Deficiency of FNDC5/Irisin Impairs the Protective Effect of Exercise Against Post-Infarction Myocardial Mitochondrial Injury.

There is ample evidence that exercise contributes to prevention and treatment of myocardial infarction. Although transmembrane protein fibronectin type III domain protein 5 (FNDC5)/Irisin is known to mediate the protective effects of exercise on ischemic heart, its effects and mechanisms on mitochondria after myocardial infarction are not fully defined. We randomized wild and FNDC5 knockout (KO) mice on which to construct a post-infarction exercise rehabilitation model, and subsequently compared the differences in cardiac and myocardial mitochondrial structure and function between groups; the FNDC5/Irisin-AMPK-Sirt1 mitochondrial pathway was further assessed by applying recombinant human Irisin, FNDC5 and/or Sirt1 knockdown (KD) treatment to neonatal mouse cardiomyocytes. Transmission electron microscopy was used to examine mitochondrial structure, Oxygraph-2k was used to measure mitochondrial function, and immunoblotting was used to assess mitochondrial genesis, mitophagy marker proteins, and pathway-related proteins. FNDC5KO induced abnormalities of myocardial mitochondrial genesis and mitophagy, weakened the improvement effect of exercise toward mitochondrial injury and was associated with deteriorated cardiac function after myocardial infarction. Sirt1KD weakened the FNDC5/Irisin-mediated regulatory effect of exercise on mitochondrial genesis and mitophagy in primary cardiomyocytes. Exercise induced FNDC5/Irisin is an important regulator of the ameliorative effects of Sirt1 on cardiac function and mitochondrial remodeling during infarction rehabilitation.