The role of proinflammatory cytokines in wasting disease during lymphocytic choriomeningitis virus infection

Infection with pathogens often leads to loss of body weight, but the cause of weight loss during infection is poorly understood. We used the infection of mice with lymphocytic choriomeningitis virus (LCMV) as a model to study how pathogens induce weight loss. If LCMV is introduced into the CNS of CTL-deficient mice, the immune response against the virus leads to a severe weight loss called wasting disease. We planned to determine what components of this antiviral immune response mediate wasting disease. By adoptive transfer, we show that CD4 T cells activated by LCMV infection are sufficient to cause wasting disease. We examined the role of cytokines in LCMV-induced wasting disease using mice lacking specific cytokines or cytokine receptors. Results of adoptive transfer experiments suggest that TNF-alpha is not involved in LCMV-induced wasting disease and show that IFN-gamma contributes to the disease. Consistent with a role for IFN-gamma in wasting, we find that IFN-gamma is necessary for LCMV-specific CD4 T cell responses in the CNS, most likely because it is required to induce MHC class II expression. Our data also indicate that IL-1 is required for LCMV-induced wasting and that IL-6 contributes to the wasting disease. Additionally, our results identify alpha-melanocyte-stimulating hormone as a potential mediator of the disease. Overall, this work defines the critical role of virus-primed CD4 T cells and of proinflammatory cytokines in the pathogenesis of wasting disease induced by LCMV infection.     

Muscle wasting in cardiac cachexia

Cardiac cachexia is a serious complication of chronic heart failure which is characterized by complex changes that overall lead to a catabolic/anabolic imbalance resulting in body wasting and a poor prognosis. The wasting process affects all body components, but particularly the skeletal musculature, causing extreme fatigue and weakness, especially in cachectic heart failure patients. Available evidence suggests that several pathophysiologic pathways play a role in the muscle wasting process. Metabolic, neurohormonal, and immune abnormalities lead to an altered regulation of proliferation, differentiation, apoptosis, and metabolism in skeletal muscle, finally resulting in deterioration of the underlying cause with symptomatic exercise intolerance. Possible treatment strategies against muscle wasting and cachexia in chronic heart failure are also described here. As there is no validated therapy for cardiac cachexia yet, further research is necessary to find more therapeutic options for the wasting process.     

Cytokine responses differ by compartment and wasting status in patients with HIV infection and healthy controls

Inflammatory cytokines are implicated in the loss of lean tissue that occurs in patients with inflammatory and infectious diseases, including HIV infection. However, it is not known whether plasma levels or cellular production of cytokines, or their antagonists, are more closely related to lean tissue loss. We studied whether plasma cytokine analysis could substitute for PBMC production assays in studies of nutrition status and disease state, and if cytokine antagonists could offer an alternative in assessing cytokine status. We used a bout of moderately difficult exercise to perturb cytokine production in 12 adults with HIV without wasting, 10 adults with HIV wasting, and nine healthy controls. Plasma and peripheral blood mononuclear cell (PBMC) production of interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra) and soluble TNF receptor type II (sTNFrII) were measured at baseline and 2, 6, 24 and 168h following exercise. PBMC production of IL-1beta, TNF-alpha and IL-6 were all higher in the HIV-infected patients without wasting than in the controls (P<0.05) or the patients with AIDS wasting (P<0.05). Plasma concentrations of TNF-alpha and IL-6 were higher in the HIV wasted patients than in the controls (P<0.05). Both plasma and PBMC levels of sTNFrII were higher in HIV patients, regardless of wasting, than in controls. These data suggest that the PBMC cytokine compartment is more sensitive to nutritional and metabolic abnormalities than is the plasma compartment. PBMC production of IL-1beta, IL-6 and TNF-alpha best distinguish between HIV patients with and without wasting, while plasma concentrations of IL-6 and TNF-alpha are elevated in AIDS wasting, but do not reliably distinguish patients with wasting from HIV-infected patients without wasting.     

Pathogenesis of wasting disease after cyclophosphamide treatment of neonatal mice.

Cyclophosphamide is a potent immunosuppressive agent and is being widely used in organ transplantation. The effects of this anti-rejection drug on lymphoid organs are poorly understood. Newborn Swiss mice injected with various doses of cyclophosphamide suffered from wasting disease at 4 weeks post treatment. The incidence of wasting disease was dose dependent. Haematological picture of the wasting animals revealed leukocytosis of variable degree. Lymphocyte/granulocyte ratio was not inhibited. The cyclophosphamide treatment caused shrinkage of lymphoid organs. Bone marrow showed degeneration of haematopoietic cells. The failure to sustain lymphopoiesis by the potential lymphoid sites following cyclophosphamide treatment and the associated immunological insufficiency resulted in the fatal wasting disease.     

