Impact of AMP-activated kinase on sex differences in hypertrophic cardiomyopathy

描述（由申请人提供）：在由许多疾病病因（包括高血压、心肌梗死和肥厚性心肌病（HCM））引起的人类心脏疾病中存在性别/性别差异。患有这些疾病的女性的心脏至少保持了足够的心脏功能，而男性通常表现出增加的腔室扩张和壁变薄，所有这些都是心脏病逐渐恶化的迹象。由心脏主要运动蛋白（1-肌球蛋白重链）中的常染色体显性突变（R403 Q）引起的HCM患者在心脏疾病进展中显示出相似的性别差异。与人类相似，在心脏中表达R403 Q突变的雄性小鼠发生HCM，其特征在于进行性左心室扩张和心脏功能障碍，而雌性小鼠显示肥大而没有扩张或功能障碍。然而，这些差异背后的机制仍然未知。由于R403 Q突变存在于细胞收缩器官的马达蛋白中，因此表达R403 Q突变的心脏被剥夺能量，这可能是由于表达R403 Q突变时收缩的能量消耗增加。因此，预测是，观察到的性别差异可能是由于男性的心脏无法匹配这种增加的能量需求相比，女性。为了支持这一观点，男性R403 Q心脏显示出与能量剥夺状态一致的代谢异常。腺苷一磷酸激活激酶（AMPK）可能是这种性别差异的中心调节因子，因为它在以下方面的作用已确立：（1）感知细胞能量状态的变化，（2）调节能量产生途径的介质，以及（3）通过磷酸化直接修饰收缩蛋白。然而，没有研究系统地解决了AMPK性别二态性与R403 Q突变的小鼠。因此，概述的实验计划旨在简明地测试以下假设：男性心脏不能适当地适应由R403 Q HCM突变引起的能量需求增加，这导致心脏功能障碍逐渐恶化。有待检验的假设是，这种两性异形的关键机制是与雌性相比，雄性中AMPK信号轴的改变。此外，这些研究将提供一个重要的基础，指导未来的研究，以确定男性和女性心脏代谢和氧化能力的根本差异，以更全面地阐明人类心血管疾病病因和治疗的性别差异。

DESCRIPTION (provided by applicant): Sex/gender differences exist in human cardiac disease resulting from many disease etoilogies including hypertension, myocardial infarction, and hypertrophic cardiomyopathy (HCM). The hearts of women with these disorders maintain, at least, adequate cardiac function whereas men typically demonstrate increased chamber dilation and wall thinning, all signs of progressively deteriorating cardiac disease. Humans with HCM caused by an autosomal dominant mutation (R403Q) in the predominant motor protein in the heart (1-myosin heavy chain) show a similar sex difference in cardiac disease progression. Like their human counterparts, male mice expressing the R403Q mutation in the heart develop HCM characterized by progressive left-ventricular dilation and cardiac dysfunction whereas females show hypertrophy without dilation or dysfunction. However, the mechanisms that underlie these differences remain unknown. Because the R403Q mutation resides in the motor protein of the cellular contractile apparatus, hearts expressing the R403Q mutation are energy deprived and that this may be due to the increased energetic cost of contraction when expressing the R403Q mutation. Therefore, the prediction is that the observed sex difference may result from the inability of male hearts to match this increased energetic demand compared to females. In support of this idea, male R403Q hearts show metabolic abnormalities consistent with an energy-deprived state. Adenosine monophosphate-activated kinase (AMPK) may be a central regulator of this sex difference because of its established role in (1) sensing changes in cellular energy state, (2) regulating mediators of energy producing pathways, and, (3) directly modifying contractile proteins by phosphorylation. Yet, no studies have systematically addressed AMPK sex dimorphisms in mice with the R403Q mutation. Therefore, the outlined experimental plan is designed to concisely test the hypothesis that male hearts do not adapt appropriately to the increase in energetic demand caused by the R403Q HCM mutation, which leads to progressively worsening cardiac dysfunction. The hypothesis to be tested is that the key mechanism that underlies this sexual dimorphism is an altered AMPK signaling axis in males compared to females. Moreover, these studies will provide a critical foundation upon which to guide future research into defining fundamental differences in metabolic and oxidative capacities of male and female hearts in order to more completely elucidate sex differences in cardiovascular disease etiology and treatment in the human population.