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.
Highlights
Ischemia-reperfusion (IR) cycles that occur during peripheral arterial disease (PAD) induce skeletal muscle injury resulting in lifestyle-limiting disability, including exercise intolerance and in the most severe cases, limb amputation
PAD pathophysiology clearly demonstrated a major role for skeletal muscle mitochondrial dysfunction and oxidative stress, which promote cell damage and death
Opening of the mitochondrial permeability transition pore (mPTP) was assessed by monitoring calcium retention capacity (CRC) of skeletal muscle mitochondria under were incubated for 30 min under stirring at 4 ◦ C in buffer R+ supplemented with KCl (800 mM) to energized conditions, as previously described [13]
Summary
Ischemia-reperfusion (IR) cycles that occur during peripheral arterial disease (PAD) induce skeletal muscle injury resulting in lifestyle-limiting disability, including exercise intolerance and in the most severe cases, limb amputation. PAD is often associated with other cardiovascular diseases including myocardial infarction, stroke and cognitive dysfunctions. With more than 200 million people diagnosed in the world, PAD is a public health issue. PAD prevalence is high in aged people and Antioxidants 2019, 8, 168; doi:10.3390/antiox8060168 www.mdpi.com/journal/antioxidants. Antioxidants 2019, 8, 168 individuals over the age of 70 present the highest risk, revascularization in nonagenarian patients appeared effective as long as the patient was not fully dependent [1,2,3,4,5,6]. Improved therapeutic options based on PAD pathophysiology are still needed. PAD pathophysiology clearly demonstrated a major role for skeletal muscle mitochondrial dysfunction and oxidative stress, which promote cell damage and death. Oxidative phosphorylation capacity is reduced, hampering adenosine triphosphate (ATP) generation [7,8,9,10,11,12,13]
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