mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission.

Fasting triggers diverse physiological adaptations including increases in circulating fatty acids and mitochondrial respiration to facilitate organismal survival. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during fasting remain incompletely understood. Here we show that fasting or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its downstream target NDRG1 at serine 336 sustains mitochondrial fission and respiratory sufficiency. Time-lapse imaging shows that NDRG1, but not the phosphorylation-deficient NDRG1Ser336Ala mutant, engages with mitochondria to facilitate fission in control cells, as well as in those lacking DRP1. Using proteomics, a small interfering RNA screen, and epistasis experiments, we show that mTORC2-phosphorylated NDRG1 cooperates with small GTPase CDC42 and effectors and regulators of CDC42 to orchestrate fission. Accordingly, RictorKO, NDRG1Ser336Ala mutants and Cdc42-deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions; however, paradoxical reactivation of mTORC2 during fasting unexpectedly drives mitochondrial fission and respiration.

Negative energy balance hinders prosocial helping behavior.

The internal state of an animal, including homeostatic requirements, modulates its behavior. Negative energy balance stimulates hunger, thus promoting a range of actions aimed at obtaining food. While these survival actions are well established, the influence of the energy status on prosocial behavior remains unexplored. We developed a paradigm to assess helping behavior in which a free mouse was faced with a conspecific trapped in a restrainer. We measured the willingness of the free mouse to liberate the confined mouse under diverse metabolic conditions. Around 42% of ad libitum-fed mice exhibited a helping behavior, as evidenced by the reduction in the latencies to release the trapped cagemate. This behavior was independent of subsequent social contact reward and was associated with changes in corticosterone indicative of emotional contagion. This decision-making process was coupled with reduced blood glucose excursions and higher Adenosine triphosphate (ATP):Adenosine diphosphate (ADP) ratios in the forebrain of helper mice, suggesting that it was a highly energy-demanding process. Interestingly, chronic (food restriction and type 2 diabetes) and acute (chemogenetic activation of hunger-promoting AgRP neurons) situations mimicking organismal negative energy balance and enhanced appetite attenuated helping behavior toward a distressed conspecific. To investigate similar effects in humans, we estimated the influence of glycated hemoglobin (a surrogate of long-term glycemic control) on prosocial behavior (namely charity donation) using the Understanding Society dataset. Our results evidenced that organismal energy status markedly influences helping behavior and that hypothalamic AgRP neurons are at the interface of metabolism and prosocial behavior.

Food craving-like episodes during pregnancy are mediated by accumbal dopaminergic circuits.

Preparation for motherhood requires a myriad of physiological and behavioural adjustments throughout gestation to provide an adequate environment for proper embryonic development1. Cravings for highly palatable foods are highly prevalent during pregnancy2 and contribute to the maintenance and development of gestational overweight or obesity3. However, the neurobiology underlying the distinct ingestive behaviours that result from craving specific foods remain unknown. Here we show that mice, similarly to humans, experience gestational food craving-like episodes. These episodes are associated with a brain connectivity reorganization that affects key components of the dopaminergic mesolimbic circuitry, which drives motivated appetitive behaviours and facilitates the perception of rewarding stimuli. Pregnancy engages a dynamic modulation of dopaminergic signalling through neurons expressing dopamine D2 receptors in the nucleus accumbens, which directly modulate food craving-like events. Importantly, persistent maternal food craving-like behaviour has long-lasting effects on the offspring, particularly in males, leading to glucose intolerance, increased body weight and increased susceptibility to develop eating disorders and anxiety-like behaviours during adulthood. Our results reveal the cognitively motivated nature of pregnancy food cravings and advocates for moderating emotional eating during gestation to prevent deterioration of the offspring's neuropsychological and metabolic health.

Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders.

Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggest that pregnenolone's effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically unhealthy patients with obesity. Our data reveal an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders.

The animal cachexia score (ACASCO).

