Labros S. Sidossis

The metabolic stress response to burn trauma: current understanding and therapies

Summary Severe burns incur a profound stress response, which is unrivaled in terms of its magnitude and duration. Recent evidence suggests that the pathophysiological stress response to severe burns persists for several years post injury. Thus, there is a pressing need for novel strategies that mitigate this response and restore normal metabolic function in burn survivors. This is the first installment of a three-part series exploring the stress response to severe burn trauma. In this article we aim to distill the current knowledge pertaining to the stress response to burn trauma, highlighting recent developments and important knowledge gaps that need to be pursued in order to develop novel therapeutic strategies which improve outcomes in burn survivors.

Effects of pharmacological interventions on muscle protein synthesis and breakdown in recovery from burns

OBJECTIVEnThe pathophysiological response to burn injury disturbs the balance between skeletal muscle protein synthesis and breakdown, resulting in severe muscle wasting. Muscle loss after burn injury is related to increased mortality and morbidity. Consequently, mitigation of this catabolic response has become a focus in the management of these patients. The aim of this review is to discuss the literature pertaining to pharmacological interventions aimed at attenuating skeletal muscle catabolism in severely burned patients.nnnDATA SELECTIONnReview of the literature related to skeletal muscle protein metabolism following burn injury was conducted. Emphasis was on studies utilizing stable isotope tracer kinetics to assess the impact of pharmacological interventions on muscle protein metabolism in severely burned patients.nnnCONCLUSIONnData support the efficacy of testosterone, oxandrolone, human recombinant growth hormone, insulin, metformin, and propranolol in improving skeletal muscle protein net balance in patients with severe burns. The mechanisms underlying the improvement of protein net balance differ between types and dosages of drugs, but their main effect is on protein synthesis. Finally, the majority of studies have been conducted during the acute hypermetabolic phase of the injury. Except for oxandrolone, the effects of drugs on muscle protein kinetics following discharge from the hospital are largely unknown.

Severe burn injury induces thermogenically functional mitochondria in murine white adipose tissue

ABSTRACT Chronic cold exposure induces functionally thermogenic mitochondria in the inguinal white adipose tissue (iWAT) of mice. Whether this response occurs in pathophysiological states remains unclear. The purpose of this study was to determine the impact of severe burn trauma on iWAT mitochondrial function in mice. Male BALB/c mice (10–12 weeks) received full-thickness scald burns to ∼30% of the body surface area. Inguinal white adipose tissue was harvested from mice at 1, 4, 10, 20, and 40 days postinjury. Total and uncoupling protein 1 (UCP1)–dependent mitochondrial thermogenesis were determined in iWAT. Citrate synthase activity was determined as a proxy of mitochondrial abundance. Immunohistochemistry was performed to assess iWAT morphology and UCP1 expression. Uncoupling protein 1–dependent respiration was significantly greater at 4 and 10 days after burn compared with sham, peaking at 20 days after burn (P < 0.001). Citrate synthase activity was threefold greater at 4, 10, 20, and 40 days after burn versus sham (P < 0.05). Per mitochondrion, UCP1 function increased after burn trauma (P < 0.05). After burn trauma, iWAT exhibited numerous multilocular lipid droplets that stained positive for UCP1. The current findings demonstrate the induction of thermogenically competent mitochondria within rodent iWAT in a model of severe burn trauma. These data identify a specific pathology that induces the browning of white adipose tissue in vivo and may offer a mechanistic explanation for the chronic hypermetabolism observed in burn victims.

The effect of hypohydration on endothelial function in young healthy adults.

PurposeHypohydration has been suggested as a predisposing factor for several pathologies including cardiovascular diseases (CVD). While CVD are the leading cause of death worldwide, no study has investigated whether acute hypohydration affects endothelial function and cardiovascular function.MethodsTen young, healthy males participated in this crossover study (age: 24.3xa0±xa02.3xa0year; weight: 80.8xa0±xa05.3xa0kg; BMI: 24.3xa0±xa00.4xa0kgxa0m−2). Each subject completed two measurements of endothelial function by flow-mediated dilation (FMD) in euhydrated and hypohydrated state separated by 24xa0h. Following baseline assessment of hydration status and FMD, the subjects completed 100xa0min of low-intensity intermittent walking exercise to achieve hypohydration of −2xa0% of individual body mass. For the rest of the day, a standardized, low water content diet was provided. The following morning, hydration markers and endothelial function were recorded.ResultsHypohydration by −1.9xa0±xa00.1xa0% of body mass resulted in decreased plasma volume by −3.5xa0±xa01.8xa0% and increased plasma osmolality by 9xa0±xa02xa0mmolxa0kg−1 (Pxa0<xa00.001). FMD as a response to hypohydration decreased by −26.8xa0±xa03.9xa0% (Pxa0<xa00.05).ConclusionThe data suggested that a small degree of hypohydration induced by moderate exercise and fluid restriction significantly impaired endothelial function.

