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Molecular changes in transcription and metabolic pathways underlying muscle atrophy in the CuZnSOD null mouse model of sarcopenia

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Abstract

Mice lacking the superoxide anion scavenger CuZn superoxide dismutase (Sod1−/− mice) develop a number of age-related phenotypes, including an early progression of muscle atrophy and weakness (sarcopenia) associated with loss of innervation. The purpose of this study was to delineate the early development of sarcopenia in the Sod1−/− mice and to measure changes in the muscle transcriptome, proteome, and eicosanoid profile at the stage when sarcopenia is markedly induced in this model (7–9 months of age). We found a strong correlation between muscle atrophy and mitochondrial state 1 hydroperoxide production, which was 40% higher in isolated mitochondria from Sod1−/− mouse gastrocnemius muscle by 2 months of age. The primary pathways showing altered gene expression in Sod1−/− mice identified by RNA-seq transcriptomic analysis are protein ubiquitination, synaptic long-term potentiation, calcium signaling, phospholipase C signaling, AMPK, and TWEAK signaling. Targeted proteomics shows elevated expression of mitochondrial proteins, fatty acid metabolism enzymes, tricarboxylic acid (TCA) cycle enzymes, and antioxidants, while enzymes involved in carbohydrate metabolism are downregulated in Sod1−/− mice. LC-MS analysis of lipids in gastrocnemius muscle detected 78 eicosanoids, of which 31 are significantly elevated in muscle from Sod1−/− mice. These data suggest that mitochondrial hydroperoxide generation is elevated prior to muscle atrophy and may be a potential driving factor of changes in the transcriptome, proteome, and eicosanoid profile of the Sod1−/− mice. Together, these analyses revealed important molecular events that occur during muscle atrophy, which will pave the way for future studies using new approaches to treat sarcopenia.

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Acknowledgments

The authors thank the Multiplex Protein Quantification Cores at Oklahoma Nathan Shock Center, Oklahoma, Clinical genomic center at Oklahoma Medical Research Foundation, Oklahoma and Lipidomics core, UCSD, La Jolla, CA, for sharing their expertise.

Funding

This work was supported by the National Institute of Health, National Institute of Aging (AG050676, AG051442) and Veterans Affairs (I01BX002595). Dr. Van Remmen is the recipient of a Senior Research Career Scientist award (1IK6BX005234) from the Department of Veterans Affairs.

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Authors and Affiliations

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

    Kavithalakshmi Sataranatarajan, Gavin Pharaoh, Jacob L. Brown, Rojina Ranjit, Katarzyna M. Piekarz, Kaitlyn Street, Caroline Kinter, Michael Kinter & Holly Van Remmen

  2. Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    Jonathan D. Wren, Constantin Georgescu & Willard M. Freeman

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

    Arlan Richardson

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

    Holly Van Remmen

  5. Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Arlan Richardson & Holly Van Remmen

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  1. Kavithalakshmi Sataranatarajan
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  2. Gavin Pharaoh
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  3. Jacob L. Brown
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  4. Rojina Ranjit
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  5. Katarzyna M. Piekarz
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  6. Kaitlyn Street
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  7. Jonathan D. Wren
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  8. Constantin Georgescu
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  9. Caroline Kinter
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  10. Michael Kinter
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  11. Willard M. Freeman
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  12. Arlan Richardson
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  13. Holly Van Remmen
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HVR designed the study. KS, GP, CG, RR, KSt, and CK performed experiments and collected data. KS, GP, KP, JW, MK, WF, AR, and HVR analyzed data. KS, GP, JB, and HVR wrote the manuscript.

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Correspondence to Holly Van Remmen.

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The current research was conducted in accordance with the recommendations of USDA guidelines by the Institutional Animal Care and Use Committee at Oklahoma Medical Research Foundation.

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Sataranatarajan, K., Pharaoh, G., Brown, J.L. et al. Molecular changes in transcription and metabolic pathways underlying muscle atrophy in the CuZnSOD null mouse model of sarcopenia. GeroScience 42, 1101–1118 (2020). https://doi.org/10.1007/s11357-020-00189-x

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