Critical Illness Myopathy: Motor Protein Function and Contractility Changes of Skeletal Muscle in Muscle Biopsies from Critcially Ill ICU Patients
Final Report Abstract
During this funded DFG project, a motorprotein function assay was developed for a global screening of specific myopathic changes in muscle biopsies from critically ill ICU patients and tumor cachexia patients. Both patient cohorts are known to develop substantial muscle weakness during the course of their disease that represents a major health and budget threat to their ongoing treatment, also predicting morbidity, mortality and setting quality of life. The acute critical illness-induced myopathy is supposed to be mediated via an overreacting immune system during critical illness and sepsis while the latter seems to be mediated by chronic inflammation and tumor induced catabolism. Our screening platform contained three established muscle profiling techniques that address the motorproteins: skinned fibre pCa-force analysis (to establish the Ca2+ sensitivity of the contractile apparatus), ‘in vitro’ motility assay (to directly visualize actin-myosin interaction for filament sliding velocity) and SDS PAGE analysis for myosin heavy chains MHC (to detect changes in isoforms distributions). In collaboration with the clinical research group KFO 192 in Berlin-Charité, skeletal muscle biopsy samples from a total of 15 critically ill intensive care unit patients were obtained for investigation. Where possible, those biopsies were obtained from the same patient at two time points: an early biopsy (median: 5 days) and a late biopsy (median: 15 days). In collaboration with the Surgery Department at TU Munich, skeletal muscle biopsies from 14 tumor patients, either with or without showing cachexia, and five control patients were obtained during elective surgery. One very striking result from both unlike patient cohorts was the finding of a Ca2+ sensitization of the motorproteins in cachectic patients vs. non-cachectic and controls as well as in some critical illness myopathy (CIM) patients during the course of critical illness (late vs. early biopsy). Sliding filament velocities were not significantly altered in ICU patients during critical illness, nor were there decisive changes in the CIM vs. non-CIM groups. This was also reflected by the myosin protein profiles that only showed subtle changes. In the tumor cachexia group, there were overall trends for a larger proportion of slower filament sliding velocities that was also paralleled by a decline in the ratio of slow-to-fast myosin isoforms. A conclusion from the study is that during ongoing systemic inflammatory processes, the organ muscle is not only affected by a generalized proteolysis leading to muscle wasting but underlying the muscle weakness, there may also be some common alterations pointing towards a remodeling of the motorprotein isoforms from a slow to a fast type, the latter also being responsible for an increased fatigability of affected muscle. This project is a first detailed approach to muscle dysfunction mechanisms on the subcellular level in acute and chronic systemic inflammation (critical illness, cancer) in patients. It is believed that the observed trends will be consolidated by including larger patient numbers in a planned follow-up project to provide sensitive and positive predictive parameters from still living muscle cells within fresh or adequately preserved patient biopsies.
