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. 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). 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. 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.

中文翻译：

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运动可通过PGC1a / FNDC5 / irisin途径增强老年小鼠严重肢体缺血后的线粒体分裂和线粒体吞噬能力，​​从而改善肌病。

老年人易患重症肢体缺血（CLI），但是常规治疗无法显着降低截肢和死亡率。尽管运动是针对线粒体以改善骨骼肌功能的有效“非药物”，但很少有研究集中于运动在CLI中的应用。使用老年C57BL / 6雄性小鼠（14个月大）建立CLI模型，以评估运动对腓肠肌灌注，性能恢复，细胞​​凋亡，线粒体功能和线粒体更新的影响。PGC1a / FNDC5 / irisin介导的潜在潜在机制已在接受电脉冲刺激（EPS）的低氧和营​​养缺乏的肌管中得到证实。运动显着加速了CLI后缺血肢体的灌注恢复和运动表现。运动可改善线粒体膜电位和总ATP产生，并减少缺血肢体的细胞凋亡。运动会增加线粒体衍生的小泡样结构的形成，并缩短缺血肢体中的线粒体长度，并伴有PGC1a / FNDC5 / irisin表达的上调。在体外，PGC1a / FNDC5 / irisin下调降低了EPS升高的PINK1，Parkin，DRP1和LC3B mRNA水平。培养基中的鸢尾素水平与肌管中线粒体裂变的表达和线粒体标志物相关。运动增强线粒体分裂和选择性自噬，以通过PGC1a / FNDC5 / irisin途径促进老年小鼠CLI后肌病的恢复，