Apoptosis and necrosis mediate skeletal muscle fiber loss in age-induced mitochondrial enzymatic abnormalities
Open accessAbstract
Sarcopenia, the age-induced loss of skeletal muscle mass and function, results from the contributions of both fiber atrophy and loss of myofibers. We have previously characterized sarcopenia in FBN rats, documenting age-dependent declines in muscle mass and fiber number along with increased fiber atrophy and fibrosis in vastus lateralis and rectus femoris muscles. Concomitant with these sarcopenic changes is an increased abundance of mitochondrial DNA deletion mutations and electron transport chain (ETC) abnormalities. In this study, we used immunohistological and histochemical approaches to define cell death pathways involved in sarcopenia. Activation of muscle cell death pathways was age-dependent with most apoptotic and necrotic muscle fibers exhibiting ETC abnormalities. Although activation of apoptosis was a prominent feature of electron transport abnormal muscle fibers, necrosis was predominant in atrophic and broken ETC-abnormal fibers. These data suggest that mitochondrial dysfunction is a major contributor to the activation of cell death processes in aged muscle fibers. The link between ETC abnormalities, apoptosis, fiber atrophy, and necrosis supports the hypothesis that mitochondrial DNA deletion mutations are causal in myofiber loss. These studies suggest a progression of events beginning with the generation and accumulation of a mtDNA deletion mutation, the concomitant development of ETC abnormalities, a subsequent triggering of apoptotic and, ultimately, necrotic events resulting in muscle fiber atrophy, breakage, and fiber loss.
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Increased apoptosis can activate E3 ligases Atrogin-1 and MuRF1, causing increased protein degradation and exacerbated aging-induced skeletal muscle loss.
“and increased apoptosis can activate E3 ligases Atrogin-1 and MuRF1, thus causing increased protein degradation and exacerbated aging-induced skeletal muscle loss [40].”
From Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK/PGC-1α Signaling Pathway (2021) · cites this paper as [40]
Apoptosis signaling has been reported in muscle and neuronal cells of aged rodents and humans.
“Apoptosis signaling has been reported in muscle and neuronal cells of aged rodents (4, 7, 26, 34, 47, 77, 88, 130), and humans (44, 145).”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [26]
A localized apoptotic and proteolytic signaling cascade that expands to neighboring regions of a muscle fiber has strong support from Aiken and co-workers.
“Our model for a localized apoptotic and proteolytic signaling cascade that expands to neighboring regions of a muscle fiber (Figure 2) has strong support from the work of Aiken and co-workers (26, 49, 50).”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [26]
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Cites
Release of chromatin protein HMGB1 by necrotic cells triggers inflammation
Scaffidi, P., Misteli, T., & Bianchi, M. E. (2002) · Nature · doi:10.1038/nature00858 · Cited by 4,221 · see citing works
Sarcopenia: origins and clinical relevance
Rosenberg, I. H. (1997) · The Journal of Nutrition · doi:10.1093/jn/127.5.990s · Cited by 2,399 · see citing works
Aging of skeletal muscle: a 12-yr longitudinal study
Frontera, W. R., Hughes, V. A., Fielding, R. A., Fiatarone, M. A., Evans, W. J., & Roubenoff, R. (2000) · Journal of Applied Physiology · doi:10.1152/jappl.2000.88.4.1321 · Cited by 1,443 · see citing works
Visser, M., Deeg, D. J. H., & Lips, P. T. A. M. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030604 · Cited by 1,100 · see citing works
The role of mitochondria in aging
Bratic, A., & Larsson, N.-G. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64125 · Cited by 1,087 · see citing works
The complement system in regulation of adaptive immunity
Carroll, M. C. (2004) · Nature Immunology · doi:10.1038/ni1113 · Cited by 1,035 · see citing works
Sarcopenia: origins and clinical relevance
Rosenberg, I. H. (2011) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2011.03.003 · Cited by 786 · see citing works
Apoptosis and Necrosis in the Liver: A Tale of Two Deaths?
