Review

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Developing models for cachexia and their implications in drug discovery 1.

Introduction

2.

Cancer cachexia

3.

Cardiac cachexia

4.

Other animal models of cachexia

5.

Conclusion

6.

Expert opinion

Masaaki Konishi†, Nicole Ebner, Stephan von Haehling, Stefan D. Anker & Jochen Springer †

University Medical Centre G€ ottingen, Institute of Innovative Clinical Trials, G€ ottingen, Germany

Introduction: Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. Systemic inflammation plays a central role in its pathophysiology. As millions of patients are in a cachectic state of chronic disease, cachexia is one of the major causes of death worldwide. Difficulties in the recruitment and follow-up of clinical trials mean that well-characterized animal models are of great importance in developing cachexia therapies. However, some of the widely used animal models have limitations in procedural reproducibility or in recapitulating in the cachectic phenotype, which has warranted the development of novel models for cachexia. Areas covered: This review focuses on some of the currently developing rodent models designed to mimic each co-morbidity in cachexia. Expert opinion: Through developing cancer models, researchers have been seeking more targets for intervention. In cardiac cachexia, technical issues have been overcome by transgenic models. Furthermore, the development of new animal models has enabled the elucidation of the roles of inflammation, anabolism/catabolism in muscle/fat tissue and anorexia on cachexia. As metabolic and inflammatory pathways in cachexia may compromise cardiac muscle, the analysis of cardiac function/tissue in non-cardiac cachexia may be a useful component of cachexia assessment common to different underlying diseases and pave the way for novel drug discovery. Keywords: animal models, cachexia, inflammation, wasting Expert Opin. Drug Discov. [Early Online]

1.

Introduction

In December 2006, scientists and clinicians of the Cachexia Consensus Working Group reached a consensus on the definition of the abnormalities that have been grouped under the name of cachexia. The definition that emerged is: ‘cachexia’ is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass [1]. Anorexia, inflammation, insulin resistance and increased muscle protein breakdown are found to be frequently associated status in cachexia. Cachexia is distinguished from starvation, age-related loss of muscle mass, primary depression, malabsorption and hyperthyroidism. This definition was also agreed in the fields of cancer [2] and clinical nutrition [3]. The prevalence of cachexia ranges from 5 to 15% in chronic heart failure and chronic obstructive pulmonary disease (COPD) to 80% in advanced cancer [4]. Mortality rates of patients with cachexia range from 10 to 15% per year in COPD through 20 -- 30% per year in chronic heart failure and chronic kidney disease to 80% in cancer [5]. As a recent estimate suggests that approximately 9 million patients are in cachectic state of chronic disease [4], cachexia is not only a complex condition that occurs in advanced stages of multiple underlying diseases but also 10.1517/17460441.2015.1041914 © 2015 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X All rights reserved: reproduction in whole or in part not permitted

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Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. Systemic inflammation plays a central role in pathophysiology of cachexia. Through developing cancer models, researchers have been seeking more targets for intervention (metastasis, dissemination and cancer-cachexia associated cardiomyopathy, etc.). In cardiac cachexia, technical issue has been overcome by the transgenic models and the salt-sensitive rat model. Other developing animal models of cachexia include the neuromuscular disease models, the burn cachexia model and the angiotensin II infusion model. As the metabolic and inflammatory pathways in cachexia may compromise the cardiac muscle, analysis of cardiac function/tissue even in non-cardiac cachexia may be a component of cachexia assessment common to the different underlying diseases and pave the way to drug discovery.

This box summarizes key points contained in the article.

