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.
Highlights
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
Exercise could enhance cardiac function and aerobic fitness in radiation-induced heart disease (RIHD) mice partly through an autocrine mechanism via FNDC5/irisin, in which autophagy was Exercise Regulate RIHD via Irisin selectively activated, suggesting that FNDC5/irisin may act as an intervening target to prevent the development of RIHD
While there was no significant difference in body weight among the groups at baseline, the body weight of the RIHD mice was significantly lower than that of the controls at the end of the 2nd and 3rd weeks after irradiation (2nd week: F value = 33.22, degrees of freedom = 2, degrees of freedom = 12, 12.26 ± 0.99 vs. 15.77 ± 0.31 g, 95%CI −4.48–−2.54, p < 0.001; 3rd week: F value = 40.84, degrees of freedom = 2, degrees of freedom = 12, 12.30 ± 0.98 vs. 17.21 ± 0.91 g, 95%CI −6.10–−3.73, p < 0.001), which indicates that RT may have affected murine body weight (Figure 1A)
Summary
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. After long-term follow-up in the same cohort, the latest data further support the close relationship between heart V5 and OS, which suggests the potential damage of cardiac toxicity on the outcome after RT (Bradley et al, 2020). The role of exercise as an effective nonpharmacological approach in controlling cardiovascular risk factors, halting the progression of cardiovascular disease and improving outcomes, has been widely accepted and limited, but growing data have supported the benefits of aerobic exercise in improving CRF and reducing cardiovascular risk in cancer survivors to relieve the “wholebody” damage caused by tumor treatment (Bhattacharya and Asaithamby, 2016), implying the potential of exercise in intervening radiation-induced heart disease (RIHD)
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