Protein homeostasis in skeletal muscle
P2
Subproject Speakers
Berlin: Jens Fielitz, MD, PD
Paris: Vincent Mouly, PhD
Patients with sepsis and immobilization often develop a life threatening muscular disorder called critical illness myopathy (CIM), which is characterized by a loss of myosin heavy chain (MHC). CIM prevents patients from being mobilized and enhances their morbidity and mortality. CIM is characterized by an activation of the protein degrading ubiquitin proteasome system (UPS) and its key E3 ubiquitin ligases Muscle RING-finger (MuRF) 1 and 3 that mediate degradation of structural proteins in the diseased skeletal muscle. This activation leads to a reduction in skeletal muscle function and skeletal muscle atrophy. Our previous work showed that MuRF1 and 3 specifically interact with, ubiquitinate, and mediate UPS-dependent degradation of structural proteins, most importantly MHC. Accordingly, mice deficient for MuRF1 and 3 developed a skeletal muscle myopathy characterized by subsarcolemmal MHC accumulation and diminished muscle performance. Our findings identified MuRF1 and 3 as key E3 ligases for the UPS-dependent turnover of MHC and revealed a potential basis for CIM. Inhibition of this pathway could be useful to prevent and treat CIM. However, the precise molecular mechanisms activating MuRF1 and 3 in CIM and its relevance for patients developing CIM are unclear. Furthermore, it is unclear which additional pathological pathways, beside inflammatory cytokines, are activated during sepsis leading to muscular wasting and CIM.
Theses in progress
Student |
University degree |
Working title |
---|---|---|
Cristina Pablo Tortola | Master, Biomedical Biotechnology Universitat Politècnica de València, Spain |
Regulation and effects of the muscular secretome in inflammation induced skeletal muscle atrophy |
Completed theses
Students |
MyoGrad PhD student from |
Thesis project |
Defence and degree |
---|---|---|---|
Salyan Bhattarai | 2013-2016 |
Functional role of ubiquitin proteasome system in idiopathic inflammatory myopathies |
Defence on March 20, 2017 in Berlin
|
Claudia Langhans | 2010-2015 | Inflammation-induced acute phase reaction leads to Critical Illness Myopathy (CIM) - Serum Amyloid A as early CIM biomarker |
Defence on March 27, 2015 in Berlin
|
Apostolos Malatras | 2014-2017 | Trafficking and secretory pathways in the systems biology of dysferlin deficiency |
Defence on Sept. 30, 2017 in Paris
|