Nutrition and sickle cell disease

A common observation in sickle cell disease is growth retardation, in particular, wasting. Wasting is associated with increased hospitalization and possibly poorer clinical outcomes. Therefore understanding the mechanism of wasting is crucial and reducing the degree of wasting by improving the nutritional status, holds the potential for modifying the course of the disease.     

Contribution of tuberculosis to slim disease in Africa.

OBJECTIVES--To assess the contribution of tuberculosis to the aetiology of the HIV wasting syndrome (slim) in Africa, a condition usually considered an enteropathy. METHODS--Clinical examination and representative necropsy study of adult patients positive for HIV. SETTING--Hospital medical wards in Abidjan, Ivory Coast. SUBJECTS--Adults positive for HIV. MAIN OUTCOME MEASURES--CD4 T lymphocyte counts before death, clinical and anthropometric data, and gross and microscopic pathology. RESULTS--Necropsy was done on 212 HIV positive adults. Tuberculosis was found in 41 of 93 with the clinical HIV wasting syndrome and in 32 of 119 without (odds ratio 2.1, 95% confidence interval 1.2 to 4.0). A significant association existed between the prevalence of tuberculosis at necropsy and the degree of cadaveric wasting (no wasting 25% (15/59); moderate wasting 40% (23/58); skeletal wasting 44% (42/95); P = 0.02). Wasting was also associated with a history of chronic diarrhoea, but no association existed between diarrhoea and tuberculosis. Median CD4 T lymphocyte counts were lowest in wasted patients irrespective of findings at necropsy and in those with chronic diarrhoea (< 60 x 10(6)/l). CONCLUSION--Wasting and chronic diarrhoea are late stage manifestations of HIV disease in Africa. The importance of tuberculosis as a contributing factor in the pathogenesis of the slim syndrome has been underestimated. In nearly half of patients dying with severe wasting, tuberculosis was the dominant pathological finding.     

Hematological and Biochemical Analyses of Blood and Serum in Pigs with Regional Ileitis with Special Reference to the Pathogenesis

Biochemical and hematological analyses of blood and serum were performed in pigs with regional ileitis and in wasting pigs with a negative necropsy. In sera from pigs with regional ileitis the levels of total protein, albumin, transferrin, alkaline phosphatase and zinc were significantly decreased compared with normal pigs of the same age. The number of white blood cells, and the concentration of Cortisol and α1-antitrypsin were significantly increased. In wasting pigs with early signs of regional ileitis or with a negative necropsy the same blood changes were observed but to a less degree. It was concluded that a wasting syndrome after weaning may precede regional ileitis. Concerning the etiology of regional ileitis the significance of malabsorption and wasting syndrome in combination with invasion of intestinal intercellular microorganisms is discussed.     

An initial comparative genomic autopsy of wasting disease in sea stars

Beginning in 2013, sea stars throughout the Eastern North Pacific were decimated by wasting disease, also known as “asteroid idiopathic wasting syndrome” (AIWS) due to its elusive aetiology. The geographic extent and taxonomic scale of AIWS meant events leading up to the outbreak were heterogeneous, multifaceted, and oftentimes unobserved; progression from morbidity to death was rapid, leaving few tell‐tale symptoms. Here, we take a forensic genomic approach to discover candidate genes that may help explain sea star wasting syndrome. We report the first genome and annotation for Pisaster ochraceus, along with differential gene expression (DGE) analyses in four size classes, three tissue types, and in symptomatic and asymptomatic individuals. We integrate nucleotide polymorphisms associated with survivors of the wasting disease outbreak, DGE associated with temperature treatments in P. ochraceus, and DGE associated with wasting in another asteroid Pycnopodia helianthoides. In P. ochraceus, we found DGE across all tissues, among size classes, and between asymptomatic and symptomatic individuals; the strongest wasting‐associated DGE signal was in pyloric caecum. We also found previously identified outlier loci co‐occur with differentially expressed genes. In cross‐species comparisons of symptomatic and asymptomatic individuals, consistent responses distinguish genes associated with invertebrate innate immunity and chemical defence, consistent with context‐dependent stress responses, defensive apoptosis, and tissue degradation. Our analyses thus highlight genomic constituents that may link suspected environmental drivers (elevated temperature) with intrinsic differences among individuals (age/size, alleles associated with susceptibility) that elicit organismal responses (e.g., coelomocyte proliferation) and manifest as sea star wasting mass mortality.     

