Craig Porter

Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT+) men and five BAT-negative (BAT−) men under thermoneutral conditions and after prolonged (5–8 h) cold exposure (CE). The two groups were similar in age, BMI, and adiposity. CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT+ group only. These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an antidiabetic tissue in humans.

Browning of Subcutaneous White Adipose Tissue in Humans after Severe Adrenergic Stress

Since the presence of brown adipose tissue (BAT) was confirmed in adult humans, BAT has become a therapeutic target for obesity and insulin resistance. We examined whether human subcutaneous white adipose tissue (sWAT) can adopt a BAT-like phenotype using a clinical model of prolonged and severe adrenergic stress. sWAT samples were collected from severely burned and healthy individuals. A subset of burn victims were prospectively followed during their acute hospitalization. Browning of sWAT was determined by the presence of multilocular adipocytes, uncoupling protein 1 (UCP1), and increased mitochondrial density and respiratory capacity. Multilocular UCP1-positive adipocytes were found in sWAT samples from burn patients. UCP1 mRNA, mitochondrial density, and leak respiratory capacity in sWAT increased after burn trauma. Our data demonstrate that human sWAT can transform from an energy-storing to an energy-dissipating tissue, which opens new research avenues in our quest to prevent and treat obesity and its metabolic complications.

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.

Resistance Exercise Training Alters Mitochondrial Function in Human Skeletal Muscle.

INTRODUCTION Loss of mitochondrial competency is associated with several chronic illnesses. Therefore, strategies that maintain or increase mitochondrial function will likely be of benefit in numerous clinical settings. Endurance exercise has long been known to increase mitochondrial function in the skeletal muscle. Comparatively little is known regarding the effect of resistance exercise training (RET) on skeletal muscle mitochondrial respiratory function. PURPOSE The purpose of the current study was to determine the effect of chronic resistance training on skeletal muscle mitochondrial respiratory capacity and function. METHODS Here, we studied the effect of a 12-wk RET program on skeletal muscle mitochondrial function in 11 young healthy men. Muscle biopsies were collected before and after the 12-wk training program, and mitochondrial respiratory capacity was determined in permeabilized myofibers by high-resolution respirometry. RESULTS RET increased lean body mass and quadriceps muscle strength by 4% and 15%, respectively (P < 0.001). Coupled mitochondrial respiration supported by complex I, and complex I and II substrates increased by 2- and 1.4-fold, respectively (P < 0.01). The ratio of coupled complex I-supported respiration to maximal respiration increased with RET (P < 0.05), as did complex I protein abundance (P < 0.05), whereas the substrate control ratio for succinate was reduced after RET (P < 0.001). Transcripts responsible for proteins critical to electron transfer and NAD production increased with training (P < 0.05), whereas transcripts involved in mitochondrial biogenesis were unaltered. CONCLUSIONS Collectively, 12 wk of RET resulted in qualitative and quantitative changes in skeletal muscle mitochondrial respiration. This adaptation was accompanied by modest changes in mitochondrial proteins and transcript expression. RET seems to be a means to augment the respiratory capacity and intrinsic function of skeletal muscle mitochondria.

The impact of severe burns on skeletal muscle mitochondrial function

Severe burns induce a pathophysiological response that affects almost every physiological system within the body. Inflammation, hypermetabolism, muscle wasting, and insulin resistance are all hallmarks of the pathophysiological response to severe burns, with perturbations in metabolism known to persist for several years post injury. Skeletal muscle is the principal depot of lean tissue within the body and as the primary site of peripheral glucose disposal, plays an important role in metabolic regulation. Following a large burn, skeletal muscle functions as and endogenous amino acid store, providing substrates for more pressing functions, such as the synthesis of acute phase proteins and the deposition of new skin. Subsequently, burn patients become cachectic, which is associated with poor outcomes in terms of metabolic health and functional capacity. While a loss of skeletal muscle contractile proteins per se will no doubt negatively impact functional capacity, detriments in skeletal muscle quality, i.e. a loss in mitochondrial number and/or function may be quantitatively just as important. The goal of this review article is to summarise the current understanding of the impact of thermal trauma on skeletal muscle mitochondrial content and function, to offer direction for future research concerning skeletal muscle mitochondrial function in patients with severe burns, and to renew interest in the role of these organelles in metabolic dysfunction following severe burns.

Early rehabilitative exercise training in the recovery from pediatric burn.