BACKGROUND: None of the published studies involving cancer cachexia experimental models have included a measure of the severity of the syndrome like the scoring system previously developed for human subjects. The aim of the present investigation was to define and validate a cachexia score usable in both rat and mouse tumor models. METHODS: In order to achieve this goal, we included in the study one rat model (Yoshida AH-130ascites hepatoma) and two mouse models (Lewis lung carcinoma and Colon26 carcinoma). The Animal cachexia score (ACASCO) includes five components: (a) body and muscle weight loss, (b) inflammation and metabolic disturbances, (c) physical performance, (d) anorexia, and (e) quality of life measured using discomfort symptoms and behavioral tests. RESULTS: Using the ACASCO values, three cut-off values were estimated by applying hierarchical cluster analysis. Four groups were originally described, one exactly below the observed mean, a second exactly over the mean, and two other groups adjusted to every cue (inferior and superior). The three cut-off values were estimated through maximization of the classification function. This was accomplished by using a similarity matrix based on the metric properties of the variables and assuming multinormal distribution. The results show that the four groups were: no cachexia, mild cachexia, moderate cachexia and advanced cachexia. CONCLUSIONS: The results obtained allow us to conclude that the score could be very useful as an endpoint in pre-clinical studies involving therapeutic strategies for cancer cachexia. The potential usefulness of ACASCO relates to the primary endpoint in pre-clinical cancer cachexia drug evaluations.

Estudio Descriptivo: Perfil Epidemiológico en la Unidad de Cuidados Intensivos Pediátricos del Hospital Vicente Corral Moscoso, 2015 - 2016 / Descriptive Research: Epidemiological Profile of the Pediatric Intensive Care Unit at Vicente Corral Moscoso Hospital, 2015 - 2016

INTRODUCCIÓN: La medicina intensiva pediátrica es una rama relativamente nueva dentro de la pediatría. En los últimos años gracias al desarrollo tecnológico y los avances en tratamientos médi-cos, se ha logrado disminuir la morbilidad y mortalidad en estas áreas críticas; sin embargo, existen complicaciones asociadas a la estancia prolongada. La mortalidad se ha correlacionado de forma inversa con la disponibilidad de cuidados intensivos, número de intensivistas pediátricos, número de camas y número de centros pediátricos de especialidad. El objetivo de este estudio fue determi-nar el perfil epidemiológico clínico de los pacientes ingresados en la Unidad de Cuidados Intensivos Pediátricos del Hospital Vicente Corral Moscoso, durante el periodo 2015-2016. MATERIALES Y MÉTODOS: Estudio descriptivo retrospectivo, el universo se constituyó de 386 pacientes ingresados en la unidad de cuidados intensivos pediátricos en los años 2015 y 2016, la información fue recolectada de las respectivas historias clínicas. Las variables estudiadas fueron: edad, sexo, mes y año de ingreso, diagnóstico, procedimientos utilizados, mortalidad y ocupación de camas. RESULTADOS:Se incluyeron 386 pacientes, 55.2% fueron varones. El promedio de edad fue 5.3 años. Las principales causas de ingreso fueron neumonía, trauma cráneo-encefálico, estatus epi-léptico y sepsis. El 50% recibió ventilación mecánica. La tasa de mortalidad fue de 17% y se asoció con falta de procedimiento quirúrgico (p= 0.026); nutrición parenteral (p= 0.023); inotrópicos y ven-tilación mecánica (p= <0.001). La estancia hospitalaria promedio fue de 6.2 días. El porcentaje de ocupación de camas fue del 92.6%. CONCLUSIONES: Con el fin de satisfacer las necesidades del creciente número de niños susceptibles de recibir cuidados críticos, cada país debería obtener datos epidemiológicos sobre de la prevalen-cia de las enfermedades que requieren cuidados intensivos pediátricos para implementar su infraes-tructura y ejecutar programas preventivos(AU)

BACKGROUND: Pediatric intensive medicine is a relatively new branch within pediatrics. In recent years, with the technological development and improvement in medical treatments, morbidity and mortality have been reduced; however, there are complications associated with prolonged hospitalization. Mortality has been inversely correlated with the availability of intensive care, number of pediatric intensivists, number of beds and number of specialty pediatric centers. The aim of this study was to determine the clinical epidemiological profile of patients admitted to the Pediatric Intensive Care Unit of the Hospital Vicente Corral Moscoso, during the period 2015 - 2016. METHODS: A retrospective descriptive study was performed; the universe included 386 patients admitted to the pediatric intensive care unit in 2015 and 2016; the information was collected from the respective medical records. The variables studied were: age, sex, month and year of admission, diagnosis, and procedures, mor-tality and bed occupancy. RESULTS: 386 patients were included, 55.2% were male. The average age was 5.3 years. The main causes of admission were pneumonia, cranioencephalic trauma, status epilepticus and sepsis. 50% received mecha-nical ventilation. The mortality rate was 17% and was associated with lack of surgical procedure (p= 0.026); parenteral nutrition (p= 0.023); inotropes and mechanical ventilation (p= <0.001). The average hospital stay was 6.2 days; the percentage of bed occupancy was 92.6%. CONCLUSIONS: In order to meet the needs of the growing number of children susceptible to critical care, each country should obtain epidemiological data on the prevalence of diseases requiring intensive pediatric care to implement its infrastructure and execute preventive programs.(AU)

