Neuron specific reduction in cuznsod is not sufficient to initiate a full sarcopenia phenotype
Open accessAbstract
Our previous studies showed that adult (8 month) mice lacking CuZn-superoxide dismutase (CuZnSOD, Sod1KO mice) have neuromuscular changes resulting in dramatic accelerated muscle atrophy and weakness that mimics age-related sarcopenia. We have further shown that loss of CuZnSOD targeted to skeletal muscle alone results in only mild weakness and no muscle atrophy. In this study, we targeted deletion of CuZnSOD specifically to neurons (nSod1KO mice) and determined the effect on muscle mass and weakness. The nSod1KO mice show a significant loss of CuZnSOD activity and protein level in brain and spinal cord but not in muscle tissue. The masses of the gastrocnemius, tibialis anterior and extensor digitorum longus (EDL) muscles were not reduced in nSod1KO compared to wild type mice, even at 20 months of age, although the quadriceps and soleus muscles showed small but statistically significant reductions in mass in the nSod1KO mice. Maximum isometric specific force was reduced by 8-10% in the gastrocnemius and EDL muscle of nSod1KO mice, while soleus was not affected. Muscle mitochondrial ROS generation and oxidative stress measured by levels of reactive oxygen/nitrogen species (RONS) regulatory enzymes, protein nitration and F2-isoprostane levels were not increased in muscle from the nSod1KO mice. Although we did not find evidence of denervation in the nSod1KO mice, neuromuscular junction morphology was altered and the expression of genes associated with denervation acetylcholine receptor subunit alpha (AChRα), the transcription factor, Runx1 and GADD45α) was increased, supporting a role for neuronal loss of CuZnSOD initiating alterations at the neuromuscular junction. These results and our previous studies support the concept that CuZnSOD deficits in either the motor neuron or muscle alone are not sufficient to initiate a full sarcopenic phenotype and that deficits in both tissues are required to recapitulate the loss of muscle observed in Sod1KO mice.
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Reduction of the cytosolic antioxidant CuZn-superoxide dismutase (CuZnSOD) observed in mouse nerves and muscle is consistent with sarcopenic muscle loss.
“For instance, the reduction of the cytosolic antioxidant CuZn-superoxide dismutase (CuZnSOD) was observed in mouse nerves and muscle, consistent with sarcopenic muscle loss (47).”
From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [47]
Loss of CuZnSOD in either neural or muscle cells recapitulates sarcopenic muscle loss in a mouse model.
“both neural and muscle losses of the cytosolic antioxidant CuZn-superoxide dismutase (CuZnSOD) recapitulated sarcopenic muscle loss in a mouse model (125).”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [125]
Absence of CuZnSOD in either neural or muscle cells alone does not produce full sarcopenic muscle loss.
“the absence of CuZnSOD in either neural or muscle cells did not manifest full sarcopenic muscle loss (125).”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [125]
Accumulation of excessive ROS contributes to damaged and dysfunctional mitochondria in muscle and neural cells.
“it is clear that accumulation of excessive ROS contributes to damaged and dysfunctional mitochondria in muscle and neural cells.”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [125]
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Mitochondria initiate and regulate sarcopenia
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“The importance of antioxidants in sarcopenia is highlighted by observations that both neural and muscle losses of the cytosolic antioxidant CuZn-superoxide dismutase (CuZnSOD) recapitulated sarcopenic muscle loss in a mouse model (125).”
BackgroundAccelerated sarcopenia in Cu/Zn superoxide dismutase knockout mice
Deepa, S. S., Van Remmen, H., Brooks, S. V., Faulkner, J. A., Larkin, L., McArdle, A., Jackson, M. J., Vasilaki, A., & Richardson, A. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.06.032 · Cited by 78 · see citing works
Self-citationReactive oxygen species in the pathogenesis of sarcopenia
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“For instance, the reduction of the cytosolic antioxidant CuZn-superoxide dismutase (CuZnSOD) was observed in mouse nerves and muscle, consistent with sarcopenic muscle loss (47).”
BackgroundA neurogenic perspective of Sarcopenia: time course study of sciatic nerves from aging mice
Krishnan, V. S., White, Z., McMahon, C. D., Hodgetts, S. I., Fitzgerald, M., Shavlakadze, T., Harvey, A. R., & Grounds, M. D. (2016) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlw019 · Cited by 32 · see citing works
- Authors
- Sataranatarajan, K., Qaisar, R., Davis, C., Sakellariou, G. K., Vasilaki, A., Zhang, Y., Liu, Y., Bhaskaran, S., McArdle, A., Jackson, M., Brooks, S. V., Richardson, A., & Van Remmen, H.
- Affiliations
- Oklahoma Medical Research Foundation (US)
- University of Michigan (US)
- University of Liverpool (GB)
- The University of Texas Southwestern Medical Center (US)
- The University of Texas at San Antonio Health Science Center (US)
- Oklahoma City VA Medical Center (US)
- ORCID
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 5
- Pages
- 140-148
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC5022075
- OpenAlex
- W2161894666
- Cited by
- 67
- References
- 28
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 7 · 2023: 7 · 2022: 9 · 2021: 10 · 2020: 7 · 2019: 3 · 2018: 6 · 2017: 7 · 2016: 6
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NIH/NIA (P01 AG020591)
- Veterans Affairs Merit Grant
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- Cu/Zn superoxide dismutase, Sod1 knockout mice, age-related sarcopenia, muscle atrophy, muscle weakness, neuromuscular junction, denervation, motor neurons, skeletal muscle, mitochondrial reactive oxygen species, oxidative stress, protein nitration, F2-isoprostanes, acetylcholine receptor alpha subunit, RUNX1, GADD45A, muscle mass
- MeSH terms
- GADD45 Proteins, Aging, Animals, Gas Chromatography-Mass Spectrometry, Microscopy, Fluorescence, Mitochondria, Neuromuscular Junction, Neurons, Nuclear Proteins, Phenotype, Receptors, Cholinergic, Superoxide Dismutase, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Muscle, Skeletal, Cell Cycle Proteins, Reactive Nitrogen Species, F2-Isoprostanes, Core Binding Factor Alpha 2 Subunit, Mice, Sarcopenia
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