The Effect Of Exercise On The Myopathy In Elderly Mice Following Critical Limb Ischemia Via PGC1a/PINK1/PARKIN Pathway

Aims:As the prevalence of peripheral artery disease(PAD)has been greatly increased with age,the elderly patients are more susceptive to critical limb ischemia(CLI),the severe manifestation of PAD,which resulted in worse prognosis.However,the conventional treatments cannot significantly decrease the amputation and mortality.Although exercise has been the effective “non-pharmacological medicine” targeting for mitochondria to improve skeletal muscle function,little data focused on the application of exercise in CLI.Our study aims to estimate the effect of exercise on skeletal muscle function following elderly CLI and the outcome of cardiovascular disease,and investigate the underlying molecularmechanism.Methods:(1)The elderly male C57BL/6 mice(14 months old)were used to establish the CLI model to assess the effect of exercise on perfusion,performance recovery,apoptosis,mitochondrial function and mitochondrial dynamics in gastrocnemius muscle.(2)The hypoxic and nutrients deprived myotube undergoing electrical pulse stimuli(EPS)was used to confirm the potential underlying mechanism mediated by PGC1a/FNDC5/irisin.(3)The elderly patients with stable coronary artery disease were enrolled to assess the relationship of physical activity,SMI,grip strength,and bone turnover markers with cardiovascular adverse outcome in the3-year follow up.Results:(1)Exercise significantly accelerated the recovery of perfusion and exercise performance in ischemic limbs following CLI.Exercise improved mitochondrial membrane potential,ATP production,and decreased apoptosis of skeletal muscle cell.Exercise increased the protein and mRNA expression of mitochondrial fission(DRP1)and mitophagy(LC3B)markers in ischemic limbs accompanying with the elevated PGC1a/PINK1/PARKIN expression(all p<0.05).(2)In vitro,the downregulated PGC1a/PINK1/PARKIN deterioratedthe EPS-elevated DRP and LC3 B mRNA expression,the inhibition of mitophagy leaded to the elevated expression of PGC1a/PINK1/PARKIN(all p<0.05).(3)The higher physical activity and grip strength in elderly patients with stable coronary artery disease were independently associated with better 3-year cardiovascular outcomes(all p<0.05).Conclusions:(1)Exercise could effectively accelerate the recovery of skeletal function following elderly CLI through improving mitochondrial function and decrease the cell apoptosis.(2)Exercise can enhance mitochondrial fission and mitophagy to promote the recovery of myopathy in elderly CLI through PGC1a/FNDC5/irisin mediated pathway.(3)Exercise can improve the outcome of elderly patients with cardiovascular disease by improving the function of skeletal muscle and regulating the mechanistic linkage between the loss of skeletal muscle mass and cardiovascular disease.