Regulation of muscle and mitochondrial health by the mitochondrial fission protein Drp1 in aged mice
Abstract
Key points: The maintenance of mitochondrial integrity is critical for skeletal muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control; however, the exact role that mitochondrial fission plays in the muscle ageing process remains unclear. Here we report that both Drp1 knockdown and Drp1 overexpression late in life in mice is detrimental to skeletal muscle function and mitochondrial health. Drp1 knockdown in 18‐month‐old mice resulted in severe skeletal muscle atrophy, mitochondrial dysfunction, muscle degeneration/regeneration, oxidative stress and impaired autophagy. Overexpressing Drp1 in 18‐month‐old mice resulted in mild skeletal muscle atrophy and decreased mitochondrial quality. Our data indicate that silencing or overexpressing Drp1 late in life is detrimental to skeletal muscle integrity. We conclude that modulating Drp1 expression is unlikely to be a viable approach to counter the muscle ageing process. Sarcopenia, the ageing‐related loss of skeletal muscle mass and function, is a debilitating process negatively impacting the quality of life of afflicted individuals. Although the mechanisms underlying sarcopenia are still only partly understood, impairments in mitochondrial dynamics, and specifically mitochondrial fission, have been proposed as an underlying mechanism. Importantly, conflicting data exist in the field and both excessive and insufficient mitochondrial fission were proposed to contribute to sarcopenia. In Drosophila melanogaster , enhancing mitochondrial fission in midlife through overexpression of dynamin‐1‐like protein (Drp1) extended lifespan and attenuated several key hallmarks of muscle ageing. Whether a similar outcome of Drp1 overexpression is observed in mammalian muscles remains unknown. In this study, we investigated the impact of knocking down and overexpressing Drp1 protein for 4 months in skeletal muscles of late middle‐aged (18 months) mice using intra‐muscular injections of adeno‐associated viruses expressing shRNA targeting Drp1 or full Drp1 cDNA. We report that knocking down Drp1 expression late in life triggers severe muscle atrophy, mitochondrial dysfunctions, degeneration/regeneration, oxidative stress and impaired autophagy. Drp1 overexpression late in life triggered mild muscle atrophy and decreased mitochondrial quality. Taken altogether, our results indicate that both overexpression and silencing of Drp1 in late middle‐aged mice negatively impact skeletal muscle mass and mitochondrial health. These data suggest that Drp1 content must remain within a narrow physiological range to preserve muscle and mitochondrial integrity during ageing. Altering Drp1 expression is therefore unlikely to be a viable target to counter sarcopenia.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Targeting Drp1 expression is unlikely to be a viable target to counter sarcopenia.
“These recent findings, therefore, indicate that targeting Drp1 expression is unlikely to be a viable target to counter sarcopenia”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [71]
Mitochondrial fission must be maintained within a specific physiological range to preserve muscle and mitochondrial health.
“indicate that mitochondrial fission must be maintained within a specific physiological range to preserve muscle and mitochondrial health.”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [71]
Knocking down or overexpressing Drp1 late in life in mouse skeletal muscle (from 18 to 22 months of age) is detrimental to skeletal muscle mass and mitochondrial health.
“we recently reported that knocking down or overexpressing Drp1 late in life in mouse skeletal muscle (from 18 to 22 months of age) is detrimental to skeletal muscle mass and mitochondrial health [71].”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [71]
Cites
Janssen, I., Heymsfield, S. B., & Ross, R. (2002) · Journal of the American Geriatrics Society · doi:10.1046/j.1532-5415.2002.50216.x · Cited by 3,139 · cited 1× · see citing works
“Sarcopenia leads to mobility impairment, falls and physical frailty (Janssen et al. 2002; Janssen et al. 2004; Kim & Choi, 2013).”
BackgroundFission and selective fusion govern mitochondrial segregation and elimination by autophagy
Twig, G., Elorza, A., Molina, A. J. A., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., et al. (2008) · The EMBO Journal · doi:10.1038/sj.emboj.7601963 · Cited by 3,082 · see citing works
Mitochondrial dynamics: overview of molecular mechanisms
Tilokani, L., Nagashima, S., Paupe, V., & Prudent, J. (2018) · Essays in Biochemistry · doi:10.1042/ebc20170104 · Cited by 1,397 · 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
Skeletal Muscle Cutpoints Associated with Elevated Physical Disability Risk in Older Men and Women
Janssen, I. (2004) · American Journal of Epidemiology · doi:10.1093/aje/kwh058 · Cited by 1,190 · see citing works
Ryu, D., Mouchiroud, L., Andreux, P. A., Katsyuba, E., Moullan, N., Nicolet-dit-Félix, A. A., Williams, E. G., Jha, P., Lo Sasso, G., Huzard, D., et al. (2016) · Nature Medicine · doi:10.1038/nm.4132 · Cited by 1,105 · see citing works
Mitochondrial Fusion and Fission in Mammals
Chan, D. C. (2006) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.22.010305.104638 · Cited by 972 · see citing works
The Machines that Divide and Fuse Mitochondria
Hoppins, S., Lackner, L., & Nunnari, J. (2007) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.76.071905.090048 · Cited by 790 · see citing works
Clinical definition of sarcopenia.
