Elke Dworatzek1, Shokoufeh Mahmoodzadeh2, Carola Schubert2, Christina Westphal3, Joachim Leber4, Angelika Kusch5, Georgios Kararigas4, Daniela Fliegner2, Maryline Moulin6, Renée Ventura-Clapier6, Jan-Ake Gustafsson7, Mercy M Davidson8, Duska Dragun5, Vera Regitz-Zagrosek2. 1. Institute of Gender in Medicine, Charité Universitaetsmedizin, Berlin, Germany Center for Cardiovascular Research, Charité Universitaetsmedizin, Berlin, Germany DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany elke.dworatzek@charite.de. 2. Institute of Gender in Medicine, Charité Universitaetsmedizin, Berlin, Germany Center for Cardiovascular Research, Charité Universitaetsmedizin, Berlin, Germany DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany. 3. Max Delbrück Center for Molecular Medicine, Berlin, Germany. 4. Institute of Gender in Medicine, Charité Universitaetsmedizin, Berlin, Germany Center for Cardiovascular Research, Charité Universitaetsmedizin, Berlin, Germany. 5. Center for Cardiovascular Research, Charité Universitaetsmedizin, Berlin, Germany Clinic for Nephrology and Intensive Care Medicine, Charité Universitaetsmedizin, Berlin, Germany. 6. INSERM, Université Paris-Sud, Paris, France. 7. Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA. 8. Department of Radiation Oncology, Columbia University, New York, NY, USA.
Abstract
AIMS: Oestrogen receptor alpha (ERα) and beta (ERβ) 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. METHODS AND RESULTS: We performed 1 and 8 weeks of voluntary cage wheel running (VCR) with male and female C57BL/6J wild-type (WT), ERα- and ERβ-deleted mice. In line with other studies, female WT mice ran more than males (P ≤ 0.001). After 8 weeks of VCR, both sexes showed an increase in left ventricular mass (females: P ≤ 0.01 and males: P ≤ 0.05) with more pronounced MH in females (P < 0.05). As previously shown, female ERα-deleted mice run less than female WT mice (P ≤ 0.001). ERβ-deleted mice showed similar running performance as WT mice (females vs. male: P ≤ 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, ERβ deletion abolished all observed sex differences. Mitochondrial remodelling occurred in female WT-VCR mice, but not in female ERβ-deleted mice. CONCLUSION: The sex-specific response of the heart to exercise is modulated by ERβ. The greater increase in physiological MH in females is mediated by induction of AKT signalling, MAPK pathways, protein synthesis, and mitochondrial adaptation via ERβ. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Oestrogen receptor alpha (ERα) and beta (ERβ) 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. METHODS AND RESULTS: We performed 1 and 8 weeks of voluntary cage wheel running (VCR) with male and female C57BL/6J wild-type (WT), ERα- and ERβ-deleted mice. In line with other studies, female WT mice ran more than males (P ≤ 0.001). After 8 weeks of VCR, both sexes showed an increase in left ventricular mass (females: P ≤ 0.01 and males: P ≤ 0.05) with more pronounced MH in females (P < 0.05). As previously shown, female ERα-deleted mice run less than female WT mice (P ≤ 0.001). ERβ-deleted mice showed similar running performance as WT mice (females vs. male: P ≤ 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, ERβ deletion abolished all observed sex differences. Mitochondrial remodelling occurred in female WT-VCR mice, but not in female ERβ-deleted mice. CONCLUSION: The sex-specific response of the heart to exercise is modulated by ERβ. The greater increase in physiological MH in females is mediated by induction of AKT signalling, MAPK pathways, protein synthesis, and mitochondrial adaptation via ERβ. Published on behalf of the European Society of Cardiology. All rights reserved.
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