one of the major causes of death worldwide. A number of treatments have been proposed for cachexia; however, no direct treatment of cachexia is available as yet. Although the precise underlying mechanisms causing cachexia remains to be elucidated, our understanding of cachexia has made some progress in recent years. Cachexia is considered a multifactorial syndrome caused by a combination of reduced food intake and abnormal metabolism, resulting in negative energy balances [6]. Pro-inflammatory cytokines (IL-1, TNF-a, IL-6 and IFN-g) play a role in both in food intake and metabolism, and are the main pathogenic mediators in cachexia [7]. Specifically, they affect CNS, immune system, hematopoietic system and protein/ lipid/glucose/iron metabolism [7,8], leading to the development of multiple symptoms (anorexia, depression, proteolysis, immunodepression, anemia, lipolysis and insulin resistance). In addition, early satiety and hormones (leptin, neuropeptide Y and ghrelin) play an important role in reduced food intake [9]. Negative energy balance is mainly seen in skeletal muscle and body fat. In skeletal muscle, myostatin activation, increased glucocorticoids and insulin resistance lead to muscle atrophy through cell death, autophagy or ubiquitin proteasome system activation [10]. In body fat (white adipose tissue), there are three different altered processes: increase in lipolytic activity, a decrease in the activity of lipoprotein lipase and reduced de novo lipogenesis in adipose tissue [11]. Although cachexia remains underestimated and untreated, large clinical trials are still lacking. Enrollment in large numbers is necessary to achieve adequate power because of wide heterogeneity of underlying diseases, pre-existing treatment and estimated high drop-out rate in cachectic patients. 2

However, recruitment difficulties due to unwillingness or frailty in such a serious condition stand in the way of successful trials. Such difficulties in clinical researches for cachexia underline the importance of well-characterized animal models. However, some of the widely used cachexia animal models have limitations in reproducibility of procedure or recapitulatability in cachectic phenotype and novel models has been warranted in this context. This review will focus on some developing rodent models designed to mimic each co-morbidity under cachexia, including cancer, heart failure and the other diseases and conditions. It will help the investigators in selecting the appropriate animal model. 2.

Cancer cachexia

Given that cancer is one of the most frequently observed cause of cachexia [5] and that cachexia contributes to > 20% of cancer deaths [12,13], it is not surprising that cancer cachexia is the most widely studied cachectic condition. The key features of cancer cachexia models are anorexia, weight loss (lean and fat mass) and increased energy expenditure [14]. The widely used in vivo models of cancer cachexia include Lewis lung carcinoma (LLC), C26 colorectal carcinoma, Yoshida hepatoma (AH-130), Walker 256 mammary adenocarcinoma, methylcholanthrene-induced sarcoma (MCG-101) and MAC16 murine colon adenocarcinoma, all of which have been extensively discussed and summarized in a previous paper [9]. Briefly, LLC is commonly available cell line for purchase and induces 6.6% of weight loss in 15 days for rats [15]. C26 undifferentiated colon carcinoma cells are injected subcutaneously and show an 18% weight loss in 20 days for mice [16]. AH-130 cells are injected intraperitoneally into rats and induce rapid weight loss of 35% in 15 days [17]. By subcutaneous injection, Walker 256 adenocarcinoma cells induce weight reduction of 6% in rats, whereas MCG 101 and MAC16 cells induce 2 -- 3% and 20 -- 30% weight loss in mice, respectively [9]. 2.1

APCMin/+ mouse model

The APCMin/+ mouse is heterozygous for a point mutation in the adenomatous polyposis coli (APC) gene. This model resembles human cachexia as it shows slow-progressive cachectic phenotype. The mouse develops colon cancer at the age of 4 weeks and starts losing weight between 14 and 20 weeks, with > 15% weight loss at 20 weeks [18,19]. In this model, IL-6, one of the main mediators of cancer cachexia, is necessary for its cachectic phenotype [20]. IL-6 was sufficient to regulate atrogin-1 gene expression [21] and mTOR activity, although the role of the latter pathway in muscle wasting and cachexia is not clear [22]. Gut barrier dysfunction and hypogonadism have also been implicated in the cachectic phenotype of this model [19,23]. Vela´zquez et al. reported the favorable effect of supplementation by a natural flavonoid quercetin for 3 weeks on mitigated plasma IL-6 and muscle signal

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Developing models for cachexia and their implications in drug discovery

transducer and activator of transcription 3 phosphorylation, and on the relative decrease in weight (-14 vs s -9minus;9%), grip strength and muscle mass [24].

