Burn trauma results in prolonged hypermetabolism and skeletal muscle wasting. How hypermetabolism contributes to muscle wasting in burn patients remains unknown. We hypothesized that oxidative stress, cytosolic protein degradation, and mitochondrial stress as a result of hypermetabolism contribute to muscle cachexia postburn. Patients (n = 14) with burns covering >30% of their total body surface area were studied. Controls (n = 13) were young healthy adults. We found that burn patients were profoundly hypermetabolic at both the skeletal muscle and systemic levels, indicating increased oxygen consumption by mitochondria. In skeletal muscle of burn patients, concurrent activation of mTORC1 signaling and elevation in the fractional synthetic rate paralleled increased levels of proteasomes and elevated fractional breakdown rate. Burn patients had greater levels of oxidative stress markers as well as higher expression of mtUPR-related genes and proteins, suggesting that burns increased mitochondrial stress and protein damage. Indeed, upregulation of cytoprotective genes suggests hypermetabolism-induced oxidative stress postburn. In parallel to mtUPR activation postburn, mitochondrial-specific proteases (LONP1 and CLPP) and mitochondrial translocases (TIM23, TIM17B, and TOM40) were upregulated, suggesting increased mitochondrial protein degradation and transport of preprotein, respectively. Our data demonstrate that proteolysis occurs in both the cytosolic and mitochondrial compartments of skeletal muscle in severely burned patients. Increased mitochondrial protein turnover may be associated with increased protein damage due to hypermetabolism-induced oxidative stress and activation of mtUPR. Our results suggest a novel role for the mitochondria in burn-induced cachexia.

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Chronic cold exposure induces functionally thermogenic mitochondria in the inguinal white adipose tissue (iWAT) of mice. Whether this response occurs in pathophysiological states remains unclear. The purpose of this study was to determine the impact of severe burn trauma on iWAT mitochondrial function in mice. Male balb-c mice (10–12 weeks) received full-thickness scald burns to ~30% of the body surface area. iWAT was harvested from mice at 1, 4, 10, 20, and 40 days post injury. Total and uncoupling protein 1 (UCP1) dependent mitochondrial thermogenesis were determined in iWAT. Citrate synthase (CS) activity was determined as a proxy of mitochondria abundance. Immunohistochemistry was performed to assess iWAT morphology and UCP1 expression. UCP1 dependent respiration was significantly greater at 4 and 10 days post burn compared to sham, peaking at 20 days post burn (P<0.001). CS activity was 3-fold greater at 4, 10, 20 and 40 days post-burn versus sham (P<0.05). Per mitochondrion, UCP1 function increased after burn trauma (P<0.05). After burn trauma, iWAT exhibited numerous multilocular lipid droplets which stained positive for UCP1. The current findings demonstrate the induction of thermogenically competent mitochondria within rodent iWAT in a model of severe burn trauma. These data identify a specific pathology which induces the browning of WAT in vivo, and may offer a mechanistic explanation for the chronic hypermetabolism observed in burn victims.