Project 13 - Regulation of muscular wasting disorders by protein kinase D1

Principal investigator
Jens Fielitz, MD, PhD

End-stage heart failure (EHF) is often associated with cardiac cachexia, resulting in skeletal muscle atrophy, reduced muscle performance, and an increased mortality. The renin-angiotensin-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.