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Purpose: The CASC-IN score has been designed with two very clear objectives: first, as a means to quantitatively assess pre-cachexia in cancer patients, and second, as a tool to discriminate the patients where cachexia staging is relevant. From this point of view, the CASC-IN tool is tightly linked with the so-called CAchexia SCOre (CASCO) previously described1 and validated2 by our research team. The results presented here classify a population of cancer patients into non-cachectic, precachectic or cachectic. Patients and Methods: An observational prospective case-control study has been performed and a total of 179 carcinoma patients and 117 age-matched control subjects were included. All the participants in the study were recruited at the Department of Medical Oncology (University of Cagliari, Cagliari, Italy) from June 2011 to September 2014. 179. Results: Using the mentioned patient's groups in the cancer group, --patients affected by a different tumour types-- the frequencies observed have been non-cachectic: 58 (32.4%), pre-cachectic: 7 (3.9%) and cachectic: 114 (63.7%). Conclusion: It is concluded that CASC-IN can be satisfactorily used for both assessing cachectic and precachectic cancer patients. It constitutes the only available tool for the classification of pre-cachectic patients.

Alterations in amino acid and protein metabolism particularly in skeletal muscle are a key feature of cancer that contributes to the cachexia syndrome. Thus, skeletal muscle protein turnover is characterized by an exacerbated rate of protein degradation, promoted by an activation of different proteolytic systems that include the ubiquitin-proteasome and the autophagic-lysosomal pathways. These changes are promoted by both hormonal alterations and inflammatory mediators released as a result of the systemic inflammatory response induced by the tumor. Other events, such as alterations in the rate of myogenesis/apoptosis and decreased regeneration potential also affect skeletal muscle in patients with cancer. Mitochondrial dysfunction also contributes to changes in skeletal muscle metabolism and further contributes to the exacerbation of the cancer-wasting syndrome. Different inflammatory mediators either released by the tumor or by the patient's healthy cells are responsible for the activation of these catabolic processes that take place in skeletal muscle and in other tissues/organs, such as liver or adipose tissues. Indeed, white adipose tissue is also subject to extensive wasting and 'browning' of some of the white adipocytes into beige cells; therefore increasing the energetic inefficiency of the patient with cancer. Recently, an interest in the role of micromRNAs either free or transported into exosomes has been related to the events that take place in white adipose tissue during cancer cachexia.

The aim of this article is to review the metabolic background of the cachectic syndrome and to analyze the recent therapeutic approaches designed to counteract the wasting suffered by the cancer patient with cachexia.The main changes associated with the development of this multiorganic syndrome are glucose intolerance, fat depletion and muscle protein hypercatabolism. Among the most promising approaches for the treatment of cachexia include the use of ghrelin agonists, beta-blockers, beta-adrenergic agonists, androgen receptor agonists and antimyostatin peptides. The multitargeted approach seems essential in these treatments, which should include the combination of both nutritional support, drugs and a suitable program of physical exercise, in order to ameliorate both anorexia and the metabolic changes associated with cachexia. In addition, another very important aspect for the design of clinical trials for the treatment of cancer cachexia is to staging cancer patients in relation with the degree of cachexia, in order to start as early as possible, this triple approach in the course of the disease, even before weight loss can be detected.Cancer cachexia has two main components: anorexia and metabolic alterations and both have to be taken into consideration for the treatment of the syndrome.

Silvia Busquets,1,2 Marta Castillejo,1 Queralt Jové,1 Baptiste Jude,3 Patricia Mejías,1 Francisco J López-Soriano,1,2 Josep M Argilés1,2 1Cancer Research Group, Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; 2Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain; 3Laboratoire de Physiologie - EA 4324 ORPHY, IBSAM, Université de Bretagne Occidentale, Brest, FranceCorrespondence: Silvia BusquetsCancer Research Group, Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Diagonal 643, Barcelona, 08028, SpainTel +34-934021002Fax +34-934021559Email silviabusquets@ub.eduBackground: During cancer cachexia, both skeletal muscle and adipose tissue losses take place. The use of β 2-agonists, formoterol in particular, has proven to be very successful in the treatment of the syndrome in pre-clinical models. The object of the present research was to study the effects of a combination of formoterol and dantrolene, an inhibitor of the ryanodine receptor 1 (RyR1), on body weight loss and cachexia in tumour-bearing animals.Methods: Rats were separated into two groups: controls (C) and tumour bearing (TB). TB group was further subdivided into four groups: untreated (saline as a vehicle), treated with Formoterol (TF) (0,3 mg/kg body weight in saline, subcutaneous (s.c.), daily), treated with Dantrolene (TD) (5 mg/kg body weight in saline, subcutaneous (s.c.), daily), and double-treated treated (TFD) with Formoterol (0,3 mg/kg body weight, subcutaneous (s.c.), daily) and Dantrolene (5 mg/kg body weight, subcutaneous (s.c.), daily). 7 days after tumour transplantation, muscle weight, grip force, and total physical activity were specified in all experimental groups.Results: While formoterol had, as in previous studies, a very positive effect in reducing muscle weight loss, dantrolene had no effects, neither on skeletal muscle nor on any of the parameters studied. Finally, the combined treatment (formoterol and dantrolene) did not result in any significant benefit on the action of the β 2-agonist.Conclusion: It is concluded that, in the preclinical cachectic model used, no synergy exists between β 2-agonist treatment and the blockade of sarcoplasmic-calcium flow.Keywords: cancer cachexia, skeletal muscle, dantrolene, formoterol, calcium, ryanodine receptor 1

