Abstract
BackgroundElderly populations are susceptible to critical limb ischemia (CLI), but conventional treatments cannot significantly decrease amputation and mortality. Although exercise is an effective “non-pharmacological medicine” targeting mitochondria to improve skeletal muscle function, few studies have focused on the application of exercise in CLI.MethodsElderly male C57BL/6 mice (14 months old) were used to establish a CLI model to assess the effect of exercise on perfusion, performance recovery, apoptosis, mitochondrial function, and mitochondrial turnover in gastrocnemius muscle. The potential underlying mechanism mediated by PGC1a/FNDC5/irisin was confirmed in hypoxic and nutrient-deprived myotubes undergoing electrical pulse stimuli (EPS).ResultsExercise significantly accelerated the perfusion recovery and exercise performance in ischemic limbs following CLI. Exercise improved the mitochondrial membrane potential and total ATP production and decreased apoptosis in the ischemic limbs. Exercise increased the formation of mitochondrial derived vesicle-like structures and decreased the mitochondrial length in the ischemic limbs, accompanied by upregulated PGC1a/FNDC5/irisin expression. In vitro, PGC1a/FNDC5/irisin downregulation decreased EPS-elevated PINK1, Parkin, DRP1, and LC3B mRNA levels. The irisin levels in the culture medium were correlated with the expression of mitochondrial fission and mitophagy markers in myotubes.ConclusionExercise enhanced mitochondrial fission and selective autophagy to promote the recovery of myopathy after CLI in elderly mice through the PGC1a/FNDC5/irisin pathway, supporting the efficacy of exercise therapy in elderly individuals with CLI and demonstrating the potential of targeting PGC1a/FNDC5/irisin as a new strategy for the treatment of CLI.
Highlights
Populations are susceptible to critical limb ischemia (CLI), but conventional treatments cannot significantly decrease amputation and mortality
The prevalence of peripheral artery disease (PAD) increases substantially with age, and elderly individuals are more susceptible to critical limb ischemia (CLI), a severe manifestation of PAD, which results in poor prognosis [1, 29]
We revealed that exercise could increase mitochondrial fission and selective autophagy to improve mitochondrial function and decreased cell apoptosis following CLI, which may be mediated by the proliferator-activated receptor gamma coactivator-1 alpha (PGC1a)/FNDC5/irisin pathway
Summary
Populations are susceptible to critical limb ischemia (CLI), but conventional treatments cannot significantly decrease amputation and mortality. Exercise is an effective “non-pharmacological medicine” targeting mitochondria to improve skeletal muscle function, few studies have focused on the application of exercise in CLI. The prevalence of peripheral artery disease (PAD) increases substantially with age, and elderly individuals are more susceptible to critical limb ischemia (CLI), a severe manifestation of PAD, which results in poor prognosis [1, 29]. Despite the application of surgical and endovascular revascularization in PAD, ischemic myopathy is often ignored, and the risk of amputation and mortality in CLI patients cannot be effectively decreased [25]. Given the decreased expression of mitochondrial protein and mRNA observed in aged skeletal muscle [18], mitochondrial adaptation to severe stress, such as CLI, can be decreased by aging
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