Hypermetabolism and hypercatabolism of skeletal muscle accompany mitochondrial stress following severe burn trauma

Abstract

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.

The Electrical Stimulation of the Bed Nucleus of the Stria Terminalis Causes Oxidative Stress in Skeletal Muscle of Rats

“…Recently, it was shown that GC secretion might be provoked by different types of stressors [ 41 ]. Some of them link oxidative stress in skeletal muscles with hypermetabolism state and with stress response to situations such as burn trauma [ 42 , 43 ]. However, other pathological conditions, for example, cancer, may stimulate endogenous GC production and contribute to metabolic derangements and the skeletal muscle loss [ 44 , 45 ].…”

<b>Aerobic capacity, physical activity and pain in adult victims of moderate to severe burns after discharge

“…The systemic metabolic response immediately after the burning that leads to hypermetabolism impacts on the cardiovascular system (Johnson, 1994;Ogunbileje et al, 2016;Benjamin, Andersen, Herndon, & Suman, 2015), and it may persist for up to twelve months after the initial event (Hart et al, 2000). Furthermore, there is evidence that heart rate can remain elevated for two years post-burn (Jeschke et al, 2008).…”

The clinically used PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in a murine model of third‐degree burn injury

“…Skeletal muscle dysfunction is another complication of burn injury (Alloju et al, 2008;Ebid et al, 2012;Ogunbileje et al, 2016), and recent studies have started to investigate the role of PARP in skeletal muscle. While in undifferentiated muscle cells PARP expression is high, its expression decreases with differentiation, and this confers oxidative stress resistance to the myocytes .…”