Uncoupled skeletal muscle mitochondria contribute to hypermetabolism in severely burned adults

Abstract

Elevated metabolic rate is a hallmark of the stress response to severe burn injury. This response is mediated in part by adrenergic stress and is responsive to changes in ambient temperature. We hypothesize that uncoupling of oxidative phosphorylation in skeletal muscle mitochondria contributes to increased metabolic rate in burn survivors. Here, we determined skeletal muscle mitochondrial function in healthy and severely burned adults. Indirect calorimetry was used to estimate metabolic rate in burn patients. Quadriceps muscle biopsies were collected on two separate occasions (11 ± 5 and 21 ± 8 days postinjury) from six severely burned adults (68 ± 19% of total body surface area burned) and 12 healthy adults. Leak, coupled, and uncoupled mitochondrial respiration was determined in permeabilized myofiber bundles. Metabolic rate was significantly greater than predicted values for burn patients at both time points (P < 0.05). Skeletal muscle oxidative capacity, citrate synthase activity, a marker of mitochondrial abundance, and mitochondrial sensitivity to oligomycin were all lower in burn patients vs. controls at both time points (P < 0.05). A greater proportion of maximal mitochondrial respiration was linked to thermogenesis in burn patients compared with controls (P < 0.05). Increased metabolic rate in severely burned adults is accompanied by derangements in skeletal muscle mitochondrial function. Skeletal muscle mitochondria from burn victims are more uncoupled, indicating greater heat production within skeletal muscle. Our findings suggest that skeletal muscle mitochondrial dysfunction contributes to increased metabolic rate in burn victims.

Energy Metabolism in Burn Injury and Current Approaches to Determine the Energy Requirements

“…3,6,7 Bu yanıt endokrin stres tepkisi, inflamatuar yanıt (çoklu mediyatörler), klasik faktörler olan yaş ve cinsiyet ile yara genişliği ve iyileşme zamanına bağlıdır. 3,8 Hasta temel olarak iki faz sergilemektedir: "ebb fazı"nda plazma hacmi ve insülin seviyelerinde azalma, şokun ilk işaretleri, hipotermi, azalmış oksijen tüketimi, doku perfüzyonu ve metabolik hızda azalma gözlenmektedir.…”

“…7,16,19,20 Ciddi yanık yaralanmalarında artan sistemik enerji harcaması, şiddetli kas katabolizması ve artan enerji harcaması nedeni ile hem boy uzunluğu hem de vücut ağırlığında üç yıla kadar büyümede gecikme görülebilmektedir. 6,14,16,19 Ayrıca, enerji substratlarının yoğun kullanımı hastada bağışıklık sistemi yetersizliği, enfeksiyonlar, önemli azot kaybı, gecikmiş yara iyileşmesi, çoklu organ yetmezliği, uzun süreli hastanede kalış ve mortaliteye neden olabilen malnütrisyona yol aç-maktadır. 4,17,20,21 Protein katabolizması, ağrı, ateş, mekanik ventilasyon, kortikosteroidler, vazoaktif ajanlar ve yara boyutu enerji tüketiminin artışına sebep olur iken; malnütrisyon, nöromusküler ajanlar enerji tüketi-mini azaltabilmektedir.…”

Therapeutic Approaches to Combatting Hypermetabolism in Severe Burn Injuries

“…mitochondrial uncoupling and thermogenesis [14]. Consequently, carbohydrate, protein, and fat stores are mobilized to satisfy these prolonged heightened energy demands, thus resulting in hyperglycemia and whole body catabolism.…”

“…Patients with burn injuries compensate for the 4000 mL/ m 2 of water that is lost per day [51][52][53][54] by raising core and skin temperatures by 2°C more than normal compared with unburned patients. This is accomplished by increasing the resting energy expenditure and basal metabolic rates via increased ATP consumption, increased substrate oxidation, and increased mitochondrial thermogenesis [3, 13,14]. Wilmore et al [55] demonstrated that increasing ambient temperatures to from 25 to 33°C decreased resting energy expenditures from a magnitude of 2.0 to 1.4 in patients with severe burn injury.…”

“…Since a majority of the oxygen consumption and 90% of ATP production in respiring cells occur inside the mitochondria [72], metabolism may be normalized by interventions restoring mitochondrial function. Porter et al have shown in a cohort of adults with large burns that skeletal muscle mitochondrial function is altered, where the coupling of oxygen consumption to ATP production is diminished [14], suggesting that skeletal muscle mitochondrial thermogenesis increases in burn patients. In a 2015 study by Porter et al, they showed that muscle mitochondrial respiratory capacity remains significantly lower in burn patients for 1-year post injury.…”