Santilli, V., Bernetti, A., Mangone, M., & Paoloni, M. (2014) · CLINICAL CASES IN MINERAL AND BONE METABOLISM · doi:10.11138/ccmbm/2014.11.3.177 · Cited by 722 · see citing works
Tezze, C., Romanello, V., Desbats, M. A., Fadini, G. P., Albiero, M., Favaro, G., Ciciliot, S., Soriano, M. E., Morbidoni, V., Cerqua, C., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.021 · Cited by 568 · see citing works
Sarcopenia: Definition, Epidemiology, and Pathophysiology
Kim, T. N., & Choi, K. M. (2013) · Journal of Bone Metabolism · doi:10.11005/jbm.2013.20.1.1 · Cited by 505 · see citing works
Song, M., Mihara, K., Chen, Y., Scorrano, L., & Dorn, G. W. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2014.12.011 · Cited by 482 · see citing works
Mitochondrial 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
Autophagy Impairment in Muscle Induces Neuromuscular Junction Degeneration and Precocious Aging
Carnio, S., LoVerso, F., Baraibar, M. A., Longa, E., Khan, M. M., Maffei, M., Reischl, M., Canepari, M., Loefler, S., Kern, H., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.061 · Cited by 423 · see citing works
Wu, S., Zhou, F., Zhang, Z., & Xing, D. (2011) · FEBS Journal · doi:10.1111/j.1742-4658.2011.08010.x · Cited by 420 · see citing works
Parkin‐independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain
Kageyama, Y., Hoshijima, M., Seo, K., Bedja, D., Sysa‐Shah, P., Andrabi, S. A., Chen, W., Höke, A., Dawson, V. L., Dawson, T. M., et al. (2014) · The EMBO Journal · doi:10.15252/embj.201488658 · Cited by 420 · see citing works
DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass
Favaro, G., Romanello, V., Varanita, T., Andrea Desbats, M., Morbidoni, V., Tezze, C., Albiero, M., Canato, M., Gherardi, G., De Stefani, D., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10226-9 · Cited by 398 · see citing works
Sebastián, D., Sorianello, E., Segalés, J., Irazoki, A., Ruiz‐Bonilla, V., Sala, D., Planet, E., Berenguer‐Llergo, A., Muñoz, J. P., Sánchez‐Feutrie, M., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201593084 · Cited by 396 · see citing works
Rana, A., Oliveira, M. P., Khamoui, A. V., Aparicio, R., Rera, M., Rossiter, H. B., & Walker, D. W. (2017) · Nature Communications · doi:10.1038/s41467-017-00525-4 · Cited by 294 · see citing works
Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice
Leduc-Gaudet, J.-P., Picard, M., Pelletier, F. S.-J., Sgarioto, N., Auger, M.-J., Vallée, J., Robitaille, R., St-Pierre, D. H., & Gouspillou, G. (2015) · Oncotarget · doi:10.18632/oncotarget.4235 · Cited by 273 · see citing works
Self-citationMitochondria: isolation, structure and function
Picard, M. A., Taivassalo, T., Gouspillou, G., & Hepple, R. T. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.212712 · Cited by 251 · see citing works
Self-citationMolecular mechanisms and physiologic functions of mitochondrial dynamics
Otera, H., & Mihara, K. (2011) · The Journal of Biochemistry · doi:10.1093/jb/mvr002 · Cited by 251 · see citing works
Age-related differences in apoptosis with disuse atrophy in soleus muscle
Leeuwenburgh, C., Gurley, C. M., Strotman, B. A., & Dupont-Versteegden, E. E. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00576.2004 · Cited by 231 · see citing works
Lanza, I. R., Zabielski, P., Klaus, K. A., Morse, D. M., Heppelmann, C. J., Bergen, H. R., Dasari, S., Walrand, S., Short, K. R., Johnson, M. L., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.11.003 · Cited by 227 · see citing works
Gouspillou, G., Sgarioto, N., Kapchinsky, S., Purves‐Smith, F., Norris, B., Pion, C. H., Barbat‐Artigas, S., Lemieux, F., Taivassalo, T., Morais, J. A., et al. (2014) · The FASEB Journal · doi:10.1096/fj.13-242750 · Cited by 217 · see citing works
Self-citationMarzetti, E., Wohlgemuth, S. E., Lees, H. A., Chung, H.-Y., Giovannini, S., & Leeuwenburgh, C. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.05.005 · Cited by 172 · see citing works
Iqbal, S., Ostojic, O., Singh, K., Joseph, A., & Hood, D. A. (2013) · Muscle & Nerve · doi:10.1002/mus.23838 · Cited by 169 · cited 5× · see citing works
“These changes in the expression of mitochondrial fusion and fission proteins were associated with mitochondrial fragmentation in aged animals (Iqbal et al. 2013).”
