Aging Exacerbates Ischemia-Reperfusion-Induced Mitochondrial Respiration Impairment in Skeletal Muscle

Abstract

Cycles of ischemia-reperfusion (IR) that occur during peripheral arterial disease (PAD) are associated with significant morbi-mortality, and aging is an irreversible risk factor of PAD. However, the effects of advanced age on IR-induced skeletal muscle mitochondrial dysfunction are not well known. Young and aged mice were therefore submitted to hindlimb IR (2 h ischemia followed by 2 h reperfusion). Skeletal muscle mitochondrial respiration, calcium retention capacity (CRC) and reactive oxygen species (ROS) production were determined using high resolution respirometry, spectrofluorometry and electronic paramagnetic resonance. IR-induced impairment in mitochondrial respiration was enhanced in old animals (VADP; from 33.0 ± 2.4 to 18.4 ± 3.8 and 32.8 ± 1.3 to 5.9 ± 2.7 pmol/s/mg wet weight; −44.2 ± 11.4% vs. −82.0 ± 8.1%, in young and aged mice, respectively). Baseline CRC was lower in old animals and IR similarly decreased the CRC in both groups (from 11.8 ± 0.9 to 4.6 ± 0.9 and 5.5 ± 0.9 to 2.1 ± 0.3 µmol/mg dry weight; −60.9 ± 7.3 and −60.9 ± 4.6%, in young and aged mice, respectively). Further, IR-induced ROS production tended to be higher in aged mice. In conclusion, aging exacerbated the deleterious effects of IR on skeletal muscle mitochondrial respiration, potentially in relation to an increased oxidative stress.

Keywords

• peripheral arterial disease
• ischemia-reperfusion
• skeletal muscle
• mitochondria
• respiration
• calcium
• oxidative stress
• reactive oxygen species
• aging