Cardiolipin content is involved in liver mitochondrial energy wasting associated with cancer-induced cachexia without the involvement of adenine nucleotide translocase

Cancer-induced cachexia describes the progressive skeletal muscle wasting associated with many cancers leading to shortened survival time in cancer patients. We previously reported that cardiolipin content and energy-wasting processes were both increased in liver mitochondria in a rat model of peritoneal carcinosis (PC)-induced cachexia. To increase the understanding of the cellular biology of cancer cachexia, we investigated the involvement of adenine nucleotide translocator (ANT) in mitochondrial energy-wasting processes in liver mitochondria of PC and pair-fed control rats and its interactions with cardiolipin in isolated liver mitochondria from healthy rats exposed to cardiolipin-enriched liposomes. We showed in this study that functional ANT content was decreased in liver mitochondria from PC rats but without any effects on the efficiency of ATP synthesis. Moreover, non-phosphorylating energy wasting was not affected by saturating concentrations of carboxyatractylate (CAT), a potent inhibitor of ANT, in liver mitochondria from PC rats. Decreased efficiency of ATP synthesis was found in normal liver mitochondria exposed to cardiolipin-enriched liposomes, with increased non-phosphorylating energy wasting, thus mimicking mitochondria from PC rats. However, the functional ANT content in these cardiolipin-enriched mitochondria was unchanged, although non-phosphorylating energy wasting was reduced by CAT-induced inhibition of ANT. Finally, non-phosphorylating energy wasting was increased in cardiolipin-enriched mitochondria with substrates for complexes 1 and 2, but not for complex 4. In conclusion, increased energy wasting measured in liver mitochondria from rats with cancer cachexia is dependent on cardiolipin but independent of ANT. Interactions between ANT and cardiolipin are modified when cancer cachexia occurs.     

Effect of experimental viral infection in thymectomized rodents

Neonatally thymectomized rodents present an increased susceptibility to experimental viral infections leading to a severe growth depression. In thymectomized mice, viral infections significantly enhance the appearance of the wasting syndrome. These data suggest that viral infections may contribute to the development of wasting syndrome.     

Muscle wasting in diabetic and in tumor-bearing rats: role of oxidative stress

Cachexia is a debilitating syndrome characterized by body weight loss, muscle wasting, and anemia. Muscle wasting results from an altered balance between protein synthesis and degradation rates. Reactive oxygen species are indicated as crucial players in the onset of muscle protein hypercatabolism by upregulating elements of the ubiquitin-proteasome pathway. The present study has been aimed at evaluating comparatively the involvement of oxidative stress in the pathogenesis of skeletal muscle wasting in two different experimental models: rats rendered hyperglycemic by treatment with streptozotocin and rats bearing the Yoshida AH-130 ascites hepatoma. For this purpose, both tumor bearers and diabetic animals have been treated with dehydroepiandrosterone (DHEA), a multifunctional steroid endowed with multitargeted antioxidant properties. We show that diabetic rats and AH-130 rats share several features, hypoinsulinemia, occurrence of oxidative stress, and positive response to DHEA administration, although the extent of the effects of DHEA largely differs between diabetic animals and tumor-bearing rats. The hypercatabolism, evaluated in terms of proteasome activity and expression of atrogin-1 and MuRF1, is activated in AH-130 rats, whereas it is lacking in streptozotocin-treated rats. Moreover, we demonstrate that the role of oxidative stress can interfere with muscle wasting through different mechanisms, not necessarily involving NF-kappaB activation. In conclusion, the present results show that, although skeletal muscle wasting occurs in both diabetic rats and tumor-host rats, the underlying mechanisms are different. Moreover, despite oxidative stress being detectable in both experimental models, its contribution to muscle wasting is not comparable.     

Physical growth of children under five years of age in Nchelenge,Zambia: Results from a district survey

This study focuses on the physical growth of children aged 0–60 months in Nchelenge District, northeast Zambia. By means of a two-stage clustered and random sampling method, 193 households were selected. Weight, height, and mid-upper-arm circumference (MUAC) of children 0–60 months were measured. Underweight, stunting, and wasting were defined as weight for age, height for age, and weight for height (W/H), respectively, ≤2 z scores below the median of the National Center for Health Statistics (NCHS) reference population. Among 250 children, prevalence rates of 30% underweight, 69.2% stunting, and 4.4% wasting were found, with the highest rates at age 12–<24 months. Prevalence of stunting, underweight, and wasting in children aged 0–<6 months and 6–<12 months suggested that a substantial proportion of infants were premature and/or small for gestational age. The literature suggests that prematurity and intrauterine growth retardation may be quite common in Africa, and this may have important implications for the interpretation of growth data and under nutrition rates. Use of the MUAC < 125 mm as an indicator of wasting resulted in higher estimates of wasting compared to W/H ≤ −2 z scores, and seemed unsuitable as a screening test for wasting in this Zambian population. © 1996 Wiley-Liss, Inc.     

