Maintenance of muscular structure and function requires a precise control of protein synthesis and degradation; abnormalities in these processes can give rise to myopathies. The ubiquitin proteasome system (UPS) is largely responsible for the degradation of long-lived proteins, such as components of the contractile apparatus of striated muscle cells. The UPS is activated during cardiac hypertrophy, heart failure and skeletal muscle atrophy leading to degradation of structural and contractile proteins, most notably myosin heavy chain, resulting in a reduction of cardiac and muscle function. Within the UPS E3 ligases mediate substrate specificity and are the rate limiting enzymes. We investigate the regulation and function of the muscle-specific E3 ligases Muscle RING-finger (MuRF) 1, 2 and 3 in myocyte remodeling. We showed that muscle RING finger (MuRF) 1, 2 and 3 are important for maintaining cardiac and skeletal muscle structure and function. Combined deletion of Trim63/MuRF1 and Trim54/MuRF3, and Trim55/MuRF2 and Trim54/MuRF3 resulted in myosin surplus myopathy of the heart and skeletal muscle. Nevertheless, the function of MuRF proteins in muscle cells is not well understood. Therefore, we are currently identifying and characterizing the regulation and function of MuRF proteins in greater detail.
Protein homeostasis is also impaired in muscle of critically ill patients. We reported an imbalanced protein homeostasis with decreased synthesis and increased degradation of muscular proteins in skeletal muscle of patients with Intensive Care Unit (ICU)-acquired weakness (ICUAW; a major comorbidity of critically ill patients). Although, inflammation is thought to be involved in the pathogenesis of ICUAW the precise disease mechanisms are not well understood.
We identified the stress responsive serine/threonine kinase protein kinase D1 (Prkd1/PKD1) as an important regulator of pathological cardiac remodeling and Ang II-induced muscle wasting. We described PKD1-dependent control of the class IIa histone deacetylase 5/transcription factor EB (TFEB) axis in muscle atrophy, and work on non-transcriptional functions of PKD1 in heart and skeletal muscle.
AG Molecular Cardiology and Muscular Proteostasis
Ernst-Moritz-Arndt Universität Greifswald
Klinik und Poliklinik für Innere Medizin B
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