Hypermetabolism and Hypercatabolism of Skeletal Muscle Accompany Mitochondrial Stress Following Severe Burn Trauma

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.

A percutaneous needle biopsy technique for sampling the supraclavicular brown adipose tissue depot of humans

Brown adipose tissue (BAT) has been proposed as a potential target tissue against obesity and its related metabolic complications. Although the molecular and functional characteristics of BAT have been intensively studied in rodents, only a few studies have used human BAT specimens due to the difficulty of sampling human BAT deposits. We established a novel positron emission tomography and computed tomography-guided Bergström needle biopsy technique to acquire human BAT specimens from the supraclavicular area in human subjects. Forty-three biopsies were performed on 23 participants. The procedure was tolerated well by the majority of participants. No major complications were noted. Numbness (9.6%) and hematoma (2.3%) were the two minor complications noted, which fully resolved. Thus, the proposed biopsy technique can be considered safe with only minimal risk of adverse events. Adoption of the proposed method is expected to increase the sampling of the supraclavicular BAT depot for research purposes so as to augment the scientific knowledge of the biology of human BAT.

Mediterranean lifestyle and cardiovascular disease prevention

BACKGROUNDnAdherence to a Mediterranean dietary pattern is a well-established protective factor against cardiovascular disease (CVD). However, diet quality is only one aspect of the overall healthy lifestyle adopted by Mediterranean populations. The latter has never been evaluated as a multi-factorial composite lifestyle. Thus, the aim of the present study was to provide a broader picture of the Mediterranean lifestyle and its effects on CVD risk, among elderly individuals.nnnMETHODSnDuring 2005-2015, 2,749 older (aged 65-100 years) from 21 Mediterranean islands (MEDIS) and the rural Mani region (Peloponnesus) of Greece were voluntarily enrolled onto the study. Dietary habits, physical activity status, socio-demographic characteristics, lifestyle parameters (sleep, smoking habits, social life and educational status) and clinical profile aspects were derived through standard procedures.nnnRESULTSnThe overall prevalence of the traditional CVD risk factors were 62.3% for hypertension, 22.3% for diabetes mellitus (type 2) and 47.7% for hypercholesterolemia. The presence of diabetes mellitus was positively predicted by the geriatric depression scale (GDS) [odds ratio (OR) =1.13, 95% confidence interval (CI): 1.02-1.25] and by an urban residential environment (OR =2.57, 95% CI: 1.10-6.06) after adjusting for several confounders. Presence of hypertension was predicted by increasing age (OR =1.07, 95% CI: 1.02-1.12), increasing body mass index (BMI) (OR =1.12, 95% CI: 1.04-1.21), the habit of midday sleep (OR =2.07, 95% CI: 1.07-4.02) and inversely predicted by the frequency of socializing with friends (OR =0.767, 95% CI: 0.616-0.955). The estimated score in the GDS was the only independent positive predictor for the presence of hypercholesterolemia (OR =1.10, 95% CI: 1.01-1.21).nnnCONCLUSIONSnLifestyle parameters such as social life, midday sleep (siesta) and residential environment are strongly associated with the presence of CVD risk factors in elderly and should be part of broader CVD prevention strategies to reduce the burden of the disease.

