Sex differences in exercise-induced physiological myocardial hypertrophy are modulated by oestrogen receptor beta

Oestrogen receptor alpha (ER alpha) and beta (ER beta) are involved in the regulation of pathological myocardial hypertrophy (MH). We hypothesize that both ER are also involved in physiological MH. Therefore, we investigated the role of ER in exercise-induced physiological MH in loss-of-function models and studied potential mechanisms of action. We performed 1 and 8 weeks of voluntary cage wheel running (VCR) with male and female C57BL/6J wild-type (WT), ER alpha- and ER beta-deleted mice. In line with other studies, female WT mice ran more than males (P a parts per thousand currency sign 0.001). After 8 weeks of VCR, both sexes showed an increase in left ventricular mass (females: P a parts per thousand currency sign 0.01 and males: P a parts per thousand currency sign 0.05) with more pronounced MH in females (P < 0.05). As previously shown, female ER alpha-deleted mice run less than female WT mice (P a parts per thousand currency sign 0.001). ER beta-deleted mice showed similar running performance as WT mice (females vs. male: P a parts per thousand currency sign 0.001), but did not develop MH. Only female WT mice showed an increase in phosphorylation of serine/threonine kinase (AKT), ERK1/2, p38-mitogen-activated protein kinase (MAPK), and ribosomal protein s6, as well as an increase in the expression of key regulators of mitochondrial function and mitochondrial respiratory chain proteins (complexes I, III, and V) after VCR. However, ER beta deletion abolished all observed sex differences. Mitochondrial remodelling occurred in female WT-VCR mice, but not in female ER beta-deleted mice. The sex-specific response of the heart to exercise is modulated by ER beta. The greater increase in physiological MH in females is mediated by induction of AKT signalling, MAPK pathways, protein synthesis, and mitochondrial adaptation via ER beta.