Age-Dependent Mechanisms of Cardiac Hypertrophy Regression Following Exercise in Female Mice

Abstract

Cardiac adaptation to exercise is a fundamental physiological process, but its regression and the underlying molecular mechanisms, particularly in relation to age, remain poorly understood. This study investigated the age-dependent differences in cardiac remodeling and molecular signaling during exercise training and detraining in young (5-week-old) and adult (24-week-old) female mice, focusing specifically on how cardiac plasticity changes with adulthood rather than senescence. While both age groups exhibited significant cardiac hypertrophy after the exercise period, young mice displayed significantly more hypertrophic growth (23% increase in left ventricular mass versus 15% in adults). During detraining, cardiac mass regression occurred more rapidly in young mice. Transcriptomic analysis revealed distinct gene expression profiles between age groups, with changes in metabolic and autophagy pathways. Notably, ERK1/2 phosphorylation increased significantly during exercise in young but not adult hearts, correlating with elevated expression of well-known genes associated with exercise, namely CITED4 and SOD2. Furthermore, increased LC3-II/LC3-I ratio and AMPK phosphorylation were observed exclusively in young mice during detraining, indicating age-specific activation of autophagy-mediated cardiac remodeling. These findings demonstrate that cardiac adaptability to exercise and detraining follows distinct molecular pathways in young versus adult mice, with the younger heart exhibiting greater plasticity through enhanced ERK signaling during hypertrophy and autophagy during regression. This age-dependent cardiac plasticity may have important implications for understanding the cardiovascular benefits of exercise across the lifespan and developing age-appropriate exercise recommendations.