P2: Protein homeostasis in skeletal muscle

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.

 



Salyan Bhattarai, MyoGrad doctoral student 2013-2017


Completed doctoral project:
Functional role of ubiquitin proteasome system in idiopathic inflammatory myopathies

Date and place of thesis defense:
March 20, 2017 in Berlin
Doctoral degree from FU Berlin



Claudia Langhans, MyoGrad doctoral student 2010-2012, doctoral student at Charité 2012-2015)


Completed doctoral project:
Inflammation-induced acute phase response leads to critical ilness myopathy (CIM) - serum amyloid A as early marker

Date and place of thesis defense:
March 27, 2015 in Berlin
Doctoral degree from Charité Universitätsmedizin Berlin



Apostolos Malatras, MyoGrad doctoral Student 2014-2017


Completed doctoral project:
Bioinformatic tools for the systems biology of dysferlin deficiency

Date and place of thesis defense:
December 13, 2017 in Paris
Doctoral degree from UPMC, Paris VI and from FU Berlin




Christina Pablo Tortola, MyoGrad doctoral student

Working title
Regulation and effects of the muscular secretome in inflammation induced skeletal muscle atrophy