Propranolol and Oxandrolone Therapy Accelerated Muscle Recovery in Burned Children

IntroductionSevere burns result in prolonged hypermetabolism and skeletal muscle catabolism. Rehabilitative exercise training (RET) programs improved muscle mass and strength in severely burned children. The combination of RET with &bgr;-blockade or testosterone analogs showed improved exercise-induced benefits on body composition and muscle function. However, the effect of RET combined with multiple drug therapy on muscle mass, strength, cardiorespiratory fitness, and protein turnover are unknown. In this placebo-controlled randomized trial, we hypothesize that RET combined with oxandrolone and propranolol (Oxprop) will improve muscle mass and function and protein turnover in severely burned children compared with burned children undergoing the same RET with a placebo. MethodsWe studied 42 severely burned children (7–17 yr) with severe burns over 30% of the total body surface area. Patients were randomized to placebo (22 control) or to Oxprop (20) and began drug administration within 96 h of admission. All patients began RET at hospital discharge as part of their standardized care. Muscle strength (N·m), power (W), V˙O2peak, body composition, and protein fractional synthetic rate and fractional breakdown rate were measured pre-RET (PRE) and post-RET (POST). ResultsMuscle strength and power, lean body mass, and V˙O2peak increased with RET in both groups (P < 0.01). The increase in strength and power was significantly greater in Oxprop versus control (P < 0.01), and strength and power was greater in Oxprop over control POST (P < 0.05). Fractional synthetic rate was significantly higher in Oxprop than control POST (P < 0.01), resulting in improved protein net balance POST (P < 0.05). ConclusionsRehabilitative exercise training improves body composition, muscle function, and cardiorespiratory fitness in children recovering from severe burns. Oxprop therapy augments RET-mediated improvements in muscle strength, power, and protein turnover.

Impact of obesity on body image dissatisfaction and social integration difficulty in adolescent and young adult burn injury survivors

Burn injury deformities and obesity have been associated with social integration difficulty and body image dissatisfaction. However, the combined effects of obesity and burn injury on social integration difficulty and body image dissatisfaction are unknown. Adolescent and young adult burn injury survivors were categorized as normal weight (n = 47) or overweight and obese (n = 21). Burn-related and anthropometric information were obtained from patients’ medical records, and validated questionnaires were used to assess the main outcomes and possible confounders. Analysis of covariance and multiple linear regressions were performed to evaluate the objectives of this study. Obese and overweight burn injury survivors did not experience increased body image dissatisfaction (12 ± 4.3 vs 13.1 ± 4.4; P = .57) or social integration difficulty (17.5 ± 6.9 vs 15.5 ± 5.7; P = .16) compared with normal weight burn injury survivors. Weight status was not a significant predictor of social integration difficulty or body image dissatisfaction (P = .19 and P = .24, respectively). However, mobility limitations predicted greater social integration difficulty (P = .005) and body image dissatisfaction (P < .001), whereas higher weight status at burn was a borderline significant predictor of body image dissatisfaction (P = .05). Obese and overweight adolescents and young adults, who sustained major burn injury as children, do not experience greater social integration difficulty and body image dissatisfaction compared with normal weight burn injury survivors. Mobility limitations and higher weight status at burn are likely more important factors affecting the long-term social integration difficulty and body image dissatisfaction of these young people.

Association of Anthropometric and Lifestyle Parameters with Fitness Levels in Greek Schoolchildren: Results from the EYZHN Program

Objective The aim of the study was to evaluate physical fitness (PF) and identify its anthropometric and lifestyle determinants in a sample of Greek schoolchildren. Methods The study sample consisted of 335,810 schoolchildren (♂: 51.3%, 6–18u2009years old). Students’ anthropometric parameters and PF levels—assessed via the Eurofit test battery—were measured by trained physical education teachers and evaluated according to the available norms, while their lifestyle habits were assessed through a questionnaire. Results In all applied PF tests, students’ performance was negatively associated with the presence of obesity and central obesity, defined through international criteria for body mass index and waist to height ratio, respectively. According to multiple logistic regression analysis, the presence of overweight/obesity [odds ratio (OR): 4.43, 95% confidence interval (CI): 3.98–4.93], low adherence to the MD (KIDMEDu2009≤u20093) (OR: 1.27, 95% CI: 1.09–1.48), and increased time spent in sedentary activities (>2u2009h per day) (OR: 1.16, 95% CI: 1.03–1.29) were positively associated with poor PF, after adjusting for age and sex. In contrast, for every 1u2009day increase in the weekly frequency of engagement in athletic activity, the probability of poor PF decreased by 26% (OR: 0.74, 95% CI: 0.72–0.77). In a similar model, the presence of central obesity emerged as an even stronger possible predictor of poor PF (OR: 5.20, 95% CI: 4.66–5.78), compared to the presence of general obesity. Conclusion Higher general or abdominal adiposity, as well as the adoption of a low-quality diet and a sedentary lifestyle, is strongly associated with low PF levels during childhood.