The Association of Mitochondrial Copy Number With Sarcopenia in Adult Survivors of Childhood Cancer

Abstract

Background: Adult childhood cancer survivors are at risk for frailty, including low muscle mass and weakness (sarcopenia). Using peripheral blood mitochondrial DNA copy number (mtDNAcn) as a proxy for functional mitochondria, this study describes cross-sectional associations between mtDNAcn and sarcopenia among survivors.

Methods: Among 1762 adult childhood cancer survivors (51.6% male; median age = 29.4 years, interquartile range [IQR] = 23.3-36.8), with a median of 20.6 years from diagnosis (IQR = 15.2-28.2), mtDNAcn estimates were derived from whole-genome sequencing. A subset was validated by quantitative polymerase chain reaction and evaluated cross-sectionally using multivariable logistic regression for their association with sarcopenia, defined by race-, age-, and sex-specific low lean muscle mass or weak grip strength. All statistical tests were 2-sided.

Results: The prevalence of sarcopenia was 27.0%, higher among female than male survivors (31.5% vs 22.9%; P < .001) and associated with age at diagnosis; 51.7% of survivors with sarcopenia were diagnosed ages 4-13 years (P = .01). Sarcopenia was most prevalent (39.0%) among central nervous system tumor survivors. Cranial radiation (odds ratio [OR] = 1.84, 95% confidence interval [CI] = 1.32 to 2.59) and alkylating agents (OR = 1.34, 95% CI = 1.04 to 1.72) increased, whereas glucocorticoids decreased odds (OR = 0.72, 95% CI = 0.56 to 0.93) of sarcopenia. mtDNAcn decreased with age (β = -0.81, P = .002) and was higher among female survivors (β = 9.23, P = .01) and among survivors with a C allele at mt.204 (β = -17.9, P = .02). In adjusted models, every standard deviation decrease in mtDNAcn increased the odds of sarcopenia 20% (OR = 1.20, 95% CI = 1.07 to 1.34).

Conclusions: A growing body of evidence supports peripheral blood mtDNAcn as a biomarker for adverse health outcomes; however, this study is the first to report an association between mtDNAcn and sarcopenia among childhood cancer survivors.

Figure 1.

qPCR validation of whole-genome sequencing mtDNAcn estimates. MtDNAcn estimates from 95 randomly selected whole-genome sequenced samples are plotted along the x-axis vs mtDNAcn estimates derived from qPCR of the same samples plotted along the y-axis. Pearson correlation test P value is 2-sided. mtDNAcn = mitochondrial DNA copy number; qPCR = quantitative polymerase chain reaction; qRT-PCR = real-time quantitative PCR.

Figure 2.

Relative odds of sarcopenia by mtDNAcn, tumor type, sex, and age at diagnosis. Models were additionally adjusted for age at assessment and haplotype. The error bars represent the 95% confidence intervals for the odds ratios (ORs). CNS = central nervous system; mtDNA = mitochondrial DNA.