Exercise Enhanced Cardiac Function in Mice With Radiation-Induced Heart Disease via the FNDC5/Irisin-Dependent Mitochondrial Turnover Pathway

Abstract

Background: Despite the development of radiation therapy (RT) techniques, concern regarding the serious and irreversible heart injury induced by RT has grown due to the lack of early intervention measures. Although exercise can act as an effective and economic nonpharmacologic strategy to combat fatigue and improve quality of life for cancer survivors, limited data on its application in radiation-induced heart disease (RIHD) and the underlying molecular mechanism are available.Methods: Fifteen young adult male mice were enrolled in this study and divided into 3 groups (including exercised RIHD group, sedentary RIHD group, and controls; n =5 samples/group). While the mice in the control group were kept in cages without irradiation, those in the exercised RIHD group underwent 3weeks of aerobic exercise on the treadmill after radiotherapy. At the end of the 3rd week following RT, FNDC5/irisin expression, cardiac function, aerobic fitness, cardiomyocyte apoptosis, mitochondrial function, and mitochondrial turnover in the myocardium were assessed to identify the protective role of exercise in RIHD and investigate the potential mechanism.Results: While sedentary RIHD group had impaired cardiac function and aerobic fitness than controls, the exercised RIHD mice had improved cardiac function and aerobic fitness, elevated ATP production and the mitochondrial protein content, decreased mitochondrial length, and increased formation of mitophagosomes compared with sedentary RIHD mice. These changes were accompanied by the elevated expression of FNDC5/irisin, a fission marker (DRP1) and mitophagy markers (PINK1 and LC3B) in exercised RIHD group than that of sedentary RIHD group, but the expression of biogenesis (TFAM) and fusion (MFN2) markers was not significantly changed.Conclusion: Exercise could enhance cardiac function and aerobic fitness in RIHD mice partly through an autocrine mechanism via FNDC5/irisin, in which autophagy was selectively activated, suggesting that FNDC5/irisin may act as an intervening target to prevent the development of RIHD.

The role of mitophagy in metabolic diseases and its exercise intervention

“…Three weeks of moderate-intensity aerobic exercise significantly increased myocardial FNDC5 expression and upregulated serum Irisin expression in irradiated X-ray-induced radiation-induced heart disease (RIHD) mice, significantly upregulated myocardial Drp1, PINK1, and LC3B expression in RIHD mice, promoted mitochondrial fission and mitophagy, and consequently increased mitochondrial protein and ATP content, decreased myocardial inflammatory cytokines infiltration and myocardial fibrosis area, upregulated LVEF, left ventricular end-diastolic dimension (LVEDD), and systolic left ventricular dimension (SLVD), and increased RIHD mice body weight, grip strength and aerobic fitness. This suggests that aerobic exercise may promote mitochondrial fission and mitophagy through the FNDC5/Irisin signaling pathway, thereby restoring cardiac function and aerobic fitness in RIHD mice ( He W. et al, 2021 ). In summary, exercise mediates the regulation of mitophagy by exerkines and delays the development of metabolic diseases.…”

Molecular Mechanisms of Exercise and Healthspan

“…A 2019 study found that mitophagy, more than macroautophagy, is critical in maintaining cardiac function in diabetic cardiomyopathy [ 99 ]. Although the necessity of exercise-induced mitophagy is not explored in this model, it has been suspected that, in other cardiac injury models, exercise may help maintain cardiac function through upregulating mitophagy [ 100 , 101 , 102 ].…”

Irisin is an Effector Molecule in Exercise Rehabilitation Following Myocardial Infarction (Review)

“…Exercise is the main inducer of irisin secretion both in healthy and dysregulated metabolism individuals (Huh et al, 2015). Studies have confirmed that exercise-induced irisin is correlated with improvement of cardiac function in general (Seo et al, 2020), which partly by modulating autophagy and mitochondrial function (Li et al, 2021a;He et al, 2021). Further previous animal studies report that irisin is implicated in cerebrovascular protective effects of exercise by alleviating ischemic neuron injury (Li et al, 2017;Lourenco et al, 2019).…”