Impacto do treinamento aeróbio de baixa intensidade na função cardíaca e em biomarcadores plasmáticos em modelo murino de toxicidade induzida pela doxorrubicina

Abstract

Introduction: Doxorubicin is an important drug used in chemotherapy treatment, but its toxic effect compromises patient survival. In this scenario, aerobic training has been studied as a non-pharmacological therapy in the search for attenuation of the toxic effects caused by doxorubicin. Objectives: The objective of this thesis was to evaluate whether low-intensity aerobic training has a reparative effect on toxicity already caused by doxorubicin, through the analysis of cardiac functional parameters and associated molecular evidence. Materials and Methods: Forty-eight Wistar rats with a mean age of six months and a mean body weight of 500 g were randomly divided into four groups identified as Control (C), Doxorubicin (D), Training (T), and Doxorubicin + Training (DT). The animals in the D and DT groups received intraperitoneal injections of doxorubicin hydrochloride once a week at a dose of 2 mg/kg over four weeks, reaching a total cumulative dose of 8 mg/kg; the other groups received intraperitoneal injections of saline solution in a similar volume. Groups T and DT underwent aerobic training after drug administration. Results: The results of the thesis will be presented in two articles. In the first article, doxorubicin administration significantly increased myocardial fibrosis in group D compared to groups C, DT, and T, and reduced cardiac functional parameters in group D, with lower values of parietal S waves (0.041 vs. 0.065; p=0.01) and septal S waves (0.04 vs. 0.064; p=0.01) compared to the control group. A marked decrease in exercise tolerance was observed in group D (62%), followed by groups DT (26.3%) and C (23%). In the second article, relevant changes were observed in the plasma spectral profile, characterized by an increase in lipid bands (~1451, 1738, 2860 cm⁻¹), a reduction in proteins (~1531 cm⁻¹), and an elevation of nucleic acid-associated markers (~1069 cm⁻¹) in animals from groups D and DT. However, low-intensity aerobic training partially attenuated these effects, highlighting that the wave number 1451cm-1 was able to significantly differentiate groups D and DT. Furthermore, ROC curve analysis investigated the discriminatory performance of each vibrational mode through spectra processed by the second derivative, showing high accuracy and significant sensitivity and specificity values in the comparison of groups D and C, DT and C (>82%). Conclusion: The results demonstrate that doxorubicin induces significant cardiotoxicity, evidenced by increased myocardial fibrosis, impaired cardiac function, and reduced tolerance to physical exertion. Low-intensity aerobic training, applied after exposure to the chemotherapeutic agent, exerted a partially reparative effect, attenuating the structural and functional cardiac alterations, the loss of physical performance, and the molecular modifications observed in the plasma. This work demonstrated that low-intensity aerobic exercise constitutes a non-pharmacological strategy that contributes to the preservation of cardiovascular function with potential adjuvant application in clinical contexts, in addition to demonstrating the potential of plasma biomarkers as useful tools for the early monitoring of these damages.