Preserved anabolic skeletal muscle capacity in response to exercise and protein intake after critical illness

Abstract Background Low muscle mass and persistent weakness are common after critical illness, but the mechanisms behind impaired recovery are incompletely understood. The aim of this study was to investigate the skeletal muscle anabolic response to combined resistance exercise and protein intake in intensive care unit (ICU) survivors, compared to matched controls without a history of critical illness. We hypothesised that residual anabolic resistance limits muscle regeneration after ICU stay. Methods Former patients were enrolled within 3 to 6 months of intensive care unit discharge. Muscle biopsies were obtained before and after resistance exercise using a flywheel leg extension ergometer, combined with ingestion of 24 g hydrolysed protein. Muscle protein fractional synthetic rate was determined from the incorporation of [ring-²H₅]phenylalanine into mixed-muscle protein during a primed continuous intravenous infusion. Anabolic and proteolytic pathways were measured using standard assays. Group-by-time differences were analysed using linear mixed models. The primary comparison was the between-group difference in pre-to-post change in muscle protein synthesis. Results Twenty ICU survivors (60 ± 12 years, 30% female, BMI 26.9 (IQR 22.9–28.7), SAPS 3 62.3 ± 15.8) and 20 age- and sex-matched controls were included. ICU survivors had significantly lower quadriceps muscle thickness ( p = 0.02) and handgrip strength ( p = 0.04) than controls. In ICU survivors, muscle protein synthesis from plasma precursor amino acids was higher at baseline than in controls (0.041%/hour vs. 0.030%/hour, p = 0.009), but increased less (Δ 0.031 vs. Δ 0.040%/hour, p = 0.04). Post-intervention muscle protein synthesis was similar between groups (0.071%/hour vs. 0.070%/hour, p = 0.70). At baseline, ICU survivors showed lower activation of the autophagy-lysosomal pathway. In both groups, the intervention increased anabolic signalling, decreased initiation of autophagy and increased parts of the ubiquitin-proteasome pathway. Conclusions In ICU survivors with persistent muscle loss and weakness, the increase in muscle protein synthesis after combined resistance exercise and protein intake was smaller than in controls, in the context of a higher baseline fractional synthetic rate. Post-intervention muscle protein synthesis rates were similar between groups. These findings provide the first mechanistic support for structured exercise-nutrition rehabilitation to promote muscle recovery after critical illness. Trial registration This study was prospectively registered at ClinicalTrials.gov (NCT05261984), 2022-02-20.