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Determinants of skeletal muscle protein turnover following severe burn trauma in children.

ABSTRACT: BACKGROUND & AIMS:Burns remain the fifth cause of non-fatal pediatric injuries globally, with muscle cachexia being a hallmark of the stress response to burns. Burn-induced muscle wasting is associated with morbidity, yet the determinants of muscle protein catabolism in response to burn trauma remains unclear. Our objective was to determine the effect of patient and injury characteristics on muscle protein kinetics in burn patients. METHODS:This retrospective, observational study was performed using protein kinetic data from pediatric patients who had severe burns (>30% of the total body surface area burned) and underwent cross-limb stable isotope infusions between 1999 and 2008 as part of prospective clinical trials. Mixed multiple regression models were used to assess associations between patient/injury characteristics and muscle protein fractional synthesis rate (FSR), net balance (NB), and rates of phenylalanine appearance (Ra; index of protein breakdown) and disappearance (Rd; index of protein synthesis) across the leg. RESULTS:A total of 268 patients who underwent 499 studies were analyzed. Increasing time post injury was associated with greater FSR (p < 0.001) and NB (p = 0.01). Males were more catabolic than females (as indicated by lower NB, p = 0.04 and greater Ra, p = 0.008), a consequence of higher protein breakdown rather than lower synthesis. Increasing burn size was associated with higher protein synthesis rate (as indicated by higher FSR, p = 0.019) and higher protein breakdown rates (as indicated by greater Ra, p = 0.001). FSR was negatively associated with age (p < 0.001). CONCLUSIONS:Data from this large patient cohort show that injury severity, sex, and time post injury influence skeletal muscle wasting in burned children. These findings suggest that individual patient characteristics should be considered when devising therapies to improve the acute care and rehabilitation of burn survivors.

SUBMITTER: Malagaris I

PROVIDER: S-EPMC6279601 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Determinants of skeletal muscle protein turnover following severe burn trauma in children.

Malagaris Ioannis I Herndon David N DN Polychronopoulou Efstathia E Rontoyanni Victoria G VG Andersen Clark R CR Suman Oscar E OE Porter Craig C Sidossis Labros S LS

Clinical nutrition (Edinburgh, Scotland) 20180604 3

<h4>Background & aims</h4>Burns remain the fifth cause of non-fatal pediatric injuries globally, with muscle cachexia being a hallmark of the stress response to burns. Burn-induced muscle wasting is associated with morbidity, yet the determinants of muscle protein catabolism in response to burn trauma remains unclear. Our objective was to determine the effect of patient and injury characteristics on muscle protein kinetics in burn patients.<h4>Methods</h4>This retrospective, observational study ...[more]

PMID: 29907353

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Project description:BackgroundHypoxemia in humans may occur during high altitude mountaineering and in patients suffering from ventilatory insufficiencies such as cardiovascular- or respiratory disease including Chronic Obstructive Pulmonary Disease (COPD). In these conditions, hypoxemia has been correlated to reduced appetite and decreased food intake. Since hypoxemia and reduced food intake intersect in various physiological and pathological conditions and both induce loss of muscle mass, we investigated whether hypoxia aggravates fasting-induced skeletal muscle atrophy and evaluated underlying protein turnover signaling.MethodsMice were kept under hypoxic (8% oxygen) or normoxic conditions (21% oxygen), or were pair-fed to the hypoxia group for 12 days. Following an additional 24 hours of fasting, muscle weight and protein turnover signaling were assessed in the gastrocnemius muscle by RT-qPCR and Western blotting.ResultsLoss of gastrocnemius muscle mass in response to fasting in the hypoxic group was increased compared to the normoxic group, but not to the pair-fed normoxic control group. Conversely, the fasting-induced increase in poly-ubiquitin conjugation, and expression of the ubiquitin 26S-proteasome E3 ligases, autophagy-lysosomal degradation-related mRNA transcripts and proteins, and markers of the integrated stress response (ISR), were attenuated in the hypoxia group compared to the pair-fed group. Mammalian target of rapamycin complex 1 (mTORC1) downstream signaling was reduced by fasting under normoxic conditions, but sustained under hypoxic conditions. Activation of AMP-activated protein kinase (AMPK) / tuberous sclerosis complex 2 (TSC2) signaling by fasting was absent, in line with retained mTORC1 activity under hypoxic conditions. Similarly, hypoxia suppressed AMPK-mediated glucocorticoid receptor (GR) signaling following fasting, which corresponded with blunted proteolytic signaling responses.ConclusionsHypoxia aggravates fasting-induced muscle wasting, and suppresses AMPK and ISR activation. Altered AMPK-mediated regulation of mTORC1 and GR may underlie aberrant protein turnover signaling and affect muscle atrophy responses in hypoxic skeletal muscle.

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Determinants of skeletal muscle protein turnover following severe burn trauma in children.

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Determinants of skeletal muscle protein turnover following severe burn trauma in children.

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