Abstract P204: Sex Differences and the Role of Estrogen Receptor β in Exercise-Induced Myocardial Hypertrophy

Abstract

We and others found sex differences in physiological myocardial hypertrophy (MH) in mice subjected to voluntary cage-wheel running (VCR) and forced exercise training. Female mice showed significantly more MH, suggesting the involvement of estrogen (E2) and estrogen receptors (ER). We therefore investigated the underlying mechanisms leading to sex differences in physiological MH and the role of E2 and ER beta (ERß). Male and female C57/Bl6 wild-type (WT) and ERß-deficient mice (ERß-/-) at the age of 12 weeks performed 8 weeks of VCR or were kept sedentary (sed). Exercise performance was monitored daily and left ventricular mass (LVM) was examined by echocardiography. RNA and protein were analyzed by Real-Time PCR and western blot. Luciferase-reporter Assays were performed with PGC-1a-, MEF2A- and MEF2C-promoter deletion constructs in a human cardiac myocyte cell line (AC16 cells) with/without E2 treatment. Female WT-mice run more than their male counterparts (6.7km/day vs. 4.2km/day; p<0.001). Females showed significant greater increase in LVM and cardiomyocyte diameter in response to exercise compared to males. VCR led to a significant activation of AKT and p38-MAPK signalling in female running-mice, but not in males. Mitochondrial biogenesis associated genes MEF2A and ATP5K mRNA expression were significantly higher in female VCR mice. Female and male ERß-/- mice showed similar running performance compared with WT-mice (6.3km/day vs. 2.7km/day; respectively; p<0.001); however they showed no changes in LVM compared to sed-controls. In contrast to WT animals, female ERß-/- mice showed no increase in AKT and p38-MAPK phosphorylation or up-regulation of mitochondrial key enzymes. E2-treatment of AC16 cells up-regulated mitochondrial target genes (PGC-1a, MEF2A NRF1/2 and TFAM) and led to nuclear translocation of PGC-1a. E2 increased transcriptional activity of PGC-1a and MEF2A/C in an ER dependent manner in cardiomyocytes. Female hearts develop more physiological MH due to exercise, characterized by a stronger activation of pathways and genes involved in the regulation of mitochondrial function. ERß is necessary for the development of physiological hypertrophy and for the activation of p38- MAPK and AKT pathways in female mice.