Ectopic lipid accumulation and reduced glucose tolerance in elderly adults are accompanied by altered skeletal muscle mitochondrial activity

Abstract

Context: Aging is associated with insulin resistance and unfavorable changes in body composition including increased fat accumulation, particularly in visceral and ectopic depots. Recent studies suggest that skeletal muscle mitochondrial activity may underlie some age-associated metabolic abnormalities.

Objective: Our objective was to measure mitochondrial capacity and coupling of the vastus lateralis muscle in elderly and young adults using novel in vivo approaches and relate mitochondrial activity to metabolic characteristics.

Design: This was a cross-sectional study.

Participants and intervention: Fourteen sedentary young (seven males and seven females, 20-34 yr of age) and 15 sedentary elderly (seven males and eight females, 70-84 yr of age) nonobese subjects selected for similar body weight underwent measures of body composition by magnetic resonance imaging and dual-energy x-ray absorptiometry, oral glucose tolerance, and in vivo mitochondrial activity by (31)P magnetic resonance and optical spectroscopy. Muscle biopsy was carried out in the same muscle to measure mitochondrial content, antioxidant activity, fiber type, and markers of mitochondrial biogenesis.

Results: Elderly volunteers had reduced mitochondrial capacity (P = 0.05) and a trend for decreased coupling efficiency (P = 0.08) despite similar mitochondrial content and fiber type distribution. This was accompanied by greater whole-body oxidative stress (P = 0.007), less skeletal muscle mass (P < 0.001), more adipose tissue in all depots (P ≤ 0.002) except intramyocellular (P = 0.72), and lower glucose tolerance (P = 0.07).

Conclusions: Elderly adults show evidence of altered mitochondrial activity along with increased adiposity, oxidative stress, and reduced glucose tolerance, independent of obesity. We propose that mild uncoupling may be induced secondary to age-associated oxidative stress as a mechanism to dissipate the proton-motive force and protect against further reactive oxygen species production and damage.

Figures

Fig. 1.

SAT (A), VAT (B), IHL (C), IMAT, (D), and IMCL (E) in young and elderly subjects. A, B, and D were measured by MRI in 14 young and 11 elderly subjects; C and E were measured by MRS in 14 young and 14 elderly subjects.

Fig. 2.

Plasma glucose (A), insulin (B), and FFA (C) during a 2-h 75-g oral glucose load. Data are on all 14 young and 15 elderly participants. *, Difference between young and elderly subjects, P ≤ 0.05; **, difference between young and elderly subjects, P < 0.10.

Fig. 3.

Maximal ATP production (A), resting ATP turnover or flux (B), resting oxygen uptake (C), and resting P/O (D) measured by spectroscopy in young and elderly subjects. For A, n = 13 young and 15 elderly; for B, n = 14 young and 13 elderly; for C and D, n = 9 young and 9 elderly.

Fig. 4.

Mitochondrial content by citrate synthase activity (maximal enzyme assay, A) and OXPHOS electron transport complexes I–V (Western blot, B) and mitochondrial biogenesis (Western blot with GAPDH as loading control, C) in the VL muscle of young and elderly subjects. For A, n = 13 young and 14 elderly; for B, n = 6 young and 7 elderly; for C, n = 8 young and 8 elderly, with n = 6 young and 7 elderly for PGC-1α. *, Difference between young and elderly subjects, P < 0.10.