A prospective clinical study on the mechanisms underlying Critical Illness Myopathy – A time‐course approach.

R3306 --> 605.15 --> Background: Critical illness myopathy (CIM) is a consequence of modern critical care resulting in general muscle wasting and paralyses of all limb and trunk muscles, and prolonged weaning from the ventilator. CIM is associated with severe morbidity/mortality and significant negative socioeconomic consequences which has become increasingly evident during the current COVID‐19 pandemic, but underlying mechanisms remain elusive. Methods: Ten neuro‐ICU patients exposed to long‐term controlled mechanical ventilation (CMV) were followed with repeated muscle biopsies 3times/week for up to 12 days. Single muscle fiber contractile recordings were conducted on the first and final biopsy. A multiomics approach was taken to analyze gene and protein expression in muscle and plasma at all six timepoints. Findings: i) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro‐ICU patients during the observation period. The myosin loss was coupled to a general transcriptional downregulation of myofibrillar proteins and activation of protein degradation pathways, resulting in significant muscle fiber atrophy and loss in force generation capacity which declined >65% during the 12‐day observation period, ii) membrane excitability was not affected as indicated by the maintained compound muscle action potential amplitude upon supramaximal stimulation of upper and lower extremity motor nerves, and iii), analyses of plasma revealed early activation of inflammatory and proinflammatory pathways, as well as a redistribution of zinc ions from plasma in parallel with the activation of zinc transporters. Interpretation: The mechanical ventilation induced lung injury with release of cytokines/chemokines and the complete mechanical silencing uniquely observed in immobilized ICU patients affecting skeletal muscle gene/protein expression are forwarded as the dominant factors triggering CIM. It is therefore suggested that future intervention strategies should target the lung injury and the mechanical silencing in critical ill ICU patients. [ABSTRACT FROM AUTHOR]