Molecular basis of inflammation: relationships between catabolic cytokines, hormones, energy balance, and muscle

Inflammation alters energy metabolism, macro- and micronutrient balances, and body composition. This review briefly describes the current understanding of how this happens, focusing on the effect of immune system activation on energy balance. Conversely, malnutrition also has a large impact on immune function, with both undernutrition (causing immune suppression) and overnutrition (causing inflammation) now well described. Improved understanding of the interplay of the immune system and metabolism can lead to new treatments for both cachexia and obesity.     

The role of hormones, cytokines and heat shock proteins during age-related muscle loss

Ageing is associated with a progressive decline of muscle mass, strength, and quality, a condition known as sarcopenia. Due to the progressive ageing of western populations, age-related sarcopenia is a major public health problem. Several possible mechanisms for age-related muscle atrophy have been described; however the precise contribution of each is unknown. Age-related muscle loss is thought to be a multi-factoral process composed of events such as physical activity, nutritional intake, oxidative stress, inflammatory insults and hormonal changes. There is a need for a greater understanding of the loss of muscle mass with age as this could have a dramatic impact on the elderly and critically ill if this research leads to maintenance or improvement in functional ability. This review aims to outline the process of skeletal muscle degeneration with ageing, normal and aberrant skeletal muscle regeneration, and to address recent research on the effects of gender and sex steroid hormones during the process of age-related muscle loss.     

Whole-body protein metabolism in chronic heart failure: relationship to anabolic and catabolic hormones

BACKGROUND: Patients with chronic heart failure frequently experience profound wasting during the course of the disease, a condition termed cardiac cachexia. Although protein is the primary structural and functional component of most tissues, few studies have examined the effect of heart failure on protein metabolism. Moreover, no study has assessed the relationship of protein turnover to hormonal alterations thought to promote cachexia. Thus, our goal was to determine if whole-body protein metabolism is altered in heart failure patients and to assess the relationship of protein kinetics to circulating levels of anabolic and catabolic hormones. METHODS: We measured whole-body protein metabolism using 13C-leucine, body composition, and circulating anabolic and catabolic hormone levels in 10 patients with chronic heart failure and 11 elderly controls. RESULTS: No differences in leucine rate of appearance, oxidation, or nonoxidative disposal were noted between heart failure patients and controls. However, in a subgroup of patients characterized by increased resting energy expenditure for their metabolic body size (n = 4; > or = 20% above that predicted from fat-free mass), leucine rate of appearance (mean +/- SE; 146 +/- 6 micromol/min), an index of protein breakdown, tended to be higher compared with patients with normal resting energy expenditure (n = 5; 120 +/- 8 micromol/min) and controls (127 +/- 4 micromol/min; p = .06). Alterations in anabolic/catabolic hormone balance did not explain increased protein breakdown in this subgroup, and no correlations were found between hormone levels and protein breakdown in the heart failure group as a whole. In contrast, increased circulating interleukin-6 soluble receptor (r = 0.829; p < .01) and reduced insulin-like growth factor-I (r =-.751; p < .05) levels were related to greater rates of leucine oxidation in heart failure patients. CONCLUSION: Our results demonstrate that, although increased protein turnover is not a generalized feature of heart failure, there is a subgroup of patients characterized by resting hypermetabolism and increased protein breakdown. Moreover, hormonal alterations related to the heart failure syndrome were related to increased protein oxidation.     

Skeletal muscle lipid concentration quantified by magnetic resonance imaging

BACKGROUND: Skeletal muscle lipid is associated with obesity and type 2 diabetes and may be altered by diet, physical activity, and weight loss. OBJECTIVE: We explored the utility of magnetic resonance imaging (MRI) for quantifying the lipid concentration of muscle tissue in vivo. DESIGN: Fat-selective MR images of the lower leg were taken in 8 normal-weight [body mass index (in kg/m(2)) < or = 24.9] and 8 obese (body mass index > 29.9) subjects to obtain spatial maps of lipid signal intensity within muscle tissue. Fast-spiral-sequence (echo time = 5.6-13.8 ms, repetition time = 1 s, 8 interleaves) MRI scans were conducted at 3.0 T by using an extremity transmit-receive coil. Lipid concentrations within muscle were determined from manually drawn regions of interest in the tibialis anterior (TA), soleus, and medial head of the gastrocnemius (MHG) muscle groups. RESULTS: There was extremely good agreement (mean R(2) = 0.985) between the fat signal intensity and the actual lipid concentration of standards containing 2.5, 5.0, and 10.0 g lipid/dL, which were placed on the subject's leg during each scan. The lipid content of both the soleus (2.99 +/- 0.37 g/dL) and the MHG (3.80 +/- 0.68 g/dL) was higher (P < 0.05) than that of the TA (1.83 +/- 0.28 g/dL). Lipid content was more than two-fold higher (P < 0.05) in the MHG of obese subjects (5.48 +/- 1.18 g/dL) than in the MHG of normal-weight subjects (2.54 +/- 0.47 g/dL), but did not differ significantly in the TA or soleus. CONCLUSIONS: MRI can be used to quantify lipid within human muscle tissue. MRI can also be used to detect differences in muscle lipid content among various muscle groups and between normal-weight and obese subjects.     