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2.2

Tsc2+/- Em- Myc tumor-bearing mice model

The Eµ-Myc transgenic mouse is a model of B lymphoma, where the lymphoid-specific IgH enhancer (Eµ) induces myc overexpression in the pre-B/B-cell compartment [25]. However, mice bearing Eµ-Myc lymphoma do not show signs of anorexia--cachexia after tumor injection [26]. The Tsc2+/-Eµ-Myc lymphoma was generated from crosses between Tsc2+/- and Eµ-Myc mice and then injected into C57BL/6 males. Mice bearing Tsc2+/-Eµ-Myc lymphoma displayed features of cachexia, including anorexia, increased catabolic markers in muscle (LC3b, Gabarap, USP19, MuRF1, MAFbx/Atrogin-1, Bnip3, and Atg4b), a reduction of body weight and increased total energy expenditure [26]. Survival was also impaired (maximum 17 days). In this model, inhibition of mTOR signaling with rapamycin or homoharringtonine reduced the production of IL-10 and attenuated the cachexic phenotype. It should be noted that mTOR signaling in this model is activated due to loss of the Tsc2 tumor suppressor gene contrary to the above-mentioned APCMin/+ mouse and, in particular, classical inflammatory cytokines are not elevated. It may be open to debate whether this model is appropriate for generalizable cachexia model. Stomach cancer models using MKN-45 cells Although stomach cancer, in particular, is frequently complicated with cachexia, few animal models of stomach cancer cachexia have been established [9]. Yanagihara et al. subcutaneously injected 15 human stomach cancer cell lines in nude mice and compared the weight reduction [27]. As a result, only mice with MKN-45 cells displayed weight loss. In addition, these mice also showed significant metastases. Although the rationale of action was not shown, treatment with isoflavone reduced weight loss [27]. However, the reduction in food intake was not stable in this model. Terawaki et al. implanted MKN45c185 and 85As2, two novel cell lines derived from MKN-45, into nude rats and successfully induced anorexia [28]. These rats showed weight loss of 6--12% at week 4, with anorexia, reduced muscle mass and strength, increased inflammatory markers and low plasma albumin levels. In these models, a traditional Japanese medicine rikkunshito, which has been shown to increase ghrelin secretion and signaling [29,30], for 7 days orally ameliorated anorexia and body composition changes [28]. 2.3

Breast cancer bone metastasis model In most of cancer cachexia models, implanted cell lines do not metastasize significantly, thus acting differently from cancer cachexia in patients [9,14]. Suominen et al. demonstrated a cachectic phenotype in the widely used in vivo model of breast cancer bone metastasis, by injecting MDA-MB-231 breast cancer cells into nude mice via left cardiac ventricle [31]. In 2.4

this established bone metastasis setting, radium-223 dichloride prevented tumor-induced cachexia and improved survival (maximum 34 vs 28 days after inoculation, p = 0.04). Radium-223 dichloride decreased osteolysis, but the mechanism under anti-cachectic effect was not discussed. Sun et al. used mice with 4T1 mammary carcinoma cells injected into an inguinal mammary fat pad as a cancer cachexia model with metastasis. The tumor-bearing mice experienced 12% reduction in weight after inoculation. They demonstrated that oral iron-saturated bovine lactoferrin, started 14 days before inoculation, attenuated cancer cachexia as evidenced by reduced weight loss and increased weight in muscle and fat [32]. However, lactoferrin had also antitumor efficacy and whether lactoferrin has anti-cachectic effect is unknown. Although both these models accompany systemic inflammation [33,34], these two studies did not measure any inflammatory markers and further studies are needed to investigate effective anti-cachectic therapy in such animal models with metastasis. ASV-B hepatocellular carcinoma mouse model The ASV-B mouse has been widely used as a transgenic hepatocellular carcinoma model [35,36]. In this model, hepatocellular carcinoma is induced by the expression of oncogenic SV40 large T antigen and resembles human hepatocellular carcinoma. Recently, Palus et al. investigated the usefulness of this model as a cachexia model [37], and also the effects of depletion of hypoxia-inducible factor (HIF)-1a, a modulator of cancer growth. The ASV-B mice showed loss of body weight (34% at week 17) and lean mass in comparison with wild-type controls. Fat mass was also reduced in ASV-B mice but not in ASV-B/HIF-1a knockout strains, which may indicate a protective effect of fat mass. Although HIF can be