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

Skeletal Muscle

Qingwei Chen¹  Chunqiu Li¹  Peng Wang²  Wuyang He³ 

[1] Department of Geriatric Cardiology, The Second Affiliated Hospital of Chongqing Medical University, No. 76 Linjiang Road, 400010, Chongqing, China;Department of Geriatric Cardiology, The Second Affiliated Hospital of Chongqing Medical University, No. 76 Linjiang Road, 400010, Chongqing, China;Department of Geriatric Cardiology, The Central Hospital of Fuling District, Chongqing, China;Department of Oncology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China;

关键词: Exercise;    Critical limb ischemia;    Skeletal muscle;    Mitochondrial turnover;    PGC1a;   

DOI  :  10.1186/s13395-020-00245-2

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY