MURF AND HYPERTROPHY · Regulation and function of the E3 ubiquitin ligases Muscle RING finger 1 and 3 in cardiac hypertrophy

Regulation and function of the E3 ubiquitin ligases Muscle RING finger 1 and 3 in cardiac hypertrophy

Intensive care unit (ICU)-acquired muscle wasting and weakness are devastating complications of critical illness. A subset of these patients develops a severe complication of muscle failure called critical illness myopathy (CIM). Both conditions are common in patients with sepsis, systemic inflammatory response syndrome, and those who are mechanically ventilated. The resultant myopathy leads to persistent functional disability that compromises patients long after discharge from the hospital. How ICU-acquired muscle failure occurs is poorly understood and there are no specific therapies. However, skeletal muscle atrophy and reduced myosin heavy chain (MyHC) are consistently observed in patients with muscle failure. Pathways leading to MyHC loss and its kinetics are ill defined since most investigators reported later time points when ICU-acquired weakness was already established. MyHC loss could be caused by a disturbed balance between its production and degradation. Several risk factors predispose to ICU-acquired weakness and skeletal muscle wasting, such as systemic inflammation, sepsis, immobilization, sedation, hyperglycemia, and corticosteroids, leading to reduced muscle mass and strength by increasing protein degradation and/or decreasing protein synthesis. The major protein-degrading system in muscle is the ubiquitin-proteasome system (UPS) that targets MyHC for breakdown. In critically ill patients, the UPS is activated and mediates muscle atrophy. During our work we investigated the kinetics of muscle protein turnover with focus on protein degradation in serial skeletal muscle biopsies from critically ill patients. We found that myofiber ultrastructure was greatly destroyed and MyHC was strongly reduced already five days after ICU admission. Expression of atrophy genes showed an early increase during critical illness. Based on our findings we conclude that decreased synthesis and increased degradation of MyHC contribute to ICU-acquired muscle wasting. The rates and timeframes suggest that pathogenesis of muscle failure is initiated very early during critical illness. The persisting reduction of MyHC implicate that sustained treatment of patients surviving ICU treatment is required. In addition, we identified serum amyloid A 1 as early marker protein to be specifically upregulated in muscle of CIM patients. These data were confirmed in cell culture and animal studies. In concert, our data showed that skeletal muscle contributes to general inflammation and acute-phase response in CIM patients. We propose that muscular SAA1 could be important for CIM pathogenesis. Further independent studies are required to confirm our findings. It needs to be shown if muscle failure in ICU patients can be reduced by early therapeutic interventions. These studies were only possible by close collaborations with anesthesiologists, neurologists and general surgeons at the Charite - Universitätsmedizin Berlin. The PhD student who worked on this project participated in the international graduate research group MyoGrad funded by the German Research Foundation and the Université Franco-Allemand. Further support for this work came from the clinical research group of muscle disorders of the German Research Foundation. These close and ongoing collaborations are evidence for a very good reintegration. With these projects we received a grant at the Charite - Universitätsmedizin Berlin to independently perform research projects on inflammation induced muscle failure.

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