Proteomic analysis of exercise-induced hypertrophy reveals sex-related mitochondrial differences mediated by AMPK

Abstract

Abstract Background Regular physical activity results in characteristic structural and functional changes in the heart, which are collectively referred to as the athlete's heart. However, the extent of exercise-induced left ventricular (LV) hypertrophy and functional changes show significant differences between men and women, the molecular background of which is not fully elucidated. Objective The aim of this study was to provide a proteomic characterization of long-term, intense exercise-induced LV myocardial hypertrophy in a rat model, with a focus on sex-related differences. Methods Our rats were divided into trained (FEx) and control female (FCo) as well as trained (MEx) and control male (MCo) groups. In the trained groups, athlete's heart was induced by a 12-week swimming protocol. Myocardial hypertrophy was confirmed by echocardiography and functional adaptation by pressure-volume analysis. Proteomic measurements based on liquid chromatograph-coupled mass spectrometry were performed on proteins isolated from our LV myocardial samples. Results Echocardiography and post-mortem myocardial mass showed significant LV hypertrophy in both sexes, which was more pronounced in female animals (tibial length normalized LV muscle mass: + 17.4% MEx vs. MCo, + 31.0% FEx vs. FCo). LV contractility increased to the same extent in both sexes. Relative expression of 3074 proteins were determined by proteomics. There was a significant change in expression of 229 proteins in males and 599 in females compared to the level of same-sex controls. Based on our gene ontological analysis, physiological LV remodeling in females is characterized by increased expression of proteins in mitochondrial function (cellular respiration and fatty acid oxidation) and biogenesis, whereas in males, proteins that bind to the actin cytoskeleton is primarily increased. Further investigation revealed that the quantity of AMP-activated protein kinase (AMPK) and sirtuin 3 (SIRT3) was increased only in female animals. Conclusions Our data suggests that physiological LV hypertrophy resulting from regular, balanced exercise is associated with sex-specific changes in the myocardial proteome. The main differences might be associated with different regulation of mitochondrial function and biogenesis, related to AMPK pathway. Our results contribute to the understanding of the development of physiological myocardial hypertrophy. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Bolyai János Research Scholarship (BO/00837/21) to OANational Research, Development and Innovation Office (NKFIH) K135076 to B.M.