title: Sex differences in exercise-induced physiological myocardial hypertrophy are modulated by oestrogen receptor beta.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Elke
authors.initials: E
authors.lastname: Dworatzek
authors.affiliation: 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.
authors.forename: Shokoufeh
authors.initials: S
authors.lastname: Mahmoodzadeh
authors.affiliation: 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.
authors.forename: Carola
authors.initials: C
authors.lastname: Schubert
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Westphal
authors.affiliation: Institute of Gender in Medicine, Charité Universitaetsmedizin, Berlin, Germany Center for Cardiovascular Research, Charité Universitaetsmedizin, Berlin, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Leber
authors.affiliation: Center for Cardiovascular Research, Charité Universitaetsmedizin, Berlin, Germany Clinic for Nephrology and Intensive Care Medicine, Charité Universitaetsmedizin, Berlin, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Kusch
authors.affiliation: Institute of Gender in Medicine, Charité Universitaetsmedizin, Berlin, Germany Center for Cardiovascular Research, Charité Universitaetsmedizin, Berlin, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Kararigas
authors.affiliation: 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.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fliegner
authors.affiliation: INSERM, Université Paris-Sud, Paris, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Moulin
authors.affiliation: INSERM, Université Paris-Sud, Paris, France.
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA.
authors.forename: Jan-Ake
authors.initials: JA
authors.lastname: Gustafsson
authors.affiliation: Department of Radiation Oncology, Columbia University, New York, NY, USA.
authors.forename: Mercy M
authors.initials: MM
authors.lastname: Davidson
authors.affiliation: Center for Cardiovascular Research, Charité Universitaetsmedizin, Berlin, Germany Clinic for Nephrology and Intensive Care Medicine, Charité Universitaetsmedizin, Berlin, Germany.
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
authors.affiliation: 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.
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology*; D002478:Cells, Cultured; D047629:Estrogen Receptor beta / Q000502:physiology*; D005260:Female; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology; D010085:Oxidative Phosphorylation; D010805:Physical Conditioning, Animal; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011960:Receptors, Estrogen / Q000502:physiology; D012727:Sex Characteristics; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Exercise-induced physiological MH; Hypertrophy associated; Mitochondrial adaptation; Oestrogen receptor; Sex; Signalling pathway