cited by 297 · see citing works
Ibebunjo, C., Chick, J. M., Kendall, T., Eash, J. K., Li, C., Zhang, Y., Vickers, C., Wu, Z., Clarke, B. A., Shi, J., et al. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01036-12 · Cited by 267 · see citing works
In vivo and in organello assessment of OXPHOS activities
Barrientos, A. (2002) · Methods · doi:10.1016/s1046-2023(02)00036-1 · Cited by 266 · see citing works
Ahlqvist, K. J., Hämäläinen, R. H., Yatsuga, S., Uutela, M., Terzioglu, M., Götz, A., Forsström, S., Salvén, P., Angers‐Loustau, A., Kopra, O., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2011.11.012 · Cited by 240 · see citing works
Aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults
Safdar, A., Hamadeh, M. J., Kaczor, J. J., Raha, S., deBeer, J., & Tarnopolsky, M. A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010778 · Cited by 217 · see citing works
Chai, R. J., Vukovic, J., Dunlop, S. A., Grounds, M. D., & Shavlakadze, T. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028090 · Cited by 214 · see citing works
Herbst, A., Pak, J. W., McKenzie, D., Bua, E., Bassiouni, M., & Aiken, J. M. (2007) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/62.3.235 · Cited by 200 · see citing works
Kinetics of Human Aging: I. Rates of Senescence Between Ages 30 and 70 Years in Healthy People
Sehl, M. E., & Yates, F. E. (2001) · The Journals of Gerontology Series A · doi:10.1093/gerona/56.5.b198 · Cited by 198 · see citing works
[43]Cytochemistry and immunocytochemistry of mitochondria in tissue sections
Sciacco, M., & Bonilla, E. (1996) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(96)64045-2 · Cited by 192 · see citing works
Longitudinal changes in body composition associated with healthy ageing: men, aged 20–96 years
Jackson, A. S., Janssen, I., Sui, X., Church, T. S., & Blair, S. N. (2011) · British Journal Of Nutrition · doi:10.1017/s0007114511003886 · Cited by 189 · see citing works
The role of systemic inflammation in age‐related muscle weakness and wasting
Degens, H. (2009) · Scandinavian Journal of Medicine and Science in Sports · doi:10.1111/j.1600-0838.2009.01018.x · Cited by 188 · see citing works
Manipulating mitochondrial DNA heteroplasmy by a mitochondrially targeted restriction endonuclease
Srivastava, S. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.26.3093 · Cited by 187 · see citing works
Mechanisms of formation and accumulation of mitochondrial DNA deletions in aging neurons
Fukui, H., & Moraes, C. T. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn437 · Cited by 185 · see citing works
Self-citationRegular exercise is beneficial to a mouse model of amyotrophic lateral sclerosis
Kirkinezos, I. G., Hernandez, D., Bradley, W. G., & Moraes, C. T. (2003) · Annals of Neurology · doi:10.1002/ana.10597 · Cited by 179 · see citing works
Self-citationDíaz, F., Thomas, C. K., García, S., Hernandez, D., & Moraes, C. T. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi307 · Cited by 179 · see citing works
Self-citationLi, Y., Lee, Y. I., & Thompson, W. J. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.3590-11.2011 · Cited by 165 · see citing works
Srivastava, S., & Moraes, C. T. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi082 · Cited by 162 · see citing works
Self-citationCoskun, P. E., Wyrembak, J., Derbereva, O., Melkonian, G., Doran, E. W., Lott, I. T., Head, E., Cotman, C. W., & Wallace, D. C. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100351 · Cited by 158 · see citing works
Detmer, S. A., Velde, C. V., Cleveland, D. W., & Chan, D. C. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm314 · Cited by 148 · see citing works
Drey, M., Sieber, C. C., Bauer, J. M., Uter, W. J. C., Dahinden, P., Fariello, R. G., & Vrijbloed, J. W. (2012) · Experimental Gerontology · doi:10.1016/j.exger.2012.05.021 · Cited by 132 · see citing works
Mitochondrial DNA Damage Level Determines Neural Stem Cell Differentiation Fate
Wang, W., Esbensen, Y., Kunke, D., Suganthan, R., Rachek, L. I., Bjørås, M., & Eide, L. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.0852-11.2011 · Cited by 131 · see citing works
Bacman, S. R., Williams, S. L., & Moraes, C. T. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp348 · Cited by 122 · see citing works
Self-citationThe Striatum Is Highly Susceptible to Mitochondrial Oxidative Phosphorylation Dysfunctions
Pickrell, A. M., Fukui, H., Wang, X., Pinto, M., & Moraes, C. T. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.6223-10.2011 · Cited by 114 · see citing works
