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Neuroprotective treatment with the nitrone compound OKN-007 mitigates age-related muscle weakness in aging mice

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Abstract

Despite the universal impact of sarcopenia on compromised health and quality of life in the elderly, promising pharmaceutical approaches that can effectively mitigate loss of muscle and function during aging have been limited. Our group and others have reported impairments in peripheral motor neurons and loss of muscle innervation as initiating factors in sarcopenia, contributing to mitochondrial dysfunction and elevated oxidative stress in muscle. We recently reported a reduction in α motor neuron loss in aging mice in response to the compound OKN-007, a proposed antioxidant and anti-inflammatory agent. In the current study, we asked whether OKN-007 treatment in wildtype male mice for 8–9 months beginning at 16 months of age can also protect muscle mass and function. At 25 months of age, we observed a reduction in the loss of whole-body lean mass, a reduced loss of innervation at the neuromuscular junction and well-preserved neuromuscular junction morphology in OKN-007 treated mice versus age matched wildtype untreated mice. The loss in muscle force generation in aging mice (~ 25%) is significantly improved with OKN-007 treatment. In contrast, OKN-007 treatment provided no protection in loss of muscle mass in aging mice. Mitochondrial function was improved by OKN-007 treatment, consistent with its potential antioxidative properties. Together, these exciting findings are the first to demonstrate that interventions through neuroprotection can be an effective therapy to counter aging-related muscle dysfunction.

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Data availability

The data that support the findings of the study are available in the manuscript and supplementary material of this article. Correspondence and requests for information should be addressed to H.V.R.

Abbreviations

NMJ:

Neuromuscular junction

ACHR:

Acetylcholine receptor

BSCB:

Blood-spinal cord barrier

OCR:

Oxygen consumption rate

ROS:

Reactive oxygen species

EDL:

Extensor digitorum longus

SERCA:

Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase

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Funding

This work was supported by the VA pilot grant (I21 BX005619), and P01 grant (P01 AG051442) from NIA, and also the VA Senior Research Career Scientist award (IK6 BX005234) to Dr. Holly Van Remmen. Dr. Jacob L. Brown is currently supported by a VA Career Development Award (1 IK2 BX005620-01A1).

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Author notes

  1. Hongyang Xu and Katarzyna M. Piekarz Contributed equally to this work.

Authors and Affiliations

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

    Hongyang Xu, Katarzyna M. Piekarz, Jacob L. Brown, Shylesh Bhaskaran & Holly Van Remmen

  2. Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    Nataliya Smith & Rheal A. Towner

  3. Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Holly Van Remmen

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

    Jacob L. Brown & Holly Van Remmen

Authors
  1. Hongyang Xu
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  2. Katarzyna M. Piekarz
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  3. Jacob L. Brown
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  4. Shylesh Bhaskaran
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  5. Nataliya Smith
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  7. Holly Van Remmen
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Contributions

H.X., K.M.P., S.B., J.L.B. and H.V.R. contributed in the conception and design of the research; H.X., K.M.P., S.B., J.L.B. performed the experiments and analyzed the data; H.X., K.M.P., S.B., J.L.B. and H.V.R. interpreted the results of the experiments; H.X. and H.V.R. prepared the figures and drafted the manuscript; H.X., S.B., J.L.B. and H.V.R. edited and revised the manuscript. All authors approved the final version of the manuscript, contributed to the article, and approved the submitted version.

Corresponding author

Correspondence to Holly Van Remmen.

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Xu, H., Piekarz, K.M., Brown, J.L. et al. Neuroprotective treatment with the nitrone compound OKN-007 mitigates age-related muscle weakness in aging mice. GeroScience (2024). https://doi.org/10.1007/s11357-024-01134-y

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  • DOI: https://doi.org/10.1007/s11357-024-01134-y

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