Malhi, H., Gores, G. J., & Lemasters, J. J. (2006) · Hepatology · doi:10.1002/hep.21062 · Cited by 688 · 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
Self-citationMitochondrial function and apoptotic susceptibility in aging skeletal muscle
Chabi, B., Ljubicic, V., Menzies, K. J., Huang, J. H., Saleem, A., & Hood, D. A. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2007.00347.x · Cited by 437 · see citing works
WANAGAT, J., CAO, Z., PATHARE, P., & AIKEN, J. M. (2001) · The FASEB Journal · doi:10.1096/fj.00-0320com · Cited by 378 · see citing works
Self-citationApoptosis in skeletal muscle with aging
Dirks, A., & Leeuwenburgh, C. (2002) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00458.2001 · Cited by 377 · see citing works
Distribution of different fibre types in human skeletal muscles
Lexell, J. E., Downham, D. Y., & Sjöstróm, M. (1986) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(86)90009-2 · Cited by 342 · see citing works
Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans
Syntichaki, P., Xu, K., Driscoll, M., & Tavernarakis, N. (2002) · Nature · doi:10.1038/nature01108 · Cited by 305 · see citing works
Macrophage Plasticity and the Role of Inflammation in Skeletal Muscle Repair
Kharraz, Y., Guerra, J., Mann, C. J., Serrano, A. L., & Muñoz‐Cánoves, P. (2013) · Mediators of Inflammation · doi:10.1155/2013/491497 · Cited by 302 · see citing works
Jang, Y. C., Lustgarten, M. S., Liu, Y., Müller, F. L., Bhattacharya, A., Liang, H., Salmon, A. B., Brooks, S. V., Larkin, L. M., Hayworth, C. R., et al. (2009) · The FASEB Journal · doi:10.1096/fj.09-146308 · Cited by 290 · see citing works
Hiona, A., Sanz, A., Kujoth, G. C., Pamplona, R., Seo, A. Y., Hofer, T., Someya, S., Miyakawa, T., Chie, N., Samhan-Arias, A. K., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011468 · Cited by 269 · see citing works
Mitochondrial abnormalities are more frequent in muscles undergoing sarcopenia
Bua, E. A., McKiernan, S. H., Wanagat, J., McKenzie, D., & Aiken, J. M. (2002) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01102.2001 · Cited by 223 · see citing works
Self-citationApoptosis in muscle atrophy: Relevance to sarcopenia
Dupont‐Versteegden, E. E. (2005) · Experimental Gerontology · doi:10.1016/j.exger.2005.04.003 · Cited by 207 · 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
Self-citationThe Physical and Biological Characterization of a Frail Mouse Model
Walston, J. D., Fedarko, N. S., Yang, H., Leng, S. X., Beamer, B. A., Espinoza, S. E., Lipton, A., Zheng, H., & Becker, K. G. (2008) · The Journals of Gerontology Series A · doi:10.1093/gerona/63.4.391 · Cited by 192 · see citing works
Dirks, A. J., & Leeuwenburgh, C. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2003.10.003 · Cited by 190 · see citing works
Cao, Z. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.21.4502 · Cited by 170 · see citing works
Müller-Höcker, J., Seibel, P., Schneiderbanger, K., & Kadenbach, B. (1993) · Virchows Archiv A Pathological Anatomy and Histopathology · doi:10.1007/bf01605127 · Cited by 168 · see citing works
Gaipl, U. S., Kuenkele, S., Voll, R. E., Beyer, T. D., Kolowos, W., Heyder, P., Kalden, J. R., & i, M. H. (2001) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400826 · Cited by 159 · see citing works
Whitman, S. A., Wacker, M. J., Richmond, S. R., & Godard, M. P. (2005) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-005-1473-8 · Cited by 156 · see citing works
The Role of Apoptosis in Age-Related Skeletal Muscle Atrophy
Dirks, A. J., & Leeuwenburgh, C. (2005) · Sports Medicine · doi:10.2165/00007256-200535060-00002 · Cited by 153 · see citing works
Aging influences cellular and molecular responses of apoptosis to skeletal muscle unloading
Siu, P. M., Pistilli, E. E., Butler, D. C., & Alway, S. E. (2004) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00239.2004 · Cited by 143 · see citing works
Late‐onset mitochondrial myopathy
Johnston, W. S. W., Karpati, G., Carpenter, S., Arnold, D. L., & Shoubridge, E. A. (1995) · Annals of Neurology · doi:10.1002/ana.410370106 · Cited by 140 · see citing works
Urinary incontinence in the elderly and age-dependent apoptosis of rhabdosphincter cells
Strasser, H., Tiefenthaler, M., Steinlechner, M., Bartsch, G. H., & Konwalinka, G. (1999) · The Lancet · doi:10.1016/s0140-6736(99)02588-x · Cited by 137 · see citing works
Molecular nature of the complement lesion.