Complement C3 and Autophagy Keep the ß Cell Alive.

Autophagy prevents pancreatic ß cell death during obesity, although the mechanism of autophagy activation in the ß cell has remained elusive. In this issue of Cell Metabolism, King et al. (2018) show that intracellular complement component C3 interacts with autophagy protein ATG16L1 and protects against ß cell death by stimulating autophagy.

Autophagy Regulates the Liver Clock and Glucose Metabolism by Degrading CRY1.

The circadian clock coordinates behavioral and circadian cues with availability and utilization of nutrients. Proteasomal degradation of clock repressors, such as cryptochrome (CRY)1, maintains periodicity. Whether macroautophagy, a quality control pathway, degrades circadian proteins remains unknown. Here we show that circadian proteins BMAL1, CLOCK, REV-ERBα, and CRY1 are lysosomal targets, and that macroautophagy affects the circadian clock by selectively degrading CRY1. Autophagic degradation of CRY1, an inhibitor of gluconeogenesis, occurs in a diurnal window when rodents rely on gluconeogenesis, suggesting that CRY1 degradation is time-imprinted to maintenance of blood glucose. High-fat feeding accelerates autophagic CRY1 degradation and contributes to obesity-associated hyperglycemia. CRY1 contains several light chain 3 (LC3)-interacting region (LIR) motifs, which facilitate the interaction of cargo proteins with the autophagosome marker LC3. Using mutational analyses, we identified two distinct LIRs on CRY1 that exert circadian glycemic control by regulating CRY1 degradation, revealing LIRs as potential targets for controlling hyperglycemia.

System-wide Benefits of Intermeal Fasting by Autophagy.

Autophagy failure is associated with metabolic insufficiency. Although caloric restriction (CR) extends healthspan, its adherence in humans is poor. We established an isocaloric twice-a-day (ITAD) feeding model wherein ITAD-fed mice consume the same food amount as ad libitum controls but at two short windows early and late in the diurnal cycle. We hypothesized that ITAD feeding will provide two intervals of intermeal fasting per circadian period and induce autophagy. We show that ITAD feeding modifies circadian autophagy and glucose/lipid metabolism that correlate with feeding-driven changes in circulating insulin. ITAD feeding decreases adiposity and, unlike CR, enhances muscle mass. ITAD feeding drives energy expenditure, lowers lipid levels, suppresses gluconeogenesis, and prevents age/obesity-associated metabolic defects. Using liver-, adipose-, myogenic-, and proopiomelanocortin neuron-specific autophagy-null mice, we mapped the contribution of tissue-specific autophagy to system-wide benefits of ITAD feeding. Our studies suggest that consuming two meals a day without CR could prevent the metabolic syndrome.

A Rat Immobilization Model Based on Cage Volume Reduction: A Physiological Model for Bed Rest?

Bed rest has been an established treatment in the past prescribed for critically illness or convalescing patients, in order to preserve their body metabolic resource, to prevent serious complications and to support their rapid path to recovery. However, it has been reported that prolonged bed rest can have detrimental consequences that may delay or prevent the recovery from clinical illness. In order to study disuse-induced changes in muscle and bone, as observed during prolonged bed rest in humans, an innovative new model of muscle disuse for rodents is presented. Basically, the animals are confined to a reduced space designed to restrict their locomotion movements and allow them to drink and eat easily, without generating physical stress. The animals were immobilized for either 7, 14, or 28 days. The immobilization procedure induced a significant decrease of food intake, both at 14 and 28 days of immobilization. The reduced food intake was not a consequence of a stress condition induced by the model since plasma corticosterone levels -an indicator of a stress response- were not altered following the immobilization period. The animals showed a significant decrease in soleus muscle mass, grip force and cross-sectional area (a measure of fiber size), together with a decrease in bone mineral density. The present model may potentially serve to investigate the effects of bed-rest in pathological states characterized by a catabolic condition, such as diabetes or cancer.

