Long-Term Skeletal Muscle Mitochondrial Dysfunction is Associated with Hypermetabolism in Severely Burned Children

Abstract

Objective The long-term impact of burn trauma on skeletal muscle bioenergetics remains unknown. Here, we determined respiratory capacity and function of skeletal muscle mitochondria in healthy individuals and in burn victims for up to two years post-injury. Methods Hypermetabolism was determined by the difference in predicted and measured metabolic rate. Biopsies were collected from the m. vastus lateralis of 16 healthy men (26±4 years) and 69 children (8±5 years) with burns encompassing ≥30% of their total body surface area. 79 biopsies were collected from cohorts of burn victims at 2 weeks (n=18), 6 months (n=18), 12 months (n=25) and 24 months (n=18) post-burn. Mitochondrial respiration was determined in saponin-permeabilized myofiber bundles. Outcomes were modeled by analysis of variance, with differences in groups assessed by Tukey-adjusted contrasts. Results Burn patients were hypermetabolic for up to two years post injury. Coupled mitochondrial respiration was lower at 2 weeks (17 (8) pmol/s/mg, P<0.001), 6 months (41 (30) pmol/s/mg, P=0.03) and 12 months (35 (14) pmol/s/mg, P<0.001) post-burn compared to healthy controls (58 (13) pmol/s/mg). Coupled respiration was greater at 6, 12 and 24 months post-burn vs. 2 weeks post-burn (P<0.001). Mitochondrial ADP and oligomycin sensitivity (measures of coupling control) were lower at all time-points post-burn vs. control (P<0.05), but greater at 6, 12 and 24 months post burn vs. 2 weeks post burn (P<0.05). Conclusions Muscle mitochondrial respiratory capacity remains significantly lower in burn victims for one-year post injury. Mitochondrial coupling control is diminished for up to two years post-injury in burn victims, resulting in greater mitochondrial thermogenesis. These quantitative and qualitative derangements in skeletal muscle bioenergetics likely contribute to the long-term pathophysiological stress response to burn trauma.

Nutrition and metabolism in burn patients

“…This hypermetabolic state reflects an increase in whole-body oxygen consumption, and a patient is usually considered hypermetabolic when resting energy expenditure (REE) is more than 10% above normal [5]. In the acute postburn injury phase, patients with a burn that covers greater than 40% of total body surface area (TBSA) have a REE between 40 and 100% above normal [6, 7]. It is important to mitigate this stress response and support the significantly increased metabolic needs of the patient as unchecked hypermetabolism results in an enormous loss of lean muscle mass, immune compromise, and delayed wound healing.

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Role of Elevated Fibrinogen in Burn-Induced Mitochondrial Dysfunction

“…Severe burn injury in humans has poor prognosis because of major complications which include neuromuscular dysfunction with muscle mass loss (36), increased vascular permeability (37), systemic inflammation, hypermetabolic state (38), insulin resistance (39) and multiple organ failure. Notably, MD has been implicated in these specific conditions (40), but detailed understanding of the mitochondrial changes have not been elucidated (38).…”

“…Notably, MD has been implicated in these specific conditions (40), but detailed understanding of the mitochondrial changes have not been elucidated (38). Specifically, MD leads to release ROS and various damaged mitochondrial molecules including high mobility group box 1 (HMGB-1).…”

The biochemical alterations underlying post-burn hypermetabolism

“…They’ve demonstrated that mitochondrial abnormalities accompany muscle cachexia, the wasting of tissue, and postulate that mitochondrial protein turnover is associated with increased protein damage due to hypermetabolism-induced oxidative stress [48]. Moreover, they’ve shown that mitochondrial coupling control is diminished, even at 2 years following a severe (>30% TBSA) burn, thus resulting in increased thermogenesis [49]. As such, much of the electrochemical potential is being directed to heat production, perhaps a mechanism to cope with the resultant heat loss that occurs through open wounds and a compromised skin barrier.…”