Muscle glycogen metabolism is rapidly dysregulated in critical illness and associates with ICU acquired weakness

Abstract

Abstract The association of perturbed skeletal muscle metabolism with ICU acquired weakness (ICUAW) is not clear. We characterised temporal changes in skeletal muscle mitochondrial function, ATP concentration, and substrate utilisation during and up to 6 months post ICU admission in critically ill patients enrolled into a randomised controlled trial of functional electrical stimulation-assisted cycle ergometry (FESCE) vs. standard care. To delineate mechanisms underpinning ICUAW we also compared the expression of genes involved in skeletal muscle mitochondrial function and substrate utilisation in the critically ill patients to control groups that had either undergone elective surgery or leg immobilisation (i.e. muscle disuse). The main finding was that mitochondrial function did not change 7 days or 6 months after ICU admission and was not impacted by FESCE. However, a 20% reduction in muscle ATP content by day 7 of ICU stay persisted after 6 months and was associated with ICUAW. Moreover, a 40% lower muscle glycogen and 2.5-fold greater muscle lactate were observed earlier at day 1 compared to elective surgery patients. These changes reflected expression of genes related to glycogen metabolism when disuse was accounted for, and of which a greater expression of the gene encoding glycogen phosphorylase (PYGM) was predictive of mortality. Muscle glycogen metabolism is rapidly dysregulated in critical illness and may contribute to ICUAW.