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy.

BACKGROUND: The effectiveness of drugs aimed at counteracting cancer cachexia is generally tested in pre-clinical rodent models, where only the tumour-induced alterations are taken into account, excluding the co-presence of anti-tumour molecules that could worsen the scenario and/or interfere with the treatment. METHODS: The aim of the present investigation has been to assess the efficacy of a multifactorial treatment, including formoterol and megestrol acetate, in cachectic tumour-bearing rats (Yoshida AH-130, a highly cachectic tumour) undergoing chemotherapy (sorafenib). RESULTS: Treatment of cachectic tumour-bearing rats with sorafenib (90 mg/kg) causes an important decrease in tumour cell content due to both reduced cell proliferation and increased apoptosis. As a consequence, animal survival significantly improves, while cachexia occurrence persists. Multi-factorial treatment using both formoterol and megestrol acetate is highly effective in preventing muscle wasting and has more powerful effects than the single formoterol administration. In addition, both physical activity and grip strength are significantly improved as compared with the untreated tumour-bearing animals. The effects of the multi-factorial treatment include increased food intake (likely due to megestrol acetate) and decreased protein degradation, as shown by the reduced expression of genes associated with both proteasome and calpain proteolytic systems. CONCLUSIONS: The combination of the two drugs proved to be a promising strategy for treating cancer cachexia in a pre-clinical setting that better resembles the human condition, thus providing a strong rationale for the use of such combination in clinical trials involving cachectic cancer patients.

Complete reversal of muscle wasting in experimental cancer cachexia: Additive effects of activin type II receptor inhibition and ß-2 agonist.

Formoterol is a highly potent ß2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of this investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the ß2-agonist formoterol in the cachectic Lewis lung carcinoma model. The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumor-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake in both control and tumor-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumor. In addition, it significantly reduced the number of metastasis. Concerning the mechanisms for the preservation of muscle mass during cachexia, the effects of formoterol and sActRIIB seemed to be additive, since formoterol reduced the rate of protein degradation (as measured in vitro as tyrosine release, using incubated isolated individual muscles) while sActRIIB only affected protein synthesis (as measured in vivo using tritiated phenylalanine). Formoterol also increased the rate of protein synthesis and this seemed to be favored by the presence of sActRIIB. Combining formoterol and sActRIIB seemed to be a very promising treatment for experimental cancer cachexia. Further studies in human patients are necessary and may lead to a highly effective treatment option for muscle wasting associated with cancer.

Combination of exercise training and erythropoietin prevents cancer-induced muscle alterations.

Cancer cachexia is a syndrome characterized by loss of skeletal muscle mass, inflammation, anorexia and anemia, contributing to patient fatigue and reduced quality of life. In addition to nutritional approaches, exercise training (EX) has been proposed as a suitable tool to manage cachexia. In the present work the effect of mild exercise training, coupled to erythropoietin (EPO) administration to prevent anemia, has been tested in tumor-bearing mice. In the C26 hosts, acute exercise does not prevent and even worsens muscle wasting. Such pattern is prevented by EPO co-administration or by the adoption of a chronic exercise protocol. EX and EPO co-treatment spares oxidative myofibers from atrophy and counteracts the oxidative to glycolytic shift, inducing PGC-1α. LLC hosts are responsive to exercise and their treatment with the EX-EPO combination prevents the loss of muscle strength and the onset of mitochondrial ultrastructural alterations, while increases muscle oxidative capacity and intracellular ATP content, likely depending on PGC-1α induction and mitophagy promotion. Consistently, muscle-specific PGC-1α overexpression prevents LLC-induced muscle atrophy and Atrogin-1 hyperexpression. Overall, the present data suggest that low intensisty exercise can be an effective tool to be included in combined therapeutic approaches against cancer cachexia, provided that anemia is coincidently treated in order to enhance the beneficial action of exercise.

Differences in food intake of tumour-bearing cachectic mice are associated with hypothalamic serotonin signalling.