The aim of this study was to investigate the effect of cachexia induced by AH-130 cells on gastrointestinal motility in rats. We evaluated food intake, body weight variation, cachexia index, gastric emptying and in vitro gastric responsiveness of control or cachexia rats. In addition, we evaluated the effect of pretreatment with atenolol (20 mg/kg, p.o.), win 55,212-2 (2 mg/kg, s.c.) or subdiaphragmatic vagotomy on the effects found. Atenolol prevented (P 0.05) the acceleration of gastric emptying (area under the curve, AUC, 20360.17 ± 1970.9 vs. 12579.2 ± 785.4 μg/min/ml), and increased gastric responsiveness to carbachol (CCh) stimulation in cachectic rats compared to control groups (CCh-6M: 63.2 ± 5.5% vs. 46.5 ± 5.7%). Vagotomy prevented (P 0.05) increase in gastric emptying acceleration (AUC 20360.17 ± 1970.9 vs. 13414.0 ± 1112.9 μg/min/ml) and caused greater in vitro gastric responsiveness of cachectic compared to control rats (CCh-6M: 63.2 ± 5.5% vs. 31.2 ± 4.7%). Win 55,212-2 attenuated the cachexia index (38.5 ± 2.1% vs. 25.8 ± 2.7%), as well as significantly (P 0.05) preventing increase in gastric emptying (AUC 20360.17 ± 1970.9 vs. 10965.4 ± 1392.3 μg/min/ml) and gastric responsiveness compared to control groups (CCh-6M: 63.2 ± 5.5% vs. 38.2 ± 3.9%). Cachexia accelerated gastric emptying and increased gastric responsiveness in vitro. These phenomena were prevented by subdiaphragmatic vagotomy and by atenolol and win 55,212-2 treatments, showing vagal involvement of β

Muscle wasting is associated with chronic diseases and cancer. Elucidation of the biological mechanism involved in the process of muscle mass loss and cachexia may help identify therapeutic targets. We hypothesized that l-carnitine treatment may differentially revert muscle fiber atrophy and other structural alterations in slow- and fast-twitch limb muscles of rats bearing the Yoshida ascites hepatoma. In soleus and gastrocnemius of tumor-bearing rats (108 AH-130 Yoshida ascites hepatoma cells inoculated intraperitoneally) with and without treatment with l-carnitine (1 g/kg body weight for 7 days, intragastric), food intake, body and muscle weights, fiber typing and morphometry, morphological features, redox balance, autophagy and proteolytic, and signaling markers were explored. Levels of carnitine palmitoyl transferase were also measured in all the study muscles. l-Carnitine treatment ameliorated the atrophy of both slow- and fast-twitch fibers (gastrocnemius particularly), muscle structural alterations (both muscles), and attenuated oxidative stress, proteolytic and signaling markers (gastrocnemius). Despite that carnitine palmitoyl transferase-1 levels increased in both muscle types in a similar fashion, l-carnitine ameliorated muscle atrophy and proteolysis in a muscle-specific manner in cancer-induced cachexia. These data reveal the need to study muscles of different fiber type composition and function to better understand whereby l-carnitine exerts its beneficial effects on the myofibers in muscle wasting processes. These findings also have potential clinical implications, since combinations of various exercise and muscle training modalities with l-carnitine should be specifically targeted for the muscle groups to be trained. The current research has been supported by Instituto de Salud Carlos‐III, contract grant numbers, CIBERES, FIS 14/00713 (FEDER), FIS 18/00075 (FEDER), Spanish Ministry of Science and Innovation, contract grant number SAF 2011–26091, Spanish Respiratory Society (SEPAR), contract grant numbers, SEPAR 2016, SEPAR 2018, Catalan Foundation of Pulmonology (FUCAP), contract grant numbers, FUCAP 2016.