Regulation by insulin of muscle protein metabolism during sepsis and other catabolic conditions.

The anabolic effect of insulin in skeletal muscle reflects increased protein synthesis and reduced protein degradation. Insulin stimulates protein synthesis mainly at the translational level by enhancing peptide chain initiation. The mechanism by which the hormone reduces protein breakdown is less well understood, but inhibition of the lysosomal pathway is probably an important component. Sepsis results in pronounced muscle catabolism, mainly reflecting increased protein breakdown, particularly myofibrillar protein breakdown, and a less prominent inhibition of protein synthesis. There is evidence that muscle protein breakdown becomes resistant to the effect of insulin during sepsis, probably at the postreceptor level. This insulin resistance may be mediated by increased beta-adrenoreceptor activity. In contrast, the stimulatory effect of insulin on muscle protein synthesis and amino acid transport is maintained during sepsis. The regulatory effect of insulin on muscle protein metabolism may be affected by other catabolic conditions as well, e.g., fasting, denervation, burn injury, and trauma.     

Skeletal muscle protein metabolism and resistance exercise

Stable isotope tracer techniques have been developed to quantify rates of muscle protein synthesis and breakdown in human subjects. These methods were applied to the study of the response to resistance exercise as well as to amino acid intake. The fractional synthetic rate (FSR) of muscle protein is stimulated for as long as 48 h following exercise. However, the anabolic effect of the stimulation of FSR after exercise is blunted by a simultaneous increase in muscle protein breakdown, such that the net balance between synthesis and breakdown remains negative in the fasted state. Elevation of plasma amino acids stimulates muscle protein synthesis. The extent of the stimulation is dependent on the dose, the profile of amino acids given, the pattern of ingestion (bolus vs. constant intake), the age of the subject, and the hormonal profile. Importantly, there is an interactive effect between resistance exercise and amino acids, such that the net anabolic response to amino acids following exercise is greater than the sum of the amino acid effects and the exercise effects alone.     

Skeletal muscle substrate metabolism during exercise: methodological considerations

The aim of the present article is to evaluate critically the various methods employed in studies designed to quantify precisely skeletal muscle substrate utilization during exercise. In general, the pattern of substrate utilization during exercise can be described well from O2 uptake measurements and the respiratory exchange ratio. However, if the aim is to quantify limb or muscle metabolism, invasive measurements have to be carried out, such as the determination of blood flow, arterio-venous (a-v) difference measurements for O2 and relevant substrates, and biopsies of the active muscle. As many substrates and metabolites may be both taken up and released by muscle at rest and during exercise, isotopes can be used to determine uptake and/or release and also fractional uptake can be accounted for. Furthermore, the use of isotopes opens up further possibilities for the estimation of oxidation rates of various substrates. There are several methodological concerns to be aware of when studying the metabolic response to exercise in human subjects. These concerns include: (1) the muscle mass involved in the exercise is largely unknown (bicycle or treadmill). Moreover, whether the muscle sample obtained from a limb muscle and the substrate and metabolite concentrations are representative can be a problem; (2) the placement of the venous catheter can be critical, and it should be secured so that the blood sample represents blood from the active muscle with a minimum of contamination from other muscles and tissues; (3) the use of net limb glycerol release to estimate lipolysis is probably not valid (triacylglycerol utilization by muscle), since glycerol can be metabolized in skeletal muscle; (4) the precision of blood-borne substrate concentrations during exercise measured by a-v difference is hampered since they become very small due to the high blood flow. Recommendations are given in order to obtain more quantitative and conclusive data in studies investigating the regulatory mechanisms for substrate choice by muscle.     

Skeletal muscle density: effects of obesity and non-insulin-dependent diabetes mellitus

Obesity is associated with increased lean mass but its effects on lean-tissue density are less clear. To examine the effects of obesity and non-insulin-dependent diabetes mellitus (NIDDM) on lean-tissue composition and density, cross-sectional computed tomography (CT) scans of the midthigh were obtained in 20 men of various weights. Obesity was associated with increases in thigh-adipose (r = 0.75) and lean-tissue volumes (r = 0.52) and with reduced density of lean tissue (r = -0.73). The increased lean tissue in obesity was due to a nonadipose tissue component with a density below the normal range of muscle, an effect compounded by NIDDM, whereas normal-density muscle volume was unchanged.     