BackgroundResultInfluentialDrummond, M. J., Addison, O., Brunker, L., Hopkins, P. N., McClain, D. A., LaStayo, P. C., & Marcus, R. L. (2014) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glu004 · Cited by 161 · see citing works
Koltai, E., Hart, N., Taylor, A. W., Goto, S., Ngo, J. K., Davies, K. J. A., & Radak, Z. (2012) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00337.2011 · Cited by 152 · see citing works
Mitochondrial energetics is impaired <i>in vivo</i> in aged skeletal muscle
Gouspillou, G., Bourdel‐Marchasson, I., Rouland, R., Calmettes, G., Biran, M., Deschodt‐Arsac, V., Miraux, S., Thiaudiere, E., Pasdois, P., Detaille, D., et al. (2014) · Aging Cell · doi:10.1111/acel.12147 · Cited by 147 · see citing works
Self-citationPicard, M. A., Ritchie, D., Thomas, M. M., Wright, K. J., & Hepple, R. T. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00745.x · Cited by 145 · see citing works
Muscle-specific Drp1 overexpression impairs skeletal muscle growth via translational attenuation
Touvier, T., De Palma, C., Rigamonti, E., Scagliola, A., Incerti, E., Mazelin, L., Thomas, J.-L., D'Antonio, M., Politi, L., Schaeffer, L., et al. (2015) · Cell Death & Disease · doi:10.1038/cddis.2014.595 · Cited by 140 · see citing works
Gouspillou, G., Sgarioto, N., Norris, B. A., Barbat‐Artigas, S., Aubertin‐Leheudre, M., Morais, J. A., Burelle, Y., Taivassalo, T., & Hepple, R. T. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103044 · Cited by 133 · see citing works
Self-citationMoore, T. M., Zhou, Z., Cohn, W., Norheim, F., Lin, A. J., Kalajian, N., Strumwasser, A. R., Cory, K., Whitney, K., Ho, T., et al. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2018.11.012 · Cited by 131 · see citing works
Hwee, D. T., Baehr, L. M., Philp, A., Baar, K., & Bodine, S. C. (2014) · Aging Cell · doi:10.1111/acel.12150 · Cited by 121 · see citing works
Parkin overexpression protects from ageing‐related loss of muscle mass and strength
Leduc‐Gaudet, J., Reynaud, O., Hussain, S. N., & Gouspillou, G. (2019) · The Journal of Physiology · doi:10.1113/jp277157 · Cited by 119 · see citing works
Self-citationGiant mitochondria do not fuse and exchange their contents with normal mitochondria
Navratil, M., Terman, A., & Arriaga, E. A. (2007) · Experimental Cell Research · doi:10.1016/j.yexcr.2007.09.013 · Cited by 94 · see citing works
Dulac, M., Leduc‐Gaudet, J., Reynaud, O., Ayoub, M., Guérin, A., Finkelchtein, M., Hussain, S. N., & Gouspillou, G. (2020) · The Journal of Physiology · doi:10.1113/jp279802 · Cited by 90 · cited 8× · see citing works
“As previously reported in young mice (Dulac et al. 2020), the substantial decrease in mitochondrial respiratory capacity triggered by Drp1 knockdown in aged mice was not associated with an increase in mitochondrial H2O2 emission, likely ruling out mitochondrial ROS overproduction as a potential…”
BackgroundResultInfluentialSelf-citationWPRE-mediated enhancement of gene expression is promoter and cell line specific
Klein, R., Ruttkowski, B., Knapp, E., Salmons, B., Günzburg, W. H., & Hohenadl, C. (2006) · Gene · doi:10.1016/j.gene.2005.12.018 · Cited by 81 · see citing works
Age-related changes in the skeletal muscle cells.