BACKGROUND: Anorexia is a common symptom among cancer patients and contributes to malnutrition and strongly impinges on quality of life. Cancer-induced anorexia is thought to be caused by an inability of food intake-regulating systems in the hypothalamus to respond adequately to negative energy balance during tumour growth. Here, we show that this impaired response of food-intake control is likely to be mediated by altered serotonin signalling and by failure in post-transcriptional neuropeptide Y (NPY) regulation. METHODS: Two tumour cachectic mouse models with different food intake behaviours were used: a C26-colon adenocarcinoma model with increased food intake and a Lewis lung carcinoma model with decreased food intake. This contrast in food intake behaviour between tumour-bearing (TB) mice in response to growth of the two different tumours was used to distinguish between processes involved in cachexia and mechanisms that might be important in food intake regulation. The hypothalamus was used for transcriptomics (affymetrix chips). RESULTS: In both models, hypothalamic expression of orexigenic NPY was significantly higher compared with controls, suggesting that this change does not directly reflect food intake status but might be linked to negative energy balance in cachexia. Expression of genes involved in serotonin signalling showed to be different between C26-TB mice and Lewis lung carcinoma-TB mice and was inversely associated with food intake. In vitro, using hypothalamic cell lines, serotonin repressed neuronal hypothalamic NPY secretion while not affecting messenger NPY expression, suggesting that serotonin signalling can interfere with NPY synthesis, transport, or secretion. CONCLUSIONS: Altered serotonin signalling is associated with changes in food intake behaviour in cachectic TB mice. Serotonins' inhibitory effect on food intake under cancer cachectic conditions is probably via affecting the NPY system. Therefore, serotonin regulation might be a therapeutic target to prevent the development of cancer-induced eating disorders.

Distinct behaviour of sorafenib in experimental cachexia-inducing tumours: the role of STAT3.

The presence of a tumour is very often associated with wasting in the host, affecting both skeletal muscle and adipose tissue. In the present study we used sorafenib, a multi-kinase inhibitor with anti-tumour activity, in order to investigate the effects of chemotherapy on wasting. Three different experimental mouse tumour models were included: C26 colon carcinoma, B16 melanoma and Lewis lung carcinoma (LLC). The results obtained clearly show that sorafenib was effective in reducing tumour growth in LLC and B16 models, while it had no effect on C26. Interestingly, sorafenib treatment reduced the signs of muscle wasting and improved the physical activity in the LLC model and also in the C26, despite the absence of antineoplastic action in the latter. Our results discard a role for IL-6 in the action of sorafenib since the drug did not affect the levels of this cytokine. Conversely, sorafenib seems to act by influencing both STAT3 and ERK activity at muscle level, leading to reduced accumulation of Pax7 and atrogin-1. Sorafenib may interfere with muscle wasting by decreasing the activation of these signal transduction pathways.

Formoterol in the treatment of experimental cancer cachexia: effects on heart function.

BACKGROUND AND AIMS: Formoterol is a highly potent ß2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species, resulting in skeletal muscle hypertrophy. Previous studies carried out in our laboratory have shown that formoterol treatment in tumour-bearing animals resulted in an amelioration of muscle loss through different mechanisms that include muscle apoptosis and proteolysis. METHODS: The study presented involved rats bearing the Yoshida AH-130 ascites tumour model-which induces a high degree of cachexia-treated with the beta-2 agonist formoterol (0.3 mg/kg BW). RESULTS: The administration of formoterol to cachectic tumour-bearing rats resulted in a significant reduction of muscle weight loss. The treatment also increased lean body mass and body water. The treatment, however, did not influence heart weight, which was much decreased as a result of tumour burden. Untreated tumour-bearing rats showed important changes in parameters related with heart function:, left ventricle (LV) ejection fraction, fractional shortening, LV diameter and volume (diastolic) and LV stroke volume, LV mass and posterior wall thickness (PWT) (both systolic and diastolic). The administration of formoterol affected LV diameter and volume, LV stroke volume and LV mass. CONCLUSIONS: The results suggest that formoterol treatment, in addition to reducing muscle wasting, does not negatively alter heart function-in fact, some cardiac parameters are improved-in animals affected by cancer cachexia.

Cachexia: a problem of energetic inefficiency.

