TY - JOUR
T1 - Sex differences in exercise-induced physiological myocardial hypertrophy are modulated by oestrogen receptor beta
AU - Dworatzek, Elke
AU - Mahmoodzadeh, Shokoufeh
AU - Schubert, Carola
AU - Westphal, Christina
AU - Leber, Joachim
AU - Kusch, Angelika
AU - Kararigas, Georgios
AU - Fliegner, Daniela
AU - Moulin, Maryline
AU - Ventura-Clapier, Renée
AU - Gustafsson, Jan Ake
AU - Davidson, Mercy M.
AU - Dragun, Duska
AU - Regitz-Zagrosek, Vera
PY - 2014/6/1
Y1 - 2014/6/1
N2 - AimsOestrogen 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 resultsWe 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.ConclusionThe 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.
AB - AimsOestrogen 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 resultsWe 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.ConclusionThe 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.
KW - Exercise-induced physiological MH
KW - Hypertrophy associated
KW - Mitochondrial adaptation
KW - Oestrogen receptor
KW - Sex
KW - Signalling pathway
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U2 - 10.1093/cvr/cvu065
DO - 10.1093/cvr/cvu065
M3 - Article
C2 - 24654233
AN - SCOPUS:84901468382
VL - 102
SP - 418
EP - 428
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 3
ER -