Apoptosis signalling is essential and precedes protein degradation in wasting skeletal muscle during catabolic conditions

Activation of skeletal muscle proteolysis leads to wasting in many types of catabolic/chronic diseases. Protein breakdown is basically accomplished by the activation of the ubiquitin-proteasome system. Interestingly, several publications have shown that DNA fragmentation also occurs in skeletal muscle tissue during catabolism. The present review suggests that activation of apoptosis precedes protein breakdown associated with muscle wasting. In addition, the role of the different proteolytic systems and their relation with apoptosis is emphasized. Altogether, the data presented could be used for the design of new approaches for the treatment of muscle wasting diseases.     

Constant light exposure aggravates POMC-mediated muscle wasting associated with hypothalamic alteration of circadian clock and SIRT1 in endotoxemia rats

Constant light exposure is widespread in the intensive care unit (ICU) and could increase the rate of brain dysfunction as delirium and sleep disorders in critical patients. And the activation of hypothalamic neuropeptides is proved to play a crucial role in regulating hypercatabolism, especially skeletal muscle wasting in critical patients, which could lead to serious complications and poor prognosis. Here we investigated the hypothesis that constant light exposure could aggravate skeletal muscle wasting in endotoxemia rats and whether it was associated with alterations of circadian clock and hypothalamic proopiomelanocortin(POMC) expression. Fifty-four adult male Sprague-Dawley rats were intraperitoneally injected with lipopolysaccharide(LPS) or saline, subjected to constant light or a 12:12?h light-dark cycle for 7 days. On day 8, rats were sacrificed across six time points in 24?h and hypothalamus tissues and skeletal muscle were obtained. Rates of muscle wasting were measured by 3-methylhistidine(3-MH) and tyrosine release as well as expression of two muscle atrophic genes, muscle ring finger 1(MuRF-1) and muscle atrophy F-box(MAFbx). The expression of circadian clock genes, silent information regulator 1(SIRT1), POMC and hypothalamic inflammatory cytokines were also detected. Results showed that LPS administration significantly increased hypothalamic POMC expression, inflammatory cytokine levels and muscle wasting rates. Meanwhile constant light exposure disrupted the circadian rhythm, declined the expression of SIRT1 as well as aggravated hypothalamic POMC overexpression and skeletal muscle wasting in rats with endotoxemia. Taken together, the results demonstrated that constant light exposure could aggravate POMC-mediated skeletal muscle wasting in endotoxemia rats, which is associated with alteration of circadian clocks and SIRT1 in the hypothalamus.     

JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia

Cachexia, the metabolic dysregulation leading to sustained loss of muscle and adipose tissue, is a devastating complication of cancer and other chronic diseases. Interleukin-6 and related cytokines are associated with muscle wasting in clinical and experimental cachexia, although the mechanisms by which they might induce muscle wasting are unknown. One pathway activated strongly by IL-6 family ligands is the JAK/STAT3 pathway, the function of which has not been evaluated in regulation of skeletal muscle mass. Recently, we showed that skeletal muscle STAT3 phosphorylation, nuclear localization, and target gene expression are activated in C26 cancer cachexia, a model with high IL-6 family ligands. Here, we report that STAT3 activation is a common feature of muscle wasting, activated in muscle by IL-6 in vivo and in vitro and by different types of cancer and sterile sepsis. Moreover, STAT3 activation proved both necessary and sufficient for muscle wasting. In C(2)C(12) myotubes and in mouse muscle, mutant constitutively activated STAT3-induced muscle fiber atrophy and exacerbated wasting in cachexia. Conversely, inhibiting STAT3 pharmacologically with JAK or STAT3 inhibitors or genetically with dominant negative STAT3 and short hairpin STAT3 reduced muscle atrophy downstream of IL-6 or cancer. These results indicate that STAT3 is a primary mediator of muscle wasting in cancer cachexia and other conditions of high IL-6 family signaling. Thus STAT3 could represent a novel therapeutic target for the preservation of skeletal muscle in cachexia.     