Skeletal muscle function and metabolism in obese women

A possible mechanism to regulate body weight during a high calorie intake may be an increased metabolic rate in skeletal muscle. To approach this hypothesis the energy metabolites, ATP, phosphocreatine, creatine, glycogen and lactate were measured in biopsies from the quadriceps femoris muscle. Concomitantly the function of the adductor pollicis muscle was studied as assessed after electrical stimulation of the ulnar nerve. The muscle function variables were, force of contraction at 5, 10, 20, and 50 Hz of stimulation, relaxation rate, and endurance. Eight obese women were studied before gastroplastic surgery and 6 months postoperatively and a weight loss of 19.4 +/- 3.4% (mean +/- SEM). Preoperatively ATP, phosphocreatine, glycogen, and lactate were significantly decreased and the same pattern was found postoperatively. These findings can be related to a low production of energy-rich phosphates or a high energy utilization. Both pre- and postoperatively there was, a decreased force of contraction at 10 Hz of stimulation (p less than 0.001), a faster relaxation rate (p less than 0.01) and a normal endurance. These functional results indicate a high metabolic rate. At admission a decreased serum insulin level indicated a moderate insulin resistance which was normalized after the weight loss. The triiodothyronine concentration was normal before and after operation. In conclusion our findings of changed muscle energy metabolite concentrations and altered muscle function indicate a high metabolic rate in skeletal muscle in obese women. This may be an adaptation in skeletal muscle energy metabolism to a high body weight.     

Zinc and regulation of inflammatory cytokines: implications for cardiometabolic disease

In atherosclerosis and diabetes mellitus, the concomitant presence of low-grade systemic inflammation and mild zinc deficiency highlights a role for zinc nutrition in the management of chronic disease. This review aims to evaluate the literature that reports on the interactions of zinc and cytokines. In humans, inflammatory cytokines have been shown both to up- and down-regulate the expression of specific cellular zinc transporters in response to an increased demand for zinc in inflammatory conditions. The acute phase response includes a rapid decline in the plasma zinc concentration as a result of the redistribution of zinc into cellular compartments. Zinc deficiency influences the generation of cytokines, including IL-1β, IL-2, IL-6, and TNF-α, and in response to zinc supplementation plasma cytokines exhibit a dose-dependent response. The mechanism of action may reflect the ability of zinc to either induce or inhibit the activation of NF-κB. Confounders in understanding the zinc-cytokine relationship on the basis of in vitro experimentation include methodological issues such as the cell type and the means of activating cells in culture. Impaired zinc homeostasis and chronic inflammation feature prominently in a number of cardiometabolic diseases. Given the high prevalence of zinc deficiency and chronic disease globally, the interplay of zinc and inflammation warrants further examination.     

Postoperative insulin resistance and circulating concentrations of stress hormones and cytokines

Insulin sensitivity was determined before and after elective surgery in 31 otherwise healthy patients undergoing elective surgery for open cholecystectomy (n = 24) or inguinal hernia repair (n = 7) and compared with concomitant plasma concentrations of stress hormones and cytokines. Insulin sensitivity was determined employing the normoglycaemic, hyperinsulinaemic clamp at a plasma insulin concentration of 380 pmol/I and a blood glucose concentration of 4.5 mmol/I. Five of the patients undergoing cholecystectomy were studied again on days 5, 9 and 20 after surgery. Preoperative insulin sensitivity ranged from 2.2 to 14.3 mg/kg/min. All patients exhibited reduced insulin sensitivity on the first postoperative day and the mean value fell from 4.7 (0.4) to 2.7 (0.5) mg/kg/min. More pronounced reductions were found after cholecystectomy. A significant increase was found in plasma concentrations of interleukin-6 (IL-6) postoperatively as compared to preoperative values. However, no significant changes were seen in the postoperative plasma concentrations of any of the hormones studied in patients undergoing hernia repair, while minor increments were seen in patients undergoing open cholecystectomy. There was a significant (r = 0.50, P = 0.005) linear relationship between the reduction in relative insulin sensitivity and the concomitant plasma levels of IL-6. However, no such relation could be confirmed between the changes in plasma hormone concentrations (neither absolute nor relative changes) and the simultaneous alteration in relative insulin sensitivity. In addition, after including three patients who had undergone ileo-anal pouch construction surgery, the relationship between postoperative insulin sensitivity and IL-6 levels was even stronger (r = 0.62, P = 0.001). These results suggest that the immunomodulating effects of endogenous IL-6 is of importance in the acute response after surgery and are associated with the development of insulin resistance, while simultaneous plasma concentrations of stress hormones seem to be less sensitive markers of the degree of postoperative metabolic disturbance.     

