Peripheral artery disease, calf skeletal muscle mitochondrial DNA copy number, and functional performance

Abstract

In people without lower extremity peripheral artery disease (PAD), mitochondrial DNA copy number declines with aging, and this decline is associated with declines in mitochondrial activity and functional performance. However, whether lower extremity ischemia is associated with lower mitochondrial DNA copy number and whether mitochondrial DNA copy number is associated with the degree of functional impairment in people with PAD is unknown. In people with and without PAD, age 65 years and older, we studied associations of the ankle-brachial index (ABI) with mitochondrial DNA copy number and associations of mitochondrial DNA copy number with functional impairment. Calf muscle biopsies were obtained from 34 participants with PAD (mean age: 73.5 years (SD 6.4), mean ABI: 0.67 (SD 0.15), mean 6-minute walk distance: 1191 feet (SD 223)) and 10 controls without PAD (mean age: 73.1 years (SD 4.7), mean ABI: 1.14 (SD 0.07), mean 6-minute walk distance: 1387 feet (SD 488)). Adjusting for age and sex, lower ABI values were associated with higher mitochondrial DNA copy number, measured in relative copy number (ABI<0.60: 914, ABI 0.60-0.90: 731, ABI 0.90-1.50: 593; p trend=0.016). The association of mitochondrial DNA copy number with the 6-minute walk distance and 4-meter walking velocity differed significantly between participants with versus without PAD ( p-value for interaction=0.001 and p=0.015, respectively). The correlation coefficient between mitochondrial DNA copy number and the 6-minute walk distance was 0.653 ( p=0.056) among people without PAD and -0.254 ( p=0.154) among people with PAD and ABI < 0.90. In conclusion, lower ABI values are associated with increased mitochondrial DNA copy number. Associations of mitochondrial DNA copy number with the 6-minute walk distance and 4-meter walking velocity significantly differed between people with versus without PAD, with stronger positive associations observed in people without PAD than in people with PAD. The cross-sectional and exploratory nature of the analyses precludes conclusions regarding causal inferences. ClinicalTrials.gov Identifier: NCT02246660.

Mitochondrial DNA copy number is associated with all‐cause mortality and cardiovascular events in patients with peripheral arterial disease

“…These results are contrasting at first glance but might be explained by the site of mtDNA‐CN measurement. McDermott et al studied local effects directly in the muscles and not systemic effects in the peripheral blood stream as we did. It is conceivable that a higher number of mitochondria might have been produced locally in the calf muscle to ensure the energy supply necessary in the weakened muscles resulting in a site‐specific increase in mtDNA‐CN .…”

“…The only other available study evaluating the role of mtDNA in PAD patients performed mtDNA‐CN measurements not in peripheral blood but in calf muscle biopsy material of 34 PAD patients and 10 controls. They found a higher mtDNA‐CN to be associated with a lower ankle‐brachial index . These results are contrasting at first glance but might be explained by the site of mtDNA‐CN measurement.…”

“…Currently, few studies that have examined the role of mtDNA content in PAD led to conflicting results. Even though there are some indications of an influence of mitochondrial function on PAD, several questions remain unanswered . Up to now, only one small study has investigated the association of mtDNA‐CN and clinical outcomes in PAD patients.…”

“…Up to now, only one small study has investigated the association of mtDNA‐CN and clinical outcomes in PAD patients. This study measured the mtDNA‐CN in muscle biopsies . We hypothesized that a low mtDNA‐CN is a predictor for the presence of PAD as well as prospective outcomes such as all‐cause mortality and cardiovascular events in patients with PAD at baseline.…”

Measuring biological aging in humans: A quest

“…Studies that use multiple mitochondrial biomarkers have revealed only a slight intercorrelation between the markers and aging, suggesting that they tap into different biological dimensions (Lara et al, 2015;Larsen et al, 2012;Marrocco, Altieri, & Peluso, 2017;Xia, Chen, McDermott, & Han, 2017). Recent data support the hypothesis that mtDNA copy number and degree of heteroplasmy-assessed in human blood cells and in tissue biopsies-provide information on mitochondrial physiology that is relevant for aging and age-related diseases (McDermott et al, 2018;Moore et al, 2017;Zhang, Wang, Ye, Picard, & Gu, 2017). Both measurements can be utilized via PCR methods or, more recently, by derivation from genome sequencing data (Ding et al, 2015).…”