Nichola M. Thompson

A systematic review of experimental treatments for mitochondrial dysfunction in sepsis and multiple organ dysfunction syndrome

Sepsis and multiple organ dysfunction syndrome (MODS) are major causes of morbidity and mortality in the intensive care unit. Recently mitochondrial dysfunction has been proposed as a key early cellular event in critical illness. A growing body of experimental evidence suggests that mitochondrial therapies are effective in sepsis and MODS. The aim of this article is to undertake a systematic review of the current experimental evidence for the use of therapies for mitochondrial dysfunction during sepsis and MODS and to classify these mitochondrial therapies. A search of the MEDLINE and PubMed databases (1950 to July 2009) and a manual review of reference lists were conducted to find experimental studies containing data on the efficacy of mitochondrial therapies in sepsis and sepsis-related MODS. Fifty-one studies were included in this review. Five categories of mitochondrial therapies were defined-substrate provision, cofactor provision, mitochondrial antioxidants, mitochondrial reactive oxygen species scavengers, and membrane stabilizers. Administration of mitochondrial therapies during sepsis was associated with improvements in mitochondrial electron transport system function, oxidative phosphorylation, and ATP production and a reduction in cellular markers of oxidative stress. Amelioration of proinflammatory cytokines, caspase activation, and prevention of the membrane permeability transition were reported. Restoration of mitochondrial bioenergetics was associated with improvements in hemodynamic parameters, organ function, and overall survival. A substantial body of evidence from experimental studies at both the cellular and the organ level suggests a beneficial role for the administration of mitochondrial therapies in sepsis and MODS. We expect that mitochondrial therapies will have an increasingly important role in the management of sepsis and MODS. Clinical trials are now required.

Moderate Daily Exercise Activates Metabolic Flexibility to Prevent Prenatally Induced Obesity

Obesity and its associated comorbidities are of major worldwide concern. It is now recognized that there are a number of metabolically distinct pathways of obesity development. The present paper investigates the effect of moderate daily exercise on the underlying mechanisms of one such pathway to obesity, through interrogation of metabolic flexibility. Pregnant Wistar rats were either fed chow ad libitum or undernourished throughout pregnancy, generating control or intrauterine growth restricted (IUGR) offspring, respectively. At 250 d of age, dual-emission x-ray absorptiometry scans and plasma analyses showed that moderate daily exercise, in the form of a measured amount of wheel running (56 m/d), prevented the development of obesity consistently observed in nonexercised IUGR offspring. Increased plasma C-peptide and hepatic atypical protein kinase Czeta levels explained increased glucose uptake and increased hepatic glycogen storage in IUGR offspring. Importantly, whereas circulating levels of retinol binding protein 4 were elevated in obese, nonexercised IUGR offspring, indicative of glucose sparing without exercise, retinol binding protein 4 levels were normalized in the exercised IUGR group. These data suggest that IUGR offspring have increased flexibility of energy storage and use and that moderate daily exercise prevents obesity development through activation of distinct pathways of energy use. Thus, despite a predisposition to develop obesity under sedentary conditions, obesity development was prevented in IUGR offspring when exercise was available. These results emphasize the importance of tailored lifestyle changes that activate distinct pathways of metabolic flexibility for obesity prevention.

Prenatally undernourished rats show increased preference for wheel running v. lever pressing for food in a choice task.

