Decline in skeletal muscle mitochondrial function with aging in humans

Abstract

Cumulative mtDNA damage occurs in aging animals, and mtDNA mutations are reported to accelerate aging in mice. We determined whether aging results in increased DNA oxidative damage and reduced mtDNA abundance and mitochondrial function in skeletal muscle of human subjects. Studies performed in 146 healthy men and women aged 18-89 yr demonstrated that mtDNA and mRNA abundance and mitochondrial ATP production all declined with advancing age. Abundance of mtDNA was positively related to mitochondrial ATP production rate, which in turn, was closely associated with aerobic capacity and glucose tolerance. The content of several mitochondrial proteins was reduced in older muscles, whereas the level of the oxidative DNA lesion, 8-oxo-deoxyguanosine, was increased, supporting the oxidative damage theory of aging. These results demonstrate that age-related muscle mitochondrial dysfunction is related to reduced mtDNA and muscle functional changes that are common in the elderly.

Fig. 1.

Decline in muscle MAPR and citrate synthase activity with age. (A–C) MAPR is shown by using glutamate plus malate (A), pyruvate plus palmitoyl-Lcarnitine plus ketoglutarate plus malate (B), and succinate plus rotenone as substrates (C), respectively. (D) Citrate synthase activity. (E and F) MAPR by using glutamate plus malate and succinate plus rotenone, respectively, after normalization for mitochondrial protein. n = 146 for all measurements.

Fig. 2.

MAPR is related to VO₂max and meal glucose tolerance. (A and B) VO₂max, after covariate adjustment for leg lean mass, declined with age (A) and was positively associated with MAPR, n = 91 (B). (C) Fasting plasma glucose was not different between younger and older people (n = 10/group), but glucose excursion after a mixed meal was higher in older people (*, P < 0.05). (D) Post meal glucose area under the curve (AUC) was inversely related to MAPR.

Fig. 3.

Relative abundance of mitochondrial proteins in muscle from young and older subjects. The percentage difference (*, P < 0.05) of older relative to young is shown (n = 10/group). Negative values indicate less protein in older subjects.

Fig. 4.

Age-related changes in mitochondrial gene transcripts, mtDNA, and DNA oxidation. (A and B) Abundance of mRNA transcripts encoding COX3 and COX4, respectively, declined with age, n = 74. (C) Abundance of mtDNA by using ND1 gene probe declined with age, n = 74. (D) The level of 8-oxo-dG, relative to 2-deoxyguanisine (dG) increased with age, n = 60.