Changes in Muscle Mass and Quality Mediate the Effect of High‐Calorie Intake on Clinical Outcomes

Abstract

Background Critically ill patients frequently experienced acquired muscle dysfunction, which adversely affects outcomes. The relationship between calorie intake, muscle dysfunction and outcomes remains unclear. This study aims to determine if early calorie intake affects patients' outcomes through changes in skeletal muscle mass or quality, and to explore changes in muscle structure and underlying molecular pathways using limb muscle biopsies in a piglet model. Methods This translational study combines data from a prospective observational study including critically ill patients and a 72‐h ventilated piglet model with early high calorie full enteral nutrition, both recording serial ultrasound measurements of limb muscle thickness and stiffness. Patients were classified into two trajectory groups based on thickness, stiffness and calorie intake. Adjusted mediation analysis quantified the effect of calorie intake on outcomes explained by muscle trajectories. The primary endpoint was ventilator‐free days at Day 28 (VFD28). In vivo limb muscle biopsies from piglets were analysed. Results Among 102 patients, 21% and 28% exhibited decreased thickness and stiffness by Day 7, respectively; 36% received high‐calorie intake at Day 7. Patients categorized into the ‘decreased trajectory group’ for both thickness and stiffness showed lower VFD28 ( p < 0.01) and longer ICU stay ( p < 0.01) compared to the ‘stable trajectory group’. High‐calorie intake was associated with significantly lower VFD28 (−8.7 days [−14.7 to −1.7]; p = 0.01), longer ICU stay ( p < 0.01) and higher ICU mortality ( p < 0.01). Decreased muscle trajectories mediated, respectively, 42% and 28% of the association between high‐calorie intake and VFD 28. The porcine model showed a limb muscle stiffness reduction associated with muscle fibre atrophy and increased intramuscular lipid content linked to decreased protein synthesis (IGF‐1 and myostatin downregulation), increased autophagy (ATG5, ATG7 and P62 increased activity) and impaired fatty acid metabolism (carnitine palmitoyltransferase 1B reduced expression). Conclusions This study demonstrates that early calorie intake in critically ill patients adversely affects muscle mass and quality, mediating negative outcomes. The porcine model helps elucidate underlying mechanisms, with early high‐calorie intake resulting in a metabolic oversupply state associated with metabolic disorders leading to muscle fibre atrophy and lipid accumulation. These results highlight the importance of targeted nutritional strategies to preserve muscle health in critically ill patients.