Sepsis Increases Muscle Proteolysis in Severely Burned Adults, but Does not Impact Whole-Body Lipid or Carbohydrate Kinetics

Abstract

Sepsis is a common and often fatal consequence of severe burn injury, but its exact effects on whole body and muscle metabolism in the burn patient is unclear. To address this, 13 septic and 11 nonseptic patients (age: 36.9 ± 13.0 years) with burns encompassing >30% of their total body surface area underwent muscle protein kinetic studies under postabsorptive conditions using bolus injections of ring-C6 and N phenylalanine isotopes. In parallel, whole-body lipid and carbohydrate kinetics were assessed using constant infusions of [U-C6]palmitate, [6,6-H2]glucose, and [H5]glycerol, and during a 2-h hyperinsulinemic euglycemic clamp. Muscle mRNA levels of genes implicated in the development of muscle cachexia were assessed by qPCR. Fractional breakdown rates of mixed-muscle proteins were found to be 2.4-fold greater in septic versus nonseptic patients (P < 0.05). No discernable differences in fractional synthetic rate of mixed-muscle proteins or rate of appearance of plasma free fatty acids, glycerol, or glucose could be observed between patient groups, although the latter was significantly associated with burn size (P < 0.05). Hyperinsulinemia stimulated whole-body glucose uptake and suppressed endogenous glucose production and whole-body lipolytic rate to equivalent degrees in both groups. Muscle mRNA levels of genes spanning autophagy, lysosomal, and ubiquitin proteasome-mediated proteolysis were not enhanced in septic versus nonseptic patients. Our results demonstrate that accelerated muscle proteolysis appears to be the principal metabolic consequence of sepsis in severe burn patients and could be a contributing factor to the accelerated loss of muscle mass in these individuals. The exact mechanistic basis for these changes remains unclear.

Figure 1:. Schematic of infusion protocol.

Muscle protein turnover assessed in the fasted state using two separate bolus injections of alternative stable-isotopes of phenylalanine. Whole-body lipid and carbohydrate kinetics were assessed over a 4 hour period, with a hyperinsulinemic clamp performed in the final two hours. REE: Resting energy expenditure.

Figure 2:. Effect of sepsis during burn injury on mixed muscle protein turnover and atrophy-gene expression.

Fractional synthetic rate (FSR; A), fractional breakdown rate (FBR; B) and net protein balance (C) in burn patients with and without sepsis. In a subset of patients (n = 5 per group) muscle mRNA levels of key atrophy-associated genes were examined by qPCR (D). mRNA levels reported as the average expression in septic patients expressed relative to non-septic burn patients. All data presented as means ± SEM. * denotes significantly different from non-septic burn patients (P < 0.05). N = 10 – 11 per group.