Sex-specific modulators of mitochondrial function

运动后，雌性小鼠比雄性小鼠出现更多的生理性心肌肥大。我们的项目调查了导致这些性别差异的机制。我们已经确定了靶线粒体基因/蛋白（PGC-1a, MEF2A, NRF1/2， TFAM）和途径（PI3K/AKT和p38-MAPK），这些基因/蛋白仅在雌性跑步小鼠的心脏中激活，或在雌激素（E2）存在的心肌细胞体外研究中激活。初步结果表明，雌性和/或E2/雌激素受体（ER）强烈影响线粒体的生物发生和功能。为了验证这一假设，我们将分析运动诱导心肌肥大小鼠模型中涉及线粒体生物发生和呼吸功能（耗氧量和atp含量）的核和线粒体关键酶的性别特异性调控。为了分析e2激活ER调控线粒体生物发生和功能的分子机制，我们将在培养细胞中确定PI3K/AKT和p38-MAPK途径的激活及其下游分子过氧化物酶体增殖体激活受体（PPAR-y）辅激活因子1a （PGC-1a）。我们将测试由PGC-1a调节的肌细胞增强因子-2 （MEF2A）、核呼吸因子（NRF1/2）和线粒体转录因子A （TFAM）的转录调节。我们将研究核编码基因产物进入线粒体的过程。最后，我们将在心脏特异性缺失ERa和ERß的小鼠模型中分别阐明ERa和ERß在心肌肥厚发生过程中代谢变化的具体作用。本研究将为探讨女性性别和/或E2/ER对HF线粒体生物发生和功能的保护机制提供重要的新见解。

Female mice develop more physiological myocardial hypertrophy than males in response to exercise. Our project investigates the mechanisms leading to these sex differences. We have identified target mitochondrial genes/proteins (PGC-1a, MEF2A, NRF1/2, TFAM) and pathways (PI3K/AKT and p38-MAPK) that are activated only in the hearts of female running mice or in in-vitro studies with cardiomyocytes in the presence of estrogen (E2). The preliminary results suggest that female sex and/or E2/estrogen receptors (ER) strongly influence mitochondrial biogenesis and function. To test this hypothesis, we will analyze the sex-specific regulation of nuclear and mitochondrial key enzymes involved in mitochondrial biogenesis and respiratory function (oxygen consumption, and ATP-content) in a mouse model of exercise-induced myocardial hypertrophy. To analyze the molecular mechanisms by which E2-activated ER regulates mitochondrial biogenesis and function, we will determine the activation of PI3K/AKT and p38-MAPK pathways, and its downstream molecule, peroxisome proliferator-activated receptor-y (PPAR-y) coactivator 1a (PGC-1a), in cultured cells. We will test the transcriptional regulation of myocyte enhancer factor-2 (MEF2A), nuclear respiratory factor (NRF1/2), and mitochondrial transcription factor A (TFAM) that are regulated by PGC-1a. We will investigate the import of nuclear-encoded gene products into the mitochondria. Finally, we will clarify the specific role of ERa and ERß on metabolic changes during the development of myocardial hypertrophy in mouse models with heartspecific deletion of ERa and ERß, respectively. This study will give significant new insight into the protective mechanism of female sex and/or E2/ER on mitochondrial biogenesis and function in HF.