Regulation of heart failure induced skeletal muscle wasting by protein kinase D1

终末期心力衰竭（EHF）通常与心脏恶病质相关，导致骨骼肌萎缩，肌肉性能降低和死亡率增加。EHF患者血浆中的肾素-血管紧张素-醛固酮系统（RAAS）及其效应物血管紧张素II（AngII）被激活，并在心脏恶病质中发挥作用。更具体地，AngII通过泛素蛋白酶体系统（UPS）增强蛋白质降解和E3泛素连接酶的表达增加直接促进骨骼肌萎缩。然而，连接AngII与E3泛素连接酶和UPS活性的转录调控的分子机制是未知的。有趣的是，AngII激活应激应答激酶蛋白激酶D1（PKD 1），PKD 1又使转录抑制因子II类组蛋白脱乙酰酶（HDAC）失活，从而激活生长因子MEF 2。事实上，当我们删除心肌细胞中的PKD 1时，AngII诱导的心脏重塑（即左心室肥大和心肌纤维化）减弱，表明PKD 1在AngII信号传导中的中心作用。此外，我们还发现骨骼肌中组成型活性PKD 1的表达缺失导致肌肉萎缩。然而，尽管PKD 1在骨骼肌中高度表达，但其在AngII诱导的骨骼肌萎缩中的作用尚不清楚。在这里，我们要测试的假设，PKD 1介导血管紧张素II诱导的骨骼肌萎缩。首先，我们希望揭示参与骨骼肌细胞中AngII介导的PKD 1激活的信号通路。我们的目的是表征骨骼肌细胞中PKD 1的新靶点，重点是蛋白质降解，并希望阐明PKD 1如何调节AngII诱导的UPS激活。其次，我们要证明的假设，血管紧张素II诱导骨骼肌消耗在体内。最后，我们想测试PKD 1信号事件是否有助于人类样本中的心脏恶病质。阐明PKD 1在心脏恶病质中的功能和调控，将为开发靶向特异性治疗方法提供基础。

End-stage heart failure (EHF) is often associated with cardiac cachexia, resulting in skeletal muscle atrophy, reduced muscle performance, and an increased mortality. The reninangiotensin- aldosterone system (RAAS) and its effector angiotensin II (AngII) are activated in EHF and play a role in cardiac cachexia. More specifically, AngII promotes skeletal muscle atrophy directly by enhancing protein degradation via the ubiquitin proteasome system (UPS) and increased expression of E3 ubiquitin ligases. However, the molecular mechanisms linking AngII with transcriptional regulation of E3 ubiquitin ligases and UPS activity are unknown. Interestingly, AngII activates the stress responsive kinase protein kinase D1 (PKD1) which in turn inactivates the transcriptional repressors class II histone deacetylases (HDACs) and thereby activates the growth factor MEF2. Indeed, when we deleted PKD1 in cardiomyocytes AngII induced cardiac remodeling (i.e. left ventricular hypertrophy and myocardial fibrosis) was attenuated, indicating a central role for PKD1 in AngII signaling. Furthermore, we found that miss-expression of constitutive active PKD1 in skeletal muscle leads to muscular atrophy. However, although PKD1 is highly expressed in skeletal muscle its role in AngII induced skeletal muscle wasting is unclear. Here we want to test the hypothesis that PKD1 mediates AngII induced skeletal muscle atrophy. First, we want to uncover the signaling pathway involved in AngII mediated PKD1 activation in skeletal myocytes. We aim to characterize novel PKD1 targets in skeletal myocytes with focus on protein degradation and want to elucidate how PKD1 regulates AngII induced UPS activation. Secondly, we want to prove the hypothesis that AngII induces skeletal muscle wasting in vivo. Finally, we want to test if PKD1 signaling events contribute to cardiac cachexia in human samples. Elucidation of function and regulation of PKD1 in cardiac cachexia will provide the basis to develop a target specific therapy to treat this disease.