Maternal nutrition during pregnancy has a significant influence in establishing patterns of metabolism and postnatal behaviours in offspring, and therefore shapes their risk of developing disorders in later life. Although it is well established that a mismatch between food consumption and energy expenditure leads to obesity and metabolic dysregulation, little research has investigated the biological origin of such behaviour. We conducted the present experiments to investigate effects of early-life nutrition on preference between wheel running and lever pressing for food during adult life. To address this issue we employed a well-established experimental approach in the rat which has shown that offspring of mothers undernourished during pregnancy develop obesity and metabolic disorders when kept under standard laboratory conditions. Using this experimental approach, two studies were conducted where offspring of ad libitum-fed dams and dams undernourished throughout pregnancy were given the choice between wheel running and pressing a response lever for food. Across subsequent conditions, the rate at which the response lever provided food was varied from 0.22 to 6.0 (study 1) and 0.19 to 3.0 (study 2) pellets per min. Compared with the control group, offspring from dams undernourished during pregnancy showed a consistently greater preference for running over lever pressing for food throughout both experiments of the study. The results of the present study provide experimental evidence that a mothers nutrition during pregnancy can result in a long-term shift in her offsprings lifestyle choices that are relevant to obesity prevention. Such a shift, if endorsed, will have substantial and wide-ranging health consequences throughout the lifespan.

Global undernutrition during gestation influences learning during adult life

Intrauterine growth restriction can lead to significant long-term health consequences such as metabolic and cardiovascular disorders, but less is known about its effects on choice and behavioral adaptation in later life. Virgin Wistar rats were time mated and randomly assigned to receive either ad-libitum access to chow or 30% of that level of nutrition during pregnancy to generate growth-restricted offspring. At 60 days of age, 6 female offspring from each group were trained on concurrent variable-interval schedules. Sessions consisted of seven randomly arranged concurrent-schedule components, each with a different reinforcer ratio that varied from 27∶1 to 1∶27, and each component lasting for 10 reinforcer deliveries. Behavioral change across reinforcers in components, measured by sensitivity to reinforcement, was consistently lower for offspring of undernourished mothers, showing that their behavior was less adaptable to environmental change. These results provide direct experimental evidence for a link between prenatal environmental conditions and reduced behavioral adaptability—learning—in later life.

Prenatally Induced Changes in Muscle Structure and Metabolic Function Facilitate Exercise-Induced Obesity Prevention

Effective regulation of energy metabolism is vital for the maintenance of optimal health, and an inability to make these dynamic adjustments is a recognized cause of obesity and metabolic disorders. Epidemiological and experimental studies have highlighted the role of prenatal factors in the disease process, and it is now generally accepted that maternal nutrition during pregnancy significantly influences intrauterine development, shaping postnatal health. Consequences of impaired nutrition during fetal development include intrauterine growth restriction (IUGR) and subsequent obesity development in adult life. We have previously shown that prenatal undernutrition has a lasting effect on behavior, with IUGR offspring expressing a higher preference for voluntary exercise, and moderate daily exercise preventing obesity development. The present study investigated skeletal muscle structure in IUGR offspring and how moderate daily exercise drives changes in metabolic pathways that promote obesity prevention. Pregnant Wistar rats were either fed chow ad libitum or undernourished, generating control or IUGR offspring respectively. Although red muscle structure indicated higher oxidative capacity in IUGR offspring, obesity prevention was not due to increased fatty acid oxidation, indicated by decreased peroxisomal proliferator-activated receptor-gamma coactivator 1 and carnitine-palmitoyltransferase 1 expression. In contrast, increased protein kinase Czeta expression and glycogen content in white muscle of exercised IUGR offspring suggests an enhanced capacity for anaerobic utilization of glucose. Furthermore, exercise-induced lactate accumulation was effectively prevented by stimulation of a lactate shuttle, driven by the increases in monocarboxylate transporters-4 and -1 in white muscle. This enhanced metabolic flexibility in IUGR offspring may facilitate muscle contractile performance and therefore support moderate daily exercise for effective obesity prevention.