Bhakdi, S., & Tranum-Jensen, J. (1978) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.75.11.5655 · Cited by 116 · see citing works
Multiple Mitochondrial DNA Deletions Associated With Age in Skeletal Muscle of Rhesus Monkeys
Lee, C. M., Chung, S. S., Kaczkowski, J. M., Weindruch, R. H., & Aiken, J. M. (1993) · Journal of Gerontology · doi:10.1093/geronj/48.6.b201 · Cited by 115 · see citing works
Self-citationSatellite cell regulation of muscle mass is altered at old age
Gallegly, J. C., Turesky, N. A., Strotman, B. A., Gurley, C. M., Peterson, C. A., & Dupont‐Versteegden, E. E. (2004) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00006.2004 · Cited by 114 · see citing works
Marzetti, E., Carter, C. S., Wohlgemuth, S. E., Lees, H. A., Giovannini, S., Anderson, B., Quinn, L. S., & Leeuwenburgh, C. (2009) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.12.008 · Cited by 113 · see citing works
Cell Death by Necrosis, a Regulated Way to Go
Henríquez, M., Armisén, R., Stutzin, A., & Quest, A. F. G. (2008) · Current Molecular Medicine · doi:10.2174/156652408784221289 · Cited by 101 · see citing works
Gokey, N. G., Cao, Z., Pak, J. W., Lee, D., McKiernan, S. H., McKenzie, D. I., Weindruch, R. H., & Aiken, J. M. (2004) · Aging Cell · doi:10.1111/j.1474-9728.2004.00122.x · Cited by 90 · see citing works
Self-citationSarcopenia Accelerates at Advanced Ages in Fisher 344xBrown Norway Rats
Lushaj, E. B., Johnson, J. K., McKenzie, D. I., & Aiken, J. M. (2008) · The Journals of Gerontology Series A · doi:10.1093/gerona/63.9.921 · Cited by 81 · see citing works
Self-citationMolecular Regulation of Apoptosis in Fast Plantaris Muscles of Aged Rats
Pistilli, E. E., Siu, P. M., & Alway, S. E. (2006) · The Journals of Gerontology Series A · doi:10.1093/gerona/61.3.245 · Cited by 67 · see citing works
Bua, E. A., McKiernan, S. H., & Aiken, J. M. (2004) · The FASEB Journal · doi:10.1096/fj.03-0668fje · Cited by 57 · see citing works
Self-citationDystrophin gene transcripts skipping the mdx mutation
Wilton, S. D., Dye, D. E., & Laing, N. G. (1997) · Muscle & Nerve · doi:10.1002/(sici)1097-4598(199706)20:6 · Cited by 52 · see citing works
Contribution of membrane localization to the apoptotic activity of PUMA
Yee, K. S. Y., & Vousden, K. H. (2007) · APOPTOSIS · doi:10.1007/s10495-007-0140-2 · Cited by 47 · see citing works
Apoptosis in multinucleated skeletal muscle myotubes.
McArdle, A., Maglara, A., Appleton, P. L., Watson, A. J. M., Grierson, I., & Jackson, M. J. (1999) · PubMed · Cited by 43 · see citing works
Malmgren, L. T., Jones, C. E., & Bookman, L. M. (2001) · Otolaryngology · doi:10.1067/mhn.2001.116449 · Cited by 39 · see citing works
Lee, C. M., Eimon, P. M., Weindruch, R. H., & Aiken, J. M. (1994) · Mechanisms of Ageing and Development · doi:10.1016/0047-6374(94)90029-9 · Cited by 31 · see citing works
Self-citationHerbst, A. J., Johnson, C. J., Hynes, K., McKenzie, D. I., & Aiken, J. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059006 · Cited by 21 · see citing works
Self-citationAlway, S. E., Morissette, M. R., & Siu, P. M. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-378638-8.00004-x · Cited by 21 · see citing works
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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
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Picca, A., Calvani, R., Bossola, M., Allocca, E., Menghi, A., Pesce, V., Lezza, A. M. S., Bernabei, R., Landi, F., & Marzetti, E. (2018) · Biological Chemistry · doi:10.1515/hsz-2017-0331 · Cited by 116 · see citing works
Mitochondrial Dysfunction in Skeletal Muscle Pathologies
Abrigo, J., Simon, F., Cabrera, D., Vilos, C., & Cabello-Verrugio, C. (2019) · Current Protein & Peptide Science · doi:10.2174/1389203720666190402100902 · Cited by 88 · see citing works
Liang, J., Zhang, H., Zeng, Z., Wu, L., Zhang, Y., Guo, Y., Lv, J., Wang, C., Fan, J., & Chen, N. (2021) · Metabolites · doi:10.3390/metabo11050323 · Cited by 84 · see citing works
Schwartz, L. M. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2018.01887 · Cited by 65 · see citing works
Exercise is muscle mitochondrial medicine
Oliveira, A. N., Richards, B. J., Slavin, M., & Hood, D. A. (2021) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000250 · Cited by 26 · see citing works
Long-Term PGC1β Overexpression Leads to Apoptosis, Autophagy and Muscle Wasting
Sopariwala, D. H., Yadav, V., Badin, P.-M., Likhite, N., Sheth, M., Lorca, S., Vila, I. K., Kim, E. R., Tong, Q., Song, M. S., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-10238-9 · Cited by 14 · see citing works
- Authors
- Cheema, N., Herbst, A., McKenzie, D., & Aiken, J. M.
- Affiliations
- University of Alberta (CA)
- Corresponding author
- Aiken, Judd M.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2015-09-14
- Volume
- 14
- Issue
- 6
- Pages
- 1085-1093
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- OpenAlex
- W1888940543
- Cited by
- 107
- References
- 46
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 8 · 2023: 11 · 2022: 9 · 2021: 13 · 2020: 9 · 2019: 9 · 2018: 9 · 2017: 13 · 2016: 5 · 2015: 1
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- NIH (R01 AG030423)
- 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, apoptosis, necrosis, mitochondrial dysfunction, muscle fiber atrophy, aging, cell death pathways
- MeSH terms
- Aging, Animals, DNA, Mitochondrial, Electron Transport, Male, Mitochondria, Necrosis, Rats, Inbred F344, Biomarkers, Apoptosis, Sequence Deletion, Muscle Fibers, Skeletal, Rats, Quadriceps Muscle, Sarcopenia
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