Burn-induced hypermetabolism and skeletal muscle dysfunction

Abstract

Critical illnesses, including sepsis, cancer cachexia, and burn injury, invoke a milieu of systemic metabolic and inflammatory derangements that ultimately results in increased energy expenditure leading to fat and lean mass catabolism. Burn injuries present a unique clinical challenge given the magnitude and duration of the hypermetabolic response compared with other forms of critical illness, which drastically increase the risk of morbidity and mortality. Skeletal muscle metabolism is particularly altered as a consequence of burn-induced hypermetabolism, as it primarily provides a main source of fuel in support of wound healing. Interestingly, muscle catabolism is sustained long after the wound has healed, indicating that additional mechanisms beyond wound healing are involved. In this review, we discuss the distinctive pathophysiological response to burn injury with a focus on skeletal muscle function and metabolism. We first examine the diverse consequences on skeletal muscle dysfunction between thermal, electrical, and chemical burns. We then provide a comprehensive overview of the known mechanisms underlying skeletal muscle dysfunction that may be attributed to hypermetabolism. Finally, we review the most promising current treatment options to mitigate muscle catabolism, and by extension improve morbidity and mortality, and end with future directions that have the potential to significantly improve patient care.

Keywords: inflammation; burn injury; hypermetabolism; muscle dysfunction.

Figure 1.

Systemic factors released postburn induce skeletal muscle dysfunction. Proinflammatory cytokines such as interleukin-6 (IL-6), interleukin-1 β (IL-1β), and tumor necrosis factor α (TNF-α), as well as damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1), heat shock proteins (HSPs), and mitochondrial DNA (mtDNA), induce muscle inflammation and proteolysis while perpetuating a state of insulin resistance. iNOS, inducible nitric oxide synthase; IR, insulin receptor; MuRF-1, muscle RING-finger protein-1.

Figure 2.

Burn injury induces organellar dysfunction in muscle tissue. Mitochondrial uncoupling accompanied by increased ROS formation stimulates the unfolded protein response in both the mitochondria (mtUPR) and endoplasmic reticulum. Organellar stress contributes to apoptosis of muscle cells in addition to insulin resistance, a hallmark of burns. BiP, binding immunoglobulin protein; CHOP, C/EBP homologous protein; DAMP, damage-associated molecular pattern; ETC, electron transport chain; IRE1, inositol-requiring enzyme 1; JNK, c-Jun N-terminal kinase; PERK, protein kinase R (PKR)-like endoplasmic reticulum kinase; UCP3, uncoupling protein-3; UPR, unfolded protein response; ROS, reactive oxygen species.

Figure 3.

Dysfunctional organ cross talk as a product of severe burn injuries. A severe burn induces the pathological browning of subcutaneous white adipose tissue, forming thermogenic “beige” fat, which is highly lipolytic. In turn, adipose modulates the function of downstream tissues such as the liver and muscle via the release of FFAs, perpetuating systemic dysfunction postburn. ER, endoplasmic reticulum; FFAs, free fatty acids; ROS, reactive oxygen species; UCP1, uncoupling protein-1.