Metabolic responses to high-fat diets rich in n-3 or n-6 long-chain polyunsaturated fatty acids in mice selected for either high body weight or leanness explain different health outcomes

BackgroundIncreasing evidence suggests that diets high in polyunsaturated fatty acids (PUFA) confer health benefits by improving insulin sensitivity and lipid metabolism in liver, muscle and adipose tissue.MethodsThe present study investigates metabolic responses in two different lines of mice either selected for high body weight (DU6) leading to rapid obesity development, or selected for high treadmill performance (DUhTP) leading to a lean phenotype. At 29 days of age the mice were fed standard chow (7.2% fat, 25.7% protein), or a high-fat diet rich in n-3 PUFA (n-3 HFD, 27.7% fat, 19% protein) or a high-fat diet rich in n-6 PUFA (n-6 HFD, 27.7% fat, 18.6% protein) for 8 weeks. The aim of the study was to determine the effect of these PUFA-rich high-fat diets on the fatty acid profile and on the protein expression of key components of insulin signalling pathways.ResultsPlasma concentrations of leptin and insulin were higher in DU6 in comparison with DUhTP mice. The high-fat diets stimulated a strong increase in leptin levels and body fat only in DU6 mice. Muscle and liver fatty acid composition were clearly changed by dietary lipid composition. In both lines of mice n-3 HFD feeding significantly reduced the hepatic insulin receptor β protein concentration which may explain decreased insulin action in liver. In contrast, protein kinase C ζ expression increased strongly in abdominal fat of n-3 HFD fed DUhTP mice, indicating enhanced insulin sensitivity in adipose tissue.ConclusionsA diet high in n-3 PUFA may facilitate a shift from fuel deposition in liver to fuel storage as fat in adipose tissue in mice. Tissue specific changes in insulin sensitivity may describe, at least in part, the health improving properties of dietary n-3 PUFA. However, important genotype-diet interactions may explain why such diets have little effect in some population groups.

Early organ-specific mitochondrial dysfunction of jejunum and lung found in rats with experimental acute pancreatitis

INTRODUCTION Multiple organ dysfunction is the main cause of death in severe acute pancreatitis. Primary mitochondrial dysfunction plays a central role in the development and progression of organ failure in critical illness. The present study investigated mitochondrial function in seven tissues during early experimental acute pancreatitis. METHODS Twenty-eight male Wistar rats (463 ± 2 g; mean ± SEM) were studied. Group 1 (n= 8), saline control; Group 2 (n= 6), caerulein-induced mild acute pancreatitis; Group 3 (n= 7) sham surgical controls; and Group 4 (n= 7), taurocholate-induced severe acute pancreatitis. Animals were euthanased at 6 h from the induction of acute pancreatitis and mitochondrial function was assessed in the heart, lung, liver, kidney, pancreas, duodenum and jejunum by mitochondrial respirometry. RESULTS Significant early mitochondrial dysfunction was present in the pancreas, lung and jejunum in both models of acute pancreatitis, however, the Heart, liver, kidney and duodenal mitochondria were unaffected. CONCLUSIONS The present study provides the first description of early organ-selective mitochondrial dysfunction in the lung and jejunum during acute pancreatitis. Research is now needed to identify the underlying pathophysiology behind the organ selective mitochondrial dysfunction, and the potential benefits of early mitochondrial-specific therapies in acute pancreatitis.

The redox status of experimental hemorrhagic shock as measured by cyclic voltammetry.

Hemorrhagic shock (HS) leads to reactive oxygen species production. However, clinicians do not have access to bedside measurements of the redox status during HS. Cyclic voltammetry (CyV) is a simple electrochemical method of measuring redox status. The aims of this study were to 1) report the first application of cyclic voltammetry to measure the acute changes in serum redox status after HS, 2) to contrast it with another severe systemic disease with a different redox pathology (acute pancreatitis [AP]), and 3) to describe the response of CyV over time in a resolving model of AP. In the acute study, 24 male Wistar rats were randomized into three groups: groups 1 (control), 2 (AP), and 3 (HS). In the time-course study, 28 rats were randomized to a sham-control as well as 6 and 24 h post-AP cohorts, respectively. Cyclic voltammetry was performed using a three-electrode system. In the acute study, the first and second voltammetric peaks increased significantly in HS. In contrast, within the AP group, only the first voltammetric peak showed a significant increase. The first voltammetric peak correlated with plasma protein carbonyls (PCs) and with thiobarbituric acid-reactive substances, whereas the second voltammetric peak correlated positively with plasma protein carbonyls. In the second study, the first voltammetric peak correlated with physiological improvements. Here, we showed that serum CyV could respond to the serum redox change in HS and AP. Cyclic voltammetry warrants evaluation as a potential real-time beside measure of a patients redox status during shock.ABBREVIATIONS - CyV - cyclic voltammetry; CVi1 - maxima of the first CyV peak; CVi2 - maxima of the second CyV peak; UA - uric acid; PBS - phosphate-buffered saline; NBF - neutral buffered formalin; NADPH - nicotinamide adenine dinucleotide phosphate

