Exercise enhances mitochondrial fission and mitophagy to improve myopathy following critical limb ischemia in elderly mice via the PGC1a/FNDC5/irisin pathway

Abstract

Background Elderly 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. Methods Elderly 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). Results Exercise 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. Conclusion Exercise 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.

Exercise Training Enhances Myocardial Mitophagy and Improves Cardiac Function via Irisin/FNDC5-PINK1/Parkin Pathway in MI Mice

“…PINK1 and Parkin expression could significantly decrease in the Irisin/FNDC5 knockout mice and accompanied with mitochondrial dysfunction in myocardium [ 38 , 39 ], which suggested that irisin/FNDC5 was positively correlated with PINK1 and Parkin expression. Our present study provided direct evidence for exercise induced up-regulated expression of Irisin and enhanced PINK1/Parkin-mediated mitophagy in the myocardium, which was consistent with the results of previous studies [ 40 , 41 , 42 ]. Our study also presented that resistance exercise group had better effect in different types of exercise and skeletal muscle electrical stimulation intervention.…”

The Role of Irisin in Exercise-Mediated Bone Health

“…PGC1α in muscle is reported to stimulate an increase in FNDC5 expression in vitro and in vivo ( Bostrom et al, 2012 ). A recent study indicates that exercise increases mitochondrial fission and selective autophagy by PGC1a/FNDC5/irisin pathway, and promotes recovery of ischemic muscle ( He et al, 2020 ). These studies suggest that irisin may play an important role in exercise relieving skeletal muscle atrophy, thereby maintaining bone load and bone mass.…”

The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity

“…Exercise is a well-established lifestyle modification that retards aging and increases human healthspan [ 283 ]. Exercise enhances mitophagy and autophagy [ 284 , 285 ], which are associated with the inhibition of mPTP. It was shown that exercise training decreases susceptibility to Ca 2+ -induced mPTP opening in heart mitochondria [ 286 ].…”