Background: The aim of the present investigation was to evaluate the effects of the administration of a juice containing essential nutrients (marine omega-3 fatty acids: EPA and DHA, a polyphenolrich juice, vitamin D3, essential amino acids and dietary fibre) (CAX) and a juice also enriched with curcumin (CUR), alone or in combination with a chemotherapeutic agent ( sorafenib ) in a mouse cancer cachexia model. Methods: Administration of CAX and CUR in the form of jellified pellets to mice bearing the Lewis lung carcinoma. Results: Administration of CAX and CUR in the form of jellified pellets to mice bearing the Lewis lung carcinoma resulted in a 12 and 18% reduction in tumour weight, respectively, but no additive effect in combination with sorafenib was seen. No effects on metastases measurements were observed. In spite of the reduction of the primary tumour, the chemotherapy treatment alone did not result in any changes in body weight. Conversely, in combination with sorafenib, both juices had an important effect on body weight loss. CUR also had an effect without chemotherapy. Concerning muscle weight, tibialis muscle mass was increased as a result of CAX and CUR treatment. Sorafenib-treated mice had a tendency towards larger tibialis muscles, this tendency being clearly significant when CAX was administered in combination with chemotherapy. In sorafenib-treated mice, juice treatment --either CAX or CUR-- resulted in a tendency to an increase in grip force. Conclusions: It is concluded that administration of omega-3/protein and omega-3/protein/curcumin-enriched fruit juices may have beneficial effects on muscle wasting and could be part of a multi-modal therapy for cancer cachexia.

Cancer cachexia is a multifactorial syndrome characterized by anorexia, weight loss and muscle wasting that impairs patients' quality of life and survival. Aim of this work was to evaluate the impact of either autophagy inhibition (knocking down beclin-1) or promotion (overexpressing TP53INP2/DOR) on cancer-induced muscle wasting. In C26 tumor-bearing mice, stress-induced autophagy inhibition was unable to rescue the loss of muscle mass and worsened muscle morphology. Treating C26-bearing mice with formoterol, a selective β2-agonist, muscle sparing was paralleled by reduced static autophagy markers, although the flux was maintained. Conversely, the stimulation of muscle autophagy exacerbated muscle atrophy in tumor-bearing mice. TP53INP2 further promoted atrogene expression and suppressed mitochondrial dynamics-related genes. Excessive autophagy might impair mitochondrial function through mitophagy. Consistently, tumor-induced mitochondrial dysfunction was detected by reduced ex vivo muscle fiber respiration. Overall, the results evoke a central role for muscle autophagy in cancer-induced muscle wasting.

Cancer cachexia has two main components: anorexia and metabolic alterations. The main changes associated with the development of this multi-organic syndrome are glucose intolerance, fat depletion and muscle protein hypercatabolism. The aim of this paper is to review the more recent therapeutic approaches designed to counteract the wasting suffered by the cancer patient with cachexia. Among the most promising approaches we can include the use of ghrelin agonists, beta-blockers, beta-adrenergic agonists, androgen receptor agonists and anti-myostatin peptides. The multi-targeted approach seems essential in these treatments, which should include the combination of both nutritional support, drugs and a suitable program of physical exercise, in order to ameliorate both anorexia and the metabolic changes associated with cachexia. In addition, another very important and crucial aspect to be taken into consideration in the design of clinical trials for the treatment of cancer cachexia is to staging cancer patients in relation with the degree of cachexia, in order to start as early as possible this triple approach in the course of the disease, even before the weight loss can be detected.

Formoterol is a highly potent β2-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 β2-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.

Cachexia is a systemic condition that occurs during many neoplastic diseases, such as cancer. Cachexia in cancer is characterized by loss of body weight and muscle and by adipose tissue wasting and systemic inflammation. Cancer cachexia is often associated with anorexia and increased energy expenditure. Even though the cachectic condition severely affects skeletal muscle, a tissue that accounts for ~40% of total body weight, it represents a multi-organ syndrome that involves tissues and organs such as white adipose tissue, brown adipose tissue, bone, brain, liver, gut and heart. Indeed, evidence suggests that non-muscle tissues and organs, as well as tumour tissues, secrete soluble factors that act on skeletal muscle to promote wasting. In addition, muscle tissue also releases various factors that can interact with the metabolism of other tissues during cancer. In this Review, we examine the effect of non-muscle tissues and inter-tissue communication in cancer cachexia and discuss studies aimed at developing novel therapeutic strategies for the condition. Cachexia is a multi-organ syndrome associated with cancer. In this Review, Josep M. Argiles and colleagues discuss the role of different tissues and organs in cancer cachexia and examine studies that investigate the development of novel therapeutics for the condition.

Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Beta-adrenoceptors attenuate muscle wasting. We hypothesized that specific muscle atrophy signaling pathways and altered metabolism may be attenuated in cancer cachectic animals receiving treatment with the beta2 agonist formoterol. In diaphragm and gastrocnemius of tumor-bearing rats (intraperitoneal inoculum, 108 AH-130 Yoshida ascites hepatoma cells, 7-day study period) with and without treatment with formoterol (0.3 mg/kg body weight/day/7days, subcutaneous), atrophy signaling pathways (NF-κB, MAPK, FoxO), proteolytic markers (ligases, proteasome, ubiquitination), autophagy markers (p62, beclin-1, LC3), myostatin, apoptosis, muscle metabolism markers, and muscle structure features were analyzed (immunoblotting, immunohistochemistry). In diaphragm and gastrocnemius of cancer cachectic rats, fiber sizes were reduced, levels of structural alterations, atrophy signaling pathways, proteasome content, protein ubiquitination, autophagy, and myostatin were increased, while those of regenerative and metabolic markers (myoD, mTOR, AKT, and PGC-1alpha) were decreased. Formoterol treatment attenuated such alterations in both muscles. Muscle wasting in this rat model of cancer-induced cachexia was characterized by induction of significant structural alterations, atrophy signaling pathways, proteasome activity, apoptotic and autophagy markers, and myostatin, along with a significant decline in the expression of muscle regenerative and metabolic markers. Treatment of the cachectic rats with formoterol partly attenuated the structural alterations and atrophy signaling, while improving other molecular perturbations similarly in both respiratory and limb muscles. The results reported in this study have relevant therapeutic implications as they showed beneficial effects of the beta2 agonist formoterol in the cachectic muscles through several key biological pathways. The authors are thankful to Dr. Ester Puig-Vilanova for her technical assistance with part of the biological experiments and to Mr. Xavier Duran for his support with all the statistical analyses and study design. The current research has been supported by Instituto de Salud Carlos-III, contract grant numbers, CIBERES, FIS 14/00713 (FEDER); Spanish Ministry of Science and Innovation, contract grant number SAF 2011-26091; Spanish Respiratory Society (SEPAR), contract grant numbers, SEPAR 2013 and SEPAR 2016; Catalan Foundation of Pulmonology (FUCAP), contract grant numbers, FUCAP 2011, FUCAP 2012, and 2016.

Background: Type 2 Diabetes Mellitus affects more than 350 million people worldwide. This metabolic disorder is characterized by insulin resistance, β-cell dysfunction and elevated hepatic glucose output. Patients with diabetes are hospitalized frequently (3-fold greater) and with longer admissions (30% longer) than the non-diabetic subjects. The aim of the study was to investigate the impact of bed rest on the metabolic changes in type II diabetes mellitus, with particular interest in skeletal muscle mass and function and metabolism. Methods: 13wk old male Zucker diabetic fatty (ZDF) rats were randomly divided into two groups: control (ZDF-Con) and cage-immobilized animals (ZDF-Cage) for 28 consecutive days in a space-restricted cage. Results: The Area Under the Curve (AUC) values for plasma glucose concentration in ZDF-Cage rats were significantly increased (approximately 4-fold as compared with ZDF-Con rats). GLUT4 gene expression in red soleus muscle of ZDF-Cage animals was reduced 2.5-fold in comparison with ZDF–Con rats. Although no apparent changes were observed either in fasting plasma glucose or insulin levels, a trend towards an increase in the HOMA-IR index and decreased levels of plasma adiponectin (-30%) were observed in ZDF-Cage animals. Moreover, ZDF-Cage rats did not lose muscle mass and force but performed a reduced total physical activity level (-22%). Conclusions: The present study results suggests that 28 days of immobilization --in a space-restriction model-- significantly impaired glucose tolerance with concomitant reduced plasmatic adiponectin levels and GLUT-4 expression in soleus muscle of type 2 diabetic rats.

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.

