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Skeletal muscle mitochondrial DNA copy number and mitochondrial DNA deletion mutation frequency as predictors of physical performance in older men and women

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Abstract

Mitochondrial DNA (mtDNA) quality and quantity relate to two hallmarks of aging—genomic instability and mitochondrial dysfunction. Physical performance relies on mitochondrial integrity and declines with age, yet the interactions between mtDNA quantity, quality, and physical performance are unclear. Using a validated digital PCR assay specific for mtDNA deletions, we tested the hypothesis that skeletal muscle mtDNA deletion mutation frequency (i.e., a measure of mtDNA quality) or mtDNA copy number predicts physical performance in older adults. Total DNA was isolated from vastus lateralis muscle biopsies and used to quantitate mtDNA copy number and mtDNA deletion frequency by digital PCR. The biopsies were obtained from a cross-sectional cohort of 53 adults aged 50 to 86 years. Before the biopsy procedure, physical performance measurements were collected, including VO2max, modified physical performance test score, 6-min walk distance, gait speed, grip strength, and total lean and leg mass. Linear regression models were used to evaluate the relationships between age, sex, and the outcomes. We found that mtDNA deletion mutation frequency increased exponentially with advancing age. On average from ages 50 to 86, deletion frequency increased from 0.008 to 0.15%, an 18-fold increase. Females may have lower deletion frequencies than males at older ages. We also measured declines in VO2max and mtDNA copy number with age in both sexes. The mtDNA deletion frequency measured from single skeletal muscle biopsies predicted 13.3% of the variation in VO2max. Copy number explained 22.6% of the variation in mtDNA deletion frequency and 10.4% of the lean mass variation. We found predictive relationships between age, mtDNA deletion mutation frequency, mtDNA copy number, and physical performance. These data are consistent with a role for mitochondrial function and genome integrity in maintaining physical performance with age. Analyses of mtDNA quality and quantity in larger cohorts and longitudinal studies could extend our understanding of the importance of mitochondrial DNA in human aging and longevity.

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Funding

This work is supported by the National Institute on Aging at the National Institutes of Health (grant numbers R56AG060880, R01AG055518, K02AG059847, and R21AR072950).

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Author notes

  1. Allen Herbst and Steven J. Prior have contributed equally to this work.

Authors and Affiliations

  1. Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, Alberta, Canada

    Allen Herbst & Judd M. Aiken

  2. Department of Kinesiology, University of Maryland School of Public Health, College Park, MD, USA

    Steven J. Prior

  3. Baltimore Veterans Affairs Medical Center Geriatric Research, Education and Clinical Center, Baltimore, MD, USA

    Steven J. Prior

  4. Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA, USA

    Cathy C. Lee & Jonathan Wanagat

  5. Division of Geriatrics, Department of Medicine, University of California, Los Angeles, 650 Charles E. Young Drive South, Rm 34-115, Los Angeles, CA, 90095, USA

    Cathy C. Lee, Austin Hoang & Jonathan Wanagat

  6. Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada

    Debbie McKenzie

  7. Department of Epidemiology and Biostatistics, Indiana University Bloomington, Bloomington, IN, USA

    Nianjun Liu, Xiwei Chen, Pengcheng Xun & David B. Allison

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  1. Allen Herbst
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Correspondence to Jonathan Wanagat.

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Herbst, A., Prior, S.J., Lee, C.C. et al. Skeletal muscle mitochondrial DNA copy number and mitochondrial DNA deletion mutation frequency as predictors of physical performance in older men and women. GeroScience 43, 1253–1264 (2021). https://doi.org/10.1007/s11357-021-00351-z

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