Gastrointestinal hormones: the regulation of appetite and the anorexia of ageing

Loss of appetite is frequently observed during ageing, termed the ‘anorexia of ageing’. Ageing is associated with the inability to appropriately increase food intake after under‐eating in the short‐ and long‐term. Older people also report lower feelings of hunger and increased feelings of satiety and fullness. Gastrointestinal peptide hormones are a major part of the appetite regulatory system and are released in response to nutritional stimuli. They can be classified as: anorexigenic (satiety) [e.g. peptide tyrosine tyrosine (PYY), glucagon‐like peptide‐1, pancreatic polypeptide, oxyntomodulin and cholecystokinin (CCK)] or orexigenic (hunger) (e.g. ghrelin). Although the control of appetite is not fully understood, it is clear that these hormones play an important role, and may influence the development and treatment of obesity and under‐nutrition. The literature shows a consistent finding that there is a loss of appetite in those aged over 65 years, although how this loss is mediated is not yet clear. Some evidence suggests that with advancing age there is an increase in satiety hormones, such as CCK and PYY, and a decrease in the hunger hormone, ghrelin. However, not all studies agree, emphasising the need for more in‐depth research to clarify age‐related changes. This knowledge will enable us to develop therapies to help prevent under‐nutrition during ageing. This review explores how age influences gastrointestinal appetite hormones in humans, as well as how this may contribute to the development of age‐related malnutrition.     

Skeletal muscle glutamate metabolism in health and disease: state of the art

PURPOSE OF REVIEW: Glutamate is an amino acid of interest because it participates in many metabolic pathways. However, there is evidence that skeletal muscle glutamate metabolism is disturbed in disease. This review presents current knowledge regarding the metabolic function and regulation of glutamate in skeletal muscle under physiological and pathophysiological circumstances. Furthermore, several options for modulating muscle glutamate concentration in order to improve glutamate metabolism are discussed. RECENT FINDINGS: The high correlation between muscle glutamate concentration and muscle glutathione concentration suggests that glutamate plays a determining role in the glutathione synthesis pathway. During exercise, glutamate plays a central role in energy provision because it participates in the tricarboxylic acid and the purine nucleotide cycles. However, a consistent finding in several diseases is reduced skeletal muscle glutamate. Remarkably, only few studies focused on modulation of muscle glutamate status either by exercise or by nutritional supplementation. There are several options for modulating glutamate metabolism, but the specific effects of the individual options require further elucidation. Nutritional supplementation of glutamate or its precursors glutamine, (ornithine) alpha-ketoglutarate, or the branched chain amino acids can influence muscle glutamate status. SUMMARY: Specific intervention studies must be conducted to investigate the effect of supplementation on skeletal muscle glutamate turnover and its related metabolic and functional consequences in healthy individuals and in patients with acute or chronic disease.     

Skeletal muscle fat infiltration: Impact of age,inactivity, and exercise

Fat infiltration within the fascial envelope of the thigh or intermuscular adispose tissue (IMAT), has been shown to be associated with both adverse metabolic and mobility impairments in older individuals. More recent findings suggest these fat deposits may be associated with increasing age and inactivity; and perhaps exercise may be able to counter or mitigate this increase in IMAT. This brief report summarizes the literature with respect to IMAT and its relationship to increasing age, physical activity levels, muscle strength, mobility and metabolism in the elderly. Further, we present preliminary data suggesting that IMAT is associated with increasing age in individuals across disease states (r=0.47, p<0.05), and that resistance exercise can decrease IMAT in older individuals with a variety of co-morbid conditions.     

Assessment of endocrine and nutritional status in age-related catabolic states of muscle and bone

PURPOSE OF REVIEW: Bone loss and muscle wasting are associated with increased morbidity and mortality in the elderly, most frequently as a result of fractures associated with poor neuromuscular conditioning leading to accidental falls. This paper reviews data that link pathways of the immune and endocrine systems with bone and muscle pathophysiology, as well as data on the impact of nutrition and physical activity on these systems. RECENT FINDINGS: The growth hormone-insulin-like growth factor I axis and deficiencies in sex steroid hormones in aging appear linked with changes in the hypothalamic-pituitary-adrenal axis and immune function, accompanied by increased activity of the tumour necrosis factor-alpha axis. This is associated with activation of the RANK/RANKL/osteoprotegerin pathway and insulin resistance, affecting muscle and bone physiology. Vitamin D deficiency contributes to bone loss and muscle wasting, whereas other nutritional defects such as zinc or magnesium deficiencies may further complicate these catabolic states. SUMMARY: As nutritional deficiencies responsible for bone and muscle derangement are correctable factors, careful nutritional assessment, in addition to evaluation of endocrine and immune status, may provide clinically important information allowing successful management of elderly patients in danger of neuromuscular dysfunction, accidental falls and bone fractures.