PURPOSE OF REVIEW The aim of the present review is to examine the impact of mitochondrial dysfunction in cancer cachexia. RECENT FINDINGS Oxidative pathways are altered in this tissue during muscle wasting and this seems to be a consequence of mitochondrial abnormalities that include altered morphology and function, decreased ATP synthesis and uncoupling. SUMMARY An alteration of energy balance is the immediate cause of cachexia. Both alterations in energy intake and expenditure are responsible for the wasting syndrome associated with different types of pathological conditions, such as cancer. Different types of molecular mechanisms contribute to energy expenditure and, therefore, involuntary body weight loss, one of which is mitochondrial dysfunction.

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.MethodsTwo 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).ResultsIn 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.ConclusionsAltered 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.

Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Beta-adrenoceptors attenuate muscle wasting. We hypothesized that specific muscle atrophy signaling pathways and altered metabolism may be attenuated in cancer cachectic animals receiving treatment with the beta

Anorexia and metabolic alterations are the main components of the cachectic syndrome. Glucose intolerance, fat depletion, muscle protein catabolism and other alterations are involved in the development of cancer cachexia, a multi-organ syndrome. Nutritional approach strategies are not satisfactory in reversing the cachectic syndrome. The aim of the present review is to deal with the recent therapeutic targeted approaches that have been designed to fight and counteract wasting in cancer patients. Indeed, some promising targeted therapeutic approaches include ghrelin agonists, selective androgen receptor agonists, β-blockers and antimyostatin peptides. However, a multi-targeted approach seems absolutely essential to treat patients affected by cancer cachexia. This approach should not only involve combinations of drugs but also nutrition and an adequate program of physical exercise, factors that may lead to a synergy, essential to overcome the syndrome. This may efficiently reverse the metabolic changes described above and, at the same time, ameliorate the anorexia. Defining this therapeutic combination of drugs/nutrients/exercise is an exciting project that will stimulate many scientific efforts. Other aspects that will, no doubt, be very important for successful treatment of cancer wasting will be an optimized design of future clinical trials, together with a protocol for staging cancer patients in relation to their degree of cachexia. This will permit that nutritional/metabolic/pharmacological support can be started early in the course of the disease, before severe weight loss occurs. Indeed, timing is crucial and has to be taken very seriously when applying the therapeutic approach.

The CAchexia SCOre (CASCO) was described as a tool for the staging of cachectic cancer patients. The aim of this study is to show the metric properties of CASCO in order to classify cachectic cancer patients into three different groups, which are associated with a numerical scoring. The final aim was to clinically validate CASCO for its use in the classification of cachectic cancer patients in clinical practice. We carried out a case -control study that enrolled prospectively 186 cancer patients and 95 age-matched controls. The score includes five components: (1) body weight loss and composition, (2) inflammation/metabolic disturbances/immunosuppression, (3) physical performance, (4) anorexia, and (5) quality of life. The present study provides clinical validation for the use of the score. In order to show the metric properties of CASCO, three different groups of cachectic cancer patients were established according to the results obtained with the statistical approach used: mild cachexia (15 ≤ × ≤ 28), moderate cachexia (29 ≤ × ≤ 46), and severe cachexia (47 ≤ × ≤ 100). In addition, a simplified version of CASCO, MiniCASCO (MCASCO), was also presented and it contributes as a valid and easy-to-use tool for cachexia staging. Significant statistically correlations were found between CASCO and other validated indexes such as Eastern Cooperative Oncology Group (ECOG) and the subjective diagnosis of cachexia by specialized oncologists. A very significant estimated correlation between CASCO and MCASCO was found that suggests that MCASCO might constitute an easy and valid tool for the staging of the cachectic cancer patients. CASCO and MCASCO provide a new tool for the quantitative staging of cachectic cancer patients with a clear advantage over previous classifications.

Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Therapeutic options are still scarce. We hypothesized that cachexia-induced muscle oxidative stress may be attenuated in response to treatment with beta2-adrenoceptor-selective agonist formoterol in rats. In diaphragm and gastrocnemius of tumor-bearing rats (108 AH-130 Yoshida ascites hepatoma cells inoculated intraperitoneally) with and without treatment with formoterol (0.3 mg/kg body weight/day for seven days, daily subcutaneous injection), redox balance (protein oxidation and nitration and antioxidants) and muscle proteins (1-dimensional immunoblots), carbonylated proteins (2-dimensional immunoblots), inflammatory cells (immunohistochemistry), and mitochondrial respiratory chain (MRC) complex activities were explored. In the gastrocnemius, but not the diaphragm, of cancer cachectic rats compared to the controls, protein oxidation and nitration levels were increased, several functional and structural proteins were carbonylated, and in both study muscles, myosin content was reduced, inflammatory cell counts were greater, while no significant differences were seen in MRC complex activities (I, II, and IV). Treatment of cachectic rats with formoterol attenuated all the events in both respiratory and limb muscles. In this in vivo model of cancer-cachectic rats, the diaphragm is more resistant to oxidative stress. Formoterol treatment attenuated the rise in oxidative stress in the limb muscles, inflammatory cell infiltration, and the loss of myosin content seen in both study muscles, whereas no effects were observed in the MRC complex activities. These findings have therapeutic implications as they demonstrate beneficial effects of the beta2 agonist through decreased protein oxidation and inflammation in cachectic muscles, especially the gastrocnemius. The study has been funded by Instituto de Salud Carlos-III, contract grant numbers, CIBERES, FIS 14/00713, Catalan Foundation of Pulmonology (FUCAP), contract grant numbers, FUCAP 2011, FUCAP 2012, and FUCAP 2016, Spanish Respiratory Society (SEPAR) 2016, and Spanish Ministry of Science and Innovation, contract grant number SAF 2011-26091. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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.