PURPOSE The purpose of this study was to determine the effects of early outpatient exercise on muscle mass, function, and fractional synthetic rate in severely burned children. METHODS Forty-seven children with ≥40% total body surface area burn performed a 12-wk standard of care rehabilitation (SOC, n = 23) or rehabilitative exercise training (RET, n = 24) immediately after hospital discharge. Dual-energy x-ray absorptiometry was used to assess lean body mass (LBM) at discharge, posttreatment, and 12 months post-burn. Muscle function was evaluated with a Biodex Isokinetic Dynamometer, and peak aerobic fitness (V˙O2peak) was measured using a modified Bruce treadmill protocol posttreatment. Stable isotope infusion studies were performed in a subset of patients (SOC, n = 13; RET, n = 11) at discharge and posttreatment to determine mixed-muscle fractional synthetic rate. RESULTS Relative peak torque (RET, 138 ± 9 N·m·kg, vs SOC, 106 ± 9 N·m·kg) and V˙O2peak (RET, 32 ± 1 mL·kg·min, vs SOC, 28 ± 1 mL·kg·min) were greater at posttreatment with RET compared with those with SOC. In addition, RET increased whole-body (9% ± 2%) and leg (17% ± 3%) LBM compared with SOC. Furthermore, the percentage change in whole-body (18% ± 3%) and leg (31% ± 4%) LBM from discharge to 12 months post-burn was greater with RET compared to SOC. Muscle fractional synthetic rate decreased from discharge to posttreatment in both groups (6.9% ± 1.1% per day vs 3.4 ± 0.4% per day); however, no differences were observed between treatment groups at each time point. CONCLUSIONS Early outpatient exercise training implemented at hospital discharge represents an effective intervention to improve muscle mass and function after severe burn injury.

Mitochondrial respiratory capacity and coupling control decline with age in human skeletal muscle.

Mitochondrial health is critical to physiological function, particularly in tissues with high ATP turnover, such as striated muscle. It has been postulated that derangements in skeletal muscle mitochondrial function contribute to impaired physical function in older adults. Here, we determined mitochondrial respiratory capacity and coupling control in skeletal muscle biopsies obtained from young and older adults. Twenty-four young (28 ± 7 yr) and thirty-one older (62 ± 8 yr) adults were studied. Mitochondrial respiration was determined in permeabilized myofibers from the vastus lateralis after the addition of substrates oligomycin and CCCP. Thereafter, mitochondrial coupling control was calculated. Maximal coupled respiration (respiration linked to ATP production) was lower in muscle from older vs. young subjects (P < 0.01), as was maximal uncoupled respiration (P = 0.06). Coupling control in response to the ATP synthase inhibitor oligomycin was lower in older adults (P < 0.05), as was the mitochondria flux control ratio, coupled respiration normalized to maximal uncoupled respiration (P < 0.05). Calculation of respiratory function revealed lower respiration linked to ATP production (P < 0.001) and greater reserve respiration (P < 0.01); i.e., respiratory capacity not used for phosphorylation in muscle from older adults. We conclude that skeletal muscle mitochondrial respiratory capacity and coupling control decline with age. Lower respiratory capacity and coupling efficiency result in a reduced capacity for ATP production in skeletal muscle of older adults.

Time-Dependent and Organ-Specific Changes in Mitochondrial Function, Mitochondrial DNA Integrity, Oxidative Stress and Mononuclear Cell Infiltration in a Mouse Model of Burn Injury.

Severe thermal injury induces a pathophysiological response that affects most of the organs within the body; liver, heart, lung, skeletal muscle among others, with inflammation and hyper-metabolism as a hallmark of the post-burn damage. Oxidative stress has been implicated as a key component in development of inflammatory and metabolic responses induced by burn. The goal of the current study was to evaluate several critical mitochondrial functions in a mouse model of severe burn injury. Mitochondrial bioenergetics, measured by Extracellular Flux Analyzer, showed a time dependent, post-burn decrease in basal respiration and ATP-turnover but enhanced maximal respiratory capacity in mitochondria isolated from the liver and lung of animals subjected to burn injury. Moreover, we detected a tissue-specific degree of DNA damage, particularly of the mitochondrial DNA, with the most profound effect detected in lungs and hearts of mice subjected to burn injury. Increased mitochondrial biogenesis in lung tissue in response to burn injury was also observed. Burn injury also induced time dependent increases in oxidative stress (measured by amount of malondialdehyde) and neutrophil infiltration (measured by myeloperoxidase activity), particularly in lung and heart. Tissue mononuclear cell infiltration was also confirmed by immunohistochemistry. The amount of poly(ADP-ribose) polymers decreased in the liver, but increased in the heart in later time points after burn. All of these biochemical changes were also associated with histological alterations in all three organs studied. Finally, we detected a significant increase in mitochondrial DNA fragments circulating in the blood immediately post-burn. There was no evidence of systemic bacteremia, or the presence of bacterial DNA fragments at any time after burn injury. The majority of the measured parameters demonstrated a sustained elevation even at 20–40 days post injury suggesting a long-lasting effect of thermal injury on organ function. The current data show that there are marked time-dependent and tissue-specific alterations in mitochondrial function induced by thermal injury, and suggest that mitochondria-specific damage is one of the earliest responses to burn injury. Mitochondria may be potential therapeutic targets in the future experimental therapy of burns.

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

OBJECTIVE The 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. DATA SELECTION Review 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. CONCLUSION Data 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.

The role of exercise in the rehabilitation of patients with severe burns

Severe burn trauma results in persistent skeletal muscle catabolism and prolonged immobilization. We hypothesize that structured rehabilitative exercise is a safe and efficacious strategy to restore lean body mass and physical function in burn victims. Here, we review the evidence for the utility of rehabilitative exercise training in restoring physiological function in burn survivors.