Myostatin promotes the wasting of human myoblast cultures through promoting ubiquitin-proteasome pathway-mediated loss of sarcomeric proteins

Myostatin is a negative regulator of skeletal muscle growth and in fact acts as a potent inducer of "cachectic-like" muscle wasting in mice. The mechanism of action of myostatin in promoting muscle wasting has been predominantly studied in murine models. Despite numerous reports linking elevated levels of myostatin to human skeletal muscle wasting conditions, little is currently known about the signaling mechanism(s) through which myostatin promotes human skeletal muscle wasting. Therefore, in this present study we describe in further detail the mechanisms behind myostatin regulation of human skeletal muscle wasting using an in vitro human primary myotube atrophy model. Treatment of human myotube populations with myostatin promoted dramatic myotubular atrophy. Mechanistically, myostatin-induced myotube atrophy resulted in reduced p-AKT concomitant with the accumulation of active dephosphorylated Forkhead Box-O (FOXO1) and FOXO3. We further show that addition of myostatin results in enhanced activation of atrogin-1 and muscle-specific RING finger protein 1 (MURF1) and reduced expression of both myosin light chain (MYL) and myosin heavy chain (MYH). In addition, we found that myostatin-induced loss of MYL and MYH proteins is dependent on the activity of the proteasome and mediated via SMAD3-dependent regulation of FOXO1 and atrogin-1. Therefore, these data suggest that the mechanism through which myostatin promotes muscle wasting is very well conserved between species, and that myostatin-induced human myotube atrophy is mediated through inhibition of insulin-like growth factor (IGF)/phosphoinositide 3-kinase (PI3-K)/AKT signaling and enhanced activation of the ubiquitin-proteasome pathway and elevated protein degradation.     

Nutritional investigations and management of captive moose

Historically, moose have been difficult to maintain in captivity when on diets of grass or legume hays and grain due to enteritis that frequently leads to chronic diarrhea/wasting disease. The development of wood-fiber diets has increased the lifespan of moose in captivity, but these diets do not completely prevent chronic wasting. Purina Mills (St. Louis, MO) hypothesized that captive moose are unable to digest starch that escapes the rumen, and therefore abnormal bacterial fermentation in the hindgut causes chronic diarrhea. An earlier study found no evidence of a digestive problem, so we tested the hypothesis that moose have difficulty metabolizing excess propionate produced from the fermentation of starch found in traditional cervid rations and high-grain wood-fiber diets. When challenged with an i.v. propionate load, moose metabolized propionate similar to healthy mule deer and domestic livestock. We then tested the hypothesis that grass forage is an initiating factor to chronic diarrhea/wasting and further hypothesized that grass, alfalfa, and other agriculture-based forages in association with an anaerobic bacteria produce inflammatory bowel disease (IBD) in moose. Captive moose that had ad libitum access to a wood-fiber pelleted moose diet and grazed in grass pastures developed chronic wasting symptoms at 2–4 years of age and died at 4.7 ± 0.3 years unless restricted from grass before the development of advanced symptoms. We isolated Bacteroides vulgatus in the feces and successfully treated a moose with chronic diarrhea/wasting disease with long-term metronidazole therapy, suggesting that the chronic enteritis causing wasting disease arises from a bacteria-associated defective immunosuppressive response similar to IBD in other species. Further support for the IBD cause of wasting in moose is that this animal will relapse within hours if the metronidazole treatment is discontinued even after many months. We developed a highly palatable high-fiber, low-starch moose ration that can be fed as the sole source of nourishment, although additional research and dietary improvements are required. Zoo Biol 16:479–494, 1997. © 1997 Wiley-Liss, Inc.     

Susceptibility of tamarin (Saguinus labiatus) red blood cell membrane lipids to oxidative stress: implications for wasting marmoset syndrome

Captive Callitrichids frequently suffer a fatal wasting disease, wasting marmoset syndrome (WMS), of unexplained cause. This paper describes studies on the erythrocytes from animals in a breeding colony of tamarins (Saguinus labiatus), in which deaths from anaemia and wasting were occurring, to seek evidence for biochemical changes which could lead to oxidative damage and premature cell lysis. In only one animal of 33 studied did the red blood cell lipids show an increased susceptibility to oxidative damage. This animal, with some degree of certainty, could be diagnosed as having WMS. It was concluded that evidence for a primary deficiency of antioxidants as a cause of unexplained deaths, or WMS, in the colony could not at present be substantiated.