Background and aims Formoterol is a highly potent β2-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.

According to a recent consensus, cachexia is a complex metabolic syndrome associated with underlying illness and characterised by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss. Cachexia occurs in the majority of terminal cancer patients and it is responsible for the deaths of 22% of cancer patients. Although body weight is, indeed, an important factor to be taken into consideration in any cachexia treatment, body composition, physical performance and quality of life should be monitored. From the results presented here, one can speculate that a single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful. The objectives of any therapeutical combination are two: an anticatabolic aim directed towards both fat and muscle catabolism and an anabolic objective leading to the synthesis of macromolecules such as contractile proteins.

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.

International audience; Approximately half of all cancer patients present with cachexia, a condition in which disease-associated metabolic changes lead to a severe loss of skeletal muscle mass. Working toward an integrated and mechanistic view of cancer cachexia, we investigated the hypothesis that cancer promotes mitochondrial uncoupling in skeletal muscle. We subjected mice to in vivo phosphorous-31 nuclear magnetic resonance (31P NMR) spectroscopy and subjected murine skeletal muscle samples to gas chromatography/mass spectrometry (GC/MS). The mice used in both experiments were Lewis lung carcinoma models of cancer cachexia. A novel 'fragmented mass isotopomer' approach was used in our dynamic analysis of 13C mass isotopomer data. Our 31P NMR and GC/MS results indicated that the adenosine triphosphate (ATP) synthesis rate and tricarboxylic acid (TCA) cycle flux were reduced by 49% and 22%, respectively, in the cancer-bearing mice (p

Summary Background & aims Tumour growth is associated with weight loss resulting from both adipose and muscle wasting. Methods Administration of l -carnitine (1 g/kg body weight) to rats bearing the AH-130 Yoshida ascites hepatoma, a highly cachectic rat tumour. Results The treatment results in a significant improvement of food intake and in muscle weight (gastrocnemius, EDL and soleus). These beneficial effects are directly related to improved physical performance (total physical activity, mean movement velocity and total travelled distance). Administration of l -carnitine decreases proteasome activity and the expression of genes related with this activity, such as ubiquitin, C8 proteasome subunit and MuRF-1. Interestingly, l -carnitine treatment also decreases caspase-3 mRNA content therefore suggesting a modulation of apoptosis. Moreover, addition of 50 μM of l -carnitine to isolated EDL muscles results in a significant decrease in the proteolytic rate suggesting a direct effect. Conclusions It can be concluded that l -carnitine supplementation may be a good approach for a multi-targeted therapy for the treatment of cancer-related cachexia.

Muscle wasting—together with body weight loss—is perhaps the most prominent characteristic of cancer cachexia. Loss of contractile muscle protein is due to different factors that include a decrease in protein synthesis together with an important activation of protein degradation. The breakdown of protein is triggered by both tumoral and inflammatory mediators through a complex intracellular network of signals that lead to the activation of the different proteolytic systems, including the ubiquitin-dependent proteolytic system, together with lysosomal and calcium-dependent proteases. In addition to changes in protein kinetics, an increased rate of apoptosis together with altered regeneration capacity also influences muscle wasting. Different approaches to counteract the changes in protein metabolism observed in the cachectic patient may contribute to improve the quality of life and, possibly, survival of cachectic cancer patients.

Formoterol is a highly potent β2-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 β2-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.

