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Senolytic treatment does not mitigate oxidative stress-induced muscle atrophy but improves muscle force generation in CuZn superoxide dismutase knockout mice

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Abstract

Oxidative stress is associated with tissue dysfunctions that can lead to reduced health. Prior work has shown that oxidative stress contributes to both muscle atrophy and cellular senescence, which is a hallmark of aging that may drive in muscle atrophy and muscle contractile dysfunction. The purpose of the study was to test the hypothesis that cellular senescence contributes to muscle atrophy or weakness. To increase potential senescence in skeletal muscle, we used a model of oxidative stress-induced muscle frailty, the CuZn superoxide dismutase knockout (Sod1KO) mouse. We treated 6-month-old wildtype (WT) and Sod1KO mice with either vehicle or a senolytic treatment of combined dasatinib (5 mg/kg) + quercetin (50 mg/kg) (D + Q) for 3 consecutive days every 15 days. We continued treatment for 7 months and sacrificed the mice at 13 months of age. Treatment with D + Q did not preserve muscle mass, reduce NMJ fragmentation, or alter muscle protein synthesis in Sod1KO mice when compared to the vehicle-treated group. However, we observed an improvement in muscle-specific force generation in Sod1KO mice treated with D + Q when compared to Sod1KO-vehicle mice. Overall, these data suggest that reducing cellular senescence via D + Q is not sufficient to mitigate loss of muscle mass in a mouse model of oxidative stress-induced muscle frailty but may mitigate some aspects of oxidative stress-induced muscle dysfunction.

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Acknowledgements

We would like to extend our gratitude to the numerous other faculties, staff, and other researchers at the Oklahoma City VA, Oklahoma Medical Research Foundation, and OUHSC for helpful discussions. Elizabeth Duggan helped with experiments for the resubmission. Some illustrations were created with BioRender.com.

Funding

Support for this work has been provided by the National Institute on Aging P01AG051442. Dr. Van Remmen is the recipient of a VA Senior Research Career Scientist award (1 IK6 BX005234). Dr. Jacob L. Brown’s postdoctoral training was supported by NIA T32 AG052363. Dr. Jacob L. Brown is currently supported by a VA Career Development Award (1 IK2 BX005620-01A1). Dr. Marcus M. Lawrence’s postdoctoral training was supported by an American Physiological Society (APS) Postdoctoral Fellowship. Dr. Benjamin F. Miller was supported by VA I01 BX005592. Arlan Richardson was supported by a VA Senior Career Research Awards (1IK6BX005238) and a VA Merit grant (I01BX004538) from the Department of Veterans Affairs.

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Authors and Affiliations

  1. Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA

    Agnieszka K. Borowik, Marcus M. Lawrence, Frederick F. Peelor III, Katarzyna M. Piekarz, Abby Crosswhite, Benjamin F. Miller, Holly Van Remmen & Jacob L. Brown

  2. Department of Kinesiology and Outdoor Recreation, Southern Utah University, Cedar City, Utah, USA

    Marcus M. Lawrence

  3. Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Katarzyna M. Piekarz

  4. Oklahoma City VA Medical Center, Oklahoma City, OK, 73104, USA

    Arlan Richardson, Benjamin F. Miller, Holly Van Remmen & Jacob L. Brown

  5. Department of Biochemistry & Molecular Biology, Oklahoma University Health Science Center, Oklahoma City, OK, 73104, USA

    Arlan Richardson

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  1. Agnieszka K. Borowik
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  2. Marcus M. Lawrence
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  3. Frederick F. Peelor III
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  8. Holly Van Remmen
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  9. Jacob L. Brown
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Correspondence to Jacob L. Brown.

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Borowik, A.K., Lawrence, M.M., Peelor, F.F. et al. Senolytic treatment does not mitigate oxidative stress-induced muscle atrophy but improves muscle force generation in CuZn superoxide dismutase knockout mice. GeroScience 46, 3219–3233 (2024). https://doi.org/10.1007/s11357-024-01070-x

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