Beregi, E., Regius, O., Hüttl, T. P., & Göbl, Z. (1988) · PubMed · Cited by 81 · see citing works
Sakellariou, G. K., Pye, D., Vasilaki, A., Zibrik, L., Palomero, J., Kabayo, T., McArdle, F., Remmen, H. V., Richardson, A. G., Tidball, J. G., et al. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00709.x · Cited by 75 · see citing works
Distelmaier, F., Valsecchi, F., Forkink, M., Vries, S. E. V. E., Swarts, H. G. P., Rodenburg, R. J., Verwiel, E. T. P., Smeitink, J. A. M., Willems, P. H. G. M., & Koopman, W. J. H. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4294 · Cited by 75 · see citing works
Automatic morphometric analysis of skeletal muscle fibers in the aging man
Poggi, P., Marchetti, C., & Scelsi, R. (1987) · The Anatomical Record · doi:10.1002/ar.1092170106 · Cited by 74 · see citing works
Faitg, J., Leduc-Gaudet, J.-P., Reynaud, O., Ferland, G., Gaudreau, P., & Gouspillou, G. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00420 · Cited by 72 · cited 1× · see citing works
“We even recently reported that the impact of ageing on mitochondrial dynamics and morphology might be fibre type specific (Faitg et al. 2019).”
BackgroundSelf-citationGouspillou, G., Bourdel-Marchasson, I., Rouland, R., Calmettes, G., Franconi, J.-M., Deschodt-Arsac, V., & Diolez, P. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2009.09.004 · Cited by 62 · see citing works
Self-citationThe role of mitochondrial fusion and fission in skeletal muscle function and dysfunction
Hood, D. A. (2015) · Frontiers in Bioscience · doi:10.2741/4303 · Cited by 50 · see citing works
Giovarelli, M., Zecchini, S., Martini, E., Garrè, M., Barozzi, S., Ripolone, M., Napoli, L., Coazzoli, M., Vantaggiato, C., Roux-Biejat, P., et al. (2020) · Cell Death & Differentiation · doi:10.1038/s41418-020-0510-7 · Cited by 41 · see citing works
Rockstein, M., & Bhatnagar, P. L. (1965) · Journal of Insect Physiology · doi:10.1016/0022-1910(65)90053-3 · Cited by 40 · see citing works
Huang, J. H., Joseph, A.-M., Ljubicic, V., Iqbal, S., & Hood, D. A. (2010) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glp201 · Cited by 35 · see citing works
Maintenance of muscle mass and load-induced growth in Muscle RING Finger 1 null mice with age
Hwee, D. T., Baehr, L. M., Philp, A., et al. (2014) · Cited by 7 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging
Leduc-Gaudet, J.-P., Hussain, S. N. A., Barreiro, E., & Gouspillou, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158179 · Cited by 268 · see citing works
“However, we recently reported that knocking down or overexpressing Drp1 late in life in mouse skeletal muscle (from 18 to 22 months of age) is detrimental to skeletal muscle mass and mitochondrial health [71].”
BackgroundSelf-citation
- Authors
- Dulac, M., Leduc‐Gaudet, J., Cefis, M., Ayoub, M., Reynaud, O., Shams, A., Moamer, A., Nery Ferreira, M. F., Hussain, S. N., & Gouspillou, G.
- Affiliations
- Université du Québec à Montréal (CA)
- Taif University (SA)
- Research Institute of the McGill University Health Centre (CA)
- Département des sciences de l'activité physique Faculté des Sciences, UQAM Québec Canada
- Corresponding author
- Gouspillou, Gilles
- ORCID
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2021-08-04
- Volume
- 599
- Issue
- 17
- Pages
- 4045-4063
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- OpenAlex
- W3182470400
- Cited by
- 51
- References
- 50
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 7 · 2023: 9 · 2022: 8 · 2021: 2
- FWCI
- 2.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Canadian Institutes of Health Research (MOV-409262, MOP-93760)
- 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
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- Drp1, mitochondrial fission, sarcopenia, muscle aging, skeletal muscle atrophy, mitochondrial dynamics, mitochondrial quality control, oxidative stress, autophagy, muscle regeneration, aged mice, muscle degeneration
- MeSH terms
- Animals, Cytoskeletal Proteins, Drosophila melanogaster, Mitochondria, Quality of Life, Muscle, Skeletal, GTP-Binding Proteins, Dynamins, Mice, Mitochondrial Dynamics
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