Self-citationCourtney, J., & Steinbach, J. H. (1981) · The Journal of Physiology · doi:10.1113/jphysiol.1981.sp013960 · Cited by 110 · see citing works
Origins and Consequences of Mitochondrial Variation in Vertebrate Muscle
Moyes, C. D., & Hood, D. A. (2003) · Annual Review of Physiology · doi:10.1146/annurev.physiol.65.092101.142705 · Cited by 88 · see citing works
Effects of Age and Sedentary Lifestyle on Skeletal Muscle NF- B Signaling in Men
Buford, T. W., Cooke, M. B., Manini, T. M., Leeuwenburgh, C., & Willoughby, D. S. (2010) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glp196 · Cited by 78 · see citing works
Habitual exercise program protects murine intestinal, skeletal, and cardiac muscles against aging
Rosa, E. F., Silva, A. C., Ihara, S. S. M., Mora, O. A., Aboulafia, J., & Nouailhetas, V. L. A. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00417.2005 · Cited by 77 · see citing works
Mitochondrial DNA copy number threshold in mtDNA depletion myopathy
Durham, S. E., Bonilla, E., Samuels, D. C., DiMauro, S., & Chinnery, P. F. (2005) · Neurology · doi:10.1212/01.wnl.0000171861.30277.88 · Cited by 52 · see citing works
Muscle weakness and neuromuscular junctions in aging and disease
Shigemoto, K., Kubo, S., Mori, S., et al. (2010) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/j.1447-0594.2010.00608.x · Cited by 45 · see citing works
Macharia, R., Otto, A., Valášek, P., & Patel, K. (2010) · Muscle & Nerve · doi:10.1002/mus.21637 · Cited by 44 · see citing works
Localization of “non-extractable” acetylcholinesterase to the vertebrate neuromuscular junction.
Rossi, S. G., & Rotundo, R. L. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)46746-9 · Cited by 40 · see citing works
Self-citationYoshioka, M., Tanaka, H., Shono, N., Snyder, E. E., Shindo, M., & St‐Amand, J. (2003) · The FASEB Journal · doi:10.1096/fj.02-1200com · Cited by 38 · see citing works
Muscle atrophy is not always sarcopenia
Hepple, R. T. (2012) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00304.2012 · Cited by 34 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mitochondrial dysfunction and sarcopenia of aging: from signaling pathways to clinical trials
Marzetti, E., Calvani, R., Cesari, M., Buford, T. W., Lorenzi, M., Behnke, B. J., & Leeuwenburgh, C. (2013) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2013.06.024 · Cited by 627 · see citing works
Mitochondria initiate and regulate sarcopenia
Alway, S. E., Mohamed, J. S., & Myers, M. J. (2017) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000101 · Cited by 153 · see citing works
“MITOCHONDRIAL PERMEABILITY TRANSITION PORE SENSITIZATION WITH AGING — MITOCHONDRIAL DYSFUNCTION Stress-induced damage to mitochondrial membranes (40,108,144,147) contributes to sensitization of the mitochondrial permeability transition pore (44).”
Background
- Authors
- Wang, X., Pickrell, A. M., Rossi, S. G., Pinto, M., Dillon, L. M., Hida, A., Rotundo, R. L., & Moraes, C. T.
- Affiliations
- University of Miami (US)
- Corresponding author
- Moraes, Carlos T.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-06-10
- Volume
- 22
- Issue
- 19
- Pages
- 3976-3986
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3766186
- OpenAlex
- W2155426150
- Cited by
- 54
- References
- 58
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 5 · 2016: 6 · 2015: 7 · 2014: 4 · 2013: 2
- FWCI
- 2.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association (11Pre7610007)
- Muscular Dystrophy Association
- National Institutes of Health
- National Institute on Aging (AG036871, R01AG036871)
- National Eye Institute (EY010804, R01EY010804)
- National Institute of Neurological Disorders and Stroke (NS079965, U01NS057994, R01NS079965, NS057994)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Keywords
- sarcopenia, muscle atrophy, mitochondrial DNA damage, satellite cells, muscle regeneration, mitochondrial dysfunction, premature aging, acetylcholinesterase, neuromuscular junction, locomotor activity, aging
- MeSH terms
- Acetylcholinesterase, Animals, DNA Damage, DNA, Mitochondrial, Female, Male, Mice, Transgenic, Mitochondria, Muscle, Motor Activity, Neuromuscular Junction, Deoxyribonucleases, Type II Site-Specific, Oxidative Stress, Muscle, Skeletal, Molecular Chaperones, Satellite Cells, Skeletal Muscle, Mice, DNA Breaks, Double-Stranded, Sarcopenia
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