Postnatal development of metabolic flexibility and enhanced oxidative capacity after prenatal undernutrition

Metabolic flexibility is the body’s ability to adapt to changing energy demand and nutrient supply. Maternal undernutrition causes growth restriction at birth and subsequent obesity development. Intriguingly, metabolic flexibility is maintained due to adaptations of muscle tissue. The aim of the present study was to investigate developmental pathways of these adaptive changes. Wistar rats received standard chow at either ad libitum (AD) or 30% of ad libitum intake (UN) throughout pregnancy. At all ages, metabolic status indicated similar insulin sensitivity in AD and UN offspring despite the development of adiposity in UN offspring at weaning. Type IIA fiber size was reduced in soleus muscle of UN offspring at weaning and they had a higher percentage of type I fibers in adulthood with a concomitantly higher oxidative capacity. Plasticity of muscle was present during the postnatal period and proposes novel pathways for the dynamic development of metabolic flexibility throughout postnatal life.

Metabolic programming of adipose tissue structure and function in male rat offspring by prenatal undernutrition

BackgroundA number of different pathways to obesity with different metabolic outcomes are recognised. Prenatal undernutrition in rats leads to increased fat deposition in adulthood. However, the form of obesity is metabolically distinct from obesity induced through other pathways (e.g. diet-induced obesity). Previous rat studies have shown that maternal undernutrition during pregnancy led to insulin hyper-secretion and obesity in offspring, but not to systemic insulin resistance. Increased muscle and liver glycogen stores indicated that glucose is taken up efficiently, reflecting an active physiological function of these energy storage tissues. It is increasingly recognised that adipose tissue plays a central role in the regulation of metabolism and pathophysiology of obesity development. The present study investigated the cell size and endocrine responsiveness of subcutaneous and visceral adipose tissue from prenatally undernourished rats. We aimed to identify whether these adipose tissue depots contribute to the altered energy metabolism observed in these offspring.MethodsAdipocyte size was measured in both subcutaneous (ScAT) and retroperitoneal adipose tissue (RpAT) in male prenatally ad libitum fed (AD) or prenatally undernourished (UN) rat offspring. Metabolic responses were investigated in adipose tissue explants stimulated by insulin and beta3 receptor agonists ex vivo. Expression of markers of insulin signalling was determined by Western blot analyses. Data were analysed by unpaired t-test or Two Way ANOVA followed by Fisher’s PLSD post-hoc test, where appropriate.ResultsAdipocytes in offspring of undernourished mothers were larger, even at a lower body weight, in both RpAT and ScAT. The insulin response of adipose tissue was reduced in ScAT, and statistically absent in RpAT of UN rats compared with control. This lack of RpAT insulin response was associated with reduced expression of insulin signalling pathway proteins. Adrenergic receptor-driven lipolysis was observed in both adipose depots; however insulin failed to express its anti-lipolytic effect in RpAT in both, AD and UN offspring.ConclusionsMetabolic dysregulation in offspring of undernourished mothers is mediated by increased adipocyte size and reduced insulin responsiveness in both ScAT and especially in RpAT. These functional and morphological changes in adipocytes were accompanied by impaired activity of the insulin signalling cascade highlighting the important role of different adipose tissue depots in the pathogenesis of metabolic disorders.