An alteration of energy balance is the immediate cause of the so-called cachexia. Although alterations of energy intake are often associated with cachexia, it has lately became clear that an increased energy expenditure is the main cause of wasting associated with different types of pathological conditions, such as cancer, infections or chronic heart failure among others. Different types of molecular mechanisms contribute to energy expenditure and, therefore, involuntary body weight loss; among them, adenosine triphosphate (ATP) consumption by sarcoplasmic reticulum Ca(2+) pumps could represent a key mechanism. In other cases, an increase in energy inefficiency will further contribute to energy imbalance.

A differential pattern of gene expression in skeletal muscle of tumor-bearing rats reveals dysregulation of excitation­contraction coupling together with additional muscle alterations.

INTRODUCTION: Cachexia is a wasting condition that manifests in several types of cancer. The main characteristic of this condition is a profound loss of muscle mass. METHODS: By using a microarray system, expression of several hundred genes was screened in skeletal muscle of rats bearing a cachexia-inducing tumor, the AH-130 Yoshida ascites hepatoma. This model induced a strong decrease in muscle mass in the tumor-bearing animals, as compared with their healthy counterparts. RESULTS: The results show important differences in gene expression in EDL skeletal muscle between tumor-bearing animals with cachexia and control animals. CONCLUSIONS: The differences observed pertain to genes related to intracellular calcium homeostasis and genes involved in the control of mitochondrial oxidative phosphorylation and protein turnover, both at the level of protein synthesis and proteolysis. Assessment of these differences may be a useful tool for the design of novel therapeutic strategies to fight this devastating syndrome.

Erythropoietin administration partially prevents adipose tissue loss in experimental cancer cachexia models.

Cancer-associated cachexia is characterized, among other symptoms, by a dramatic loss of both muscle and fat. In addition, the cachectic syndrome is often associated with anemia. The object of the present investigation was to assess the effects of erythropoietin (EPO) treatment on experimental cancer cachexia models. The results clearly show that, in addition to the improvement of the hematocrit, EPO treatment promoted a partial preservation of adipose tissue while exerting negligible effects on muscle loss. Administration of EPO to tumor-bearing animals resulted in a significant increase of lipoprotein lipase (LPL) activity in adipose tissue, suggesting that the treatment favored triacylglycerol (TAG) accumulation in the adipose tissue. In vitro experiments using both adipose tissue slices and 3T3-L1 adipocytes suggests that EPO is able to increase the lipogenic rate through the activation of its specific receptor (EPOR). This metabolic pathway, in addition to TAG uptake by LPL, may contribute to the beneficial effects of EPO on fat preservation in cancer cachexia.

Mitochondrial and sarcoplasmic reticulum abnormalities in cancer cachexia: altered energetic efficiency?

BACKGROUND: Cachexia is a wasting condition that manifests in several types of cancer, and the main characteristic is the profound loss of muscle mass. METHODS: The Yoshida AH-130 tumor model has been used and the samples have been analyzed using transmission electronic microscopy, real-time PCR and Western blot techniques. RESULTS: Using in vivo cancer cachectic model in rats, here we show that skeletal muscle loss is accompanied by fiber morphologic alterations such as mitochondrial disruption, dilatation of sarcoplasmic reticulum and apoptotic nuclei. Analyzing the expression of some factors related to proteolytic and thermogenic processes, we observed in tumor-bearing animals an increased expression of genes involved in proteolysis such as ubiquitin ligases Muscle Ring Finger 1 (MuRF-1) and Muscle Atrophy F-box protein (MAFBx). Moreover, an overexpression of both sarco/endoplasmic Ca(2+)-ATPase (SERCA1) and adenine nucleotide translocator (ANT1), both factors related to cellular energetic efficiency, was observed. Tumor burden also leads to a marked decreased in muscle ATP content. CONCLUSIONS: In addition to muscle proteolysis, other ATP-related pathways may have a key role in muscle wasting, both directly by increasing energetic inefficiency, and indirectly, by affecting the sarcoplasmic reticulum-mitochondrial assembly that is essential for muscle function and homeostasis. GENERAL SIGNIFICANCE: The present study reports profound morphological changes in cancer cachectic muscle, which are visualized mainly in alterations in sarcoplasmic reticulum and mitochondria. These alterations are linked to pathways that can account for energy inefficiency associated with cancer cachexia.