Muscle glycogen metabolism is rapidly dysregulated in critical illness, which may have implications for muscle ATP resynthesis and ICU-acquired weakness.

The association of perturbed skeletal muscle metabolism with intensive care unit (ICU)-acquired weakness (ICUAW) is not clear. The objective of the present study was to characterize temporal changes in skeletal muscle mitochondrial function, ATP concentration, and substrate utilization during and up to 6 mo post-ICU admission in critically ill patients, and to delineate mechanisms underpinning ICUAW by comparing the expression of genes involved in skeletal muscle mitochondrial function and substrate utilization in the critically ill patients to control groups that had either undergone elective surgery or leg immobilization (i.e., muscle disuse). The study design was a randomized controlled trial of functional electrical stimulation-assisted cycle ergometry (FESCE) versus standard care, with skeletal muscle mitochondrial respirometry defined a priori in a nested subgroup of patients as the primary outcome. Mitochondrial respirometry did not change 7 days or 6 mo 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 mo and tended to associate with ICUAW (P = 0.078, R2 = 0.582). Moreover, a 40% lower muscle glycogen and 2.5-fold greater muscle lactate were observed earlier at day 1 compared with elective surgery patients. These changes reflected expression of genes related to glycogen metabolism when disuse was accounted for, and a greater expression of the gene encoding glycogen phosphorylase (PYGM) was predictive of mortality. We conclude that muscle glycogen metabolism is rapidly dysregulated in critical illness, which may have implications for muscle ATP resynthesis and ICUAW.NEW & NOTEWORTHY The association of skeletal muscle metabolism with intensive care unit (ICU)-acquired weakness (ICUAW) is not clear. We report for the first time that reduced muscle ATP content by day 7 of ICU stay persisted after 6 mo and tended to be associated with ICUAW. Moreover, lower muscle glycogen and greater muscle lactate were observed earlier at day 1 compared with elective surgery patients. These changes reflected the expression of genes related to glycogen metabolism, which were predictive of mortality.