Summary Background & aims Cachexia is a multi-organic syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting and inflammation, being often associated with anorexia. The aim of the present investigation was to study the effects of megestrol acetate (MA) on the rate of leucine incorporation into muscle tissue and on the uptake of AIB (a non-metabolizable analogue of alanine) in both skeletal muscle and liver tissue. Methods The effects of MA (100 mg/kg) were tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). Tissue amino acid uptake was assessed by means of the alanine analogue α-amino-3H-isobutyrate (AIB). 14C-leucine oxidation and tissue protein incorporation were also determined. Results Administration of MA to tumour-bearing rats resulted in an important reversal of the muscle wasting process, as reflected by individual muscle weights. Treatment with the progestogen resulted in an increased AIB uptake together with an increased leucine incorporation in skeletal muscle. MA treatment significantly decreased AIB uptake by the liver. Conclusions MA treatment results in both a significant increased uptake of neutral amino acids (AIB) by skeletal muscle and a significant incorporation of the branched-chain amino acid leucine into muscle protein, indicating a clear anabolic action of the drug on muscle tissue.

Cancer cachexia is a complex syndrome characterized by inflammation, body weight loss, muscle, and adipose tissue wasting that is responsible for the death of a considerable percentage of cancer patients. In addition, during cachexia muscle strength and endurance are dramatically reduced, limiting the ability to perform daily activities and severely affecting the patient’s quality of life. Different studies have emphasized that a single therapy may not be completely successful in the treatment of cachexia. Beyond pharmacological strategies, exercise training has been suggested as a promising countermeasure to prevent cachexia, in order to restore both strength and endurance, depending on the type of exercise. Unfortunately, a small number of studies, in both clinical and experimental settings, have been performed to date. Moreover, when considering exercise in cancer, several factors have to be taken into consideration, in particular those alterations that could limit the capacity to perform exercise and consequently the resulting beneficial or detrimental effects. This editorial is aimed at stimulating the debate on the suitability of including exercise training in a multi-functional approach against cachexia taking into consideration both limitations and advantages.

The main aim of the present review is to summarize and evaluate the different molecular mechanisms and catabolic mediators (mainly cytokines) involved in cancer cachexia since they may represent targets for future promising clinical investigations.

Proteolysis in skeletal muscle is mainly carried out by the activity of the ubiquitin-dependent proteolytic system. For the study of protein degradation through the ubiquitin-proteasome pathway, we used a model of hyperthermia in murine myotubes. In C2C12 cells, hyperthermia (41°C) induced a significant increase in both the rate of protein synthesis (18%) and degradation (51%). Interestingly, the addition of the β(2) -adrenoceptor agonist formoterol resulted in a significant decrease in protein degradation (21%) without affecting protein synthesis. The decrease in proteolytic rate was associated with decreases in gene expression of the different components of the ubiquitin-dependent proteolytic system. The effects of the β(2) -agonist on protein degradation were dependent exclusively on cAMP formation, because inhibition of adenylyl cyclase completely abolished the effects of formoterol on protein degradation. It can be concluded that hyperthermia is a suitable model for studying the anti-proteolytic potential of drugs used in the treatment of muscle wasting.

PURPOSE: The development of cancer cachexia is the most common manifestation of advanced malignant disease. METHOD: The effects on muscle regeneration of β2�adrenoceptor agonist formoterol (0.3 mg/kg) were tested in cachectic tumourbearing rats (Yoshida AH�130 ascit es hepatoma). RESULTS: Administration of formoterol results in a significant increase in the mass and protein content of tibialis muscle in tumourbearin grats. This increase is associated with a decreased myogenin mRNA content together with an increased Pax�7 gene expression. Bupivacaine treatment by local injection results in an important reduction in tibialis weight together with significant increases in Pax�7, myogenin and MyoD gene expression. Formoterol treatment in bupivacainetreated rats results in significant increases in Pax�7 together with significant decreases in myogenin mRNA content, suggesting that this β2�agonist is favouring muscle regeneration by stimulating the proliferation of satellite cells. Altogether, the data reinforce the potential role of formoterol in the treatment of muscle wasting diseases.

Cancer cachexia occurs in the majority of cancer patients before death, and it is responsible for the death of 22% of cancer patients. One of the most relevant characteristics of cachexia is that of asthenia, which reflects significant muscle wasting noted in cachectic cancer patients The aim of the present study was to assess whether the β(2)-adrenergic agonist formoterol is associated with an improvement in physiological parameters such as grip force and total physical activity in cachetic rats. Administration of the β(2)-agonist formoterol (0.3 mg/kg for 7 days) in rats bearing Yoshida AH-130 ascites hepatoma tumors, a model which induces a strong loss of both body and muscle weight, resulted in a significant reversal of the muscle wasting process, as reflected by individual muscle weights. The anti-wasting effects of the drug were also observed in terms of total physical activity and grip force, thus resulting in an improvement in physical performance in cachectic tumor-bearing rats.

Summary Background & aims Cachexia is a multiorganic syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting and inflammation, being often associated with anorexia. The aim of the present investigation was to examine the effect of megestrol acetate (MA) in cachectic tumour-bearing animals analyzing changes in muscle proteolysis and in parameters related with quality of life. Methods The effects of MA (100 mg/kg) were tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). Results Administration of MA to tumour-bearing rats resulted in an important reversal of the muscle wasting process, as reflected by individual muscle weights. MA also decreased the rate of protein degradation in incubated isolated skeletal muscles. Real-time PCR analysis revealed that MA treatment resulted in a decrease in ubiquitin, E2 and atrogin-1 mRNA content in muscles, therefore suggesting that the main anti-proteolytic action of the drug may be based on an inhibition of the ATP-ubiquitin-dependent proteolytic system. The drug also improves appetite, weight loss, total physical activity and grip force. Conclusions The results indicate that treatment with megestrol acetate increases appetite, weight loss, physical performance and muscle force in tumour-bearing rats suggesting that MA is a good candidate for muscle wasting treatment.

The hypothesis we tested was that administering corticotropin-releasing factor receptor agonists preserves muscle mass during cancer that is related to changes in tissue gene expression. cDNA microarrays were used to compare mRNAs from muscle and adipose tissues of non-treated and agonist-treated tumor-bearing rats. In muscle of non-tumor-bearing agonist-treated animals we observed decreased expression of genes associated with fatty acid uptake and esterification. In tumor-bearing animals, CRF2R agonist administration produced decreased mRNA content of the atrogene lipin-1. In white adipose tissue, agonist treatment of non-tumor-bearing animals induced genes typically related to muscle structure and function. The fact that this treatment decreased expression of atrogenes could have clinical application. In addition, agonist treatment changed the gene pattern of adipose tissue to render it similar to that of skeletal muscle; thus, treatment with this agonist alters the gene pattern to what could be called "muscularization of white adipose tissue."

In fast- and slow-twitch limb and heart muscles of cachectic rats, redox balance and muscle structure were explored. The nature of the oxidatively modified proteins also was identified in these muscles. Reactive carbonyls, hydroxynonenal (HNE)- and malondialdehyde (MDA)-protein adducts, and antioxidant enzyme levels were determined in limb and heart muscles of cachectic (7 days after inoculation of Yoshida AH-130 ascites hepatoma) and control rats. Moreover, carbonylated proteins were identified (proteomics), and fiber-type composition evaluated (morphometry) in these muscles. In cachectic rats, compared with the controls: (a) HNE- and MDA-protein adducts levels were greater in gastrocnemius, tibialis anterior, soleus, and heart; (b) in the gastrocnemius, type II fiber size was reduced, and the intensity of carbonylated protein immunostaining was significantly greater in these fibers; and (c) proteins involved in glycolysis, ATP production and distribution, carbon dioxide hydration, muscle contraction, and mitochondrial metabolism were significantly more carbonylated in limb and heart muscles. Cancer cachexia alters redox balance in fast- and slow-twitch limb and heart muscles of rats, inducing increased oxidative modifications of key proteins involved in muscle structure and function. Additionally, it induces a reduction in type II fiber size in the gastrocnemius, which is associated with increased protein oxidation.

Previous studies have demonstrated an effect of corticotropin-releasing factor 2 receptor (CRF2R) agonists in the maintenance of skeletal muscle mass. The aim of this study was to evaluate the effects of a CRF2R agonist in preserving skeletal muscle in a mouse cachexia model. Implantation of a fast-growing tumor to mice (Lewis lung carcinoma) resulted in a clear cachectic state characterized by a profound muscle wasting. We found that administration of a CRF2R agonist (PG-873637) at 100 microg/kg/day by means of osmotic minipumps to tumor-bearing mice resulted in beneficial effects on muscle weight loss. Thus, muscle loss was partially reversed by the CRF2R agonist at different stages of tumor growth (at day 14 after tumor inoculation: 12% in tibialis posterior; 9% in gastrocnemius; and 48% in soleus). Moreover, the CRF2R agonist significantly reduced both the number of metastases and their mass (at day 19 after tumor inoculation: 66% and 61%, respectively). These data suggest a potentially beneficial effect of the CRF2R agonist in preserving skeletal muscle during cancer cachexia and open a line of research for the development of new therapeutic approaches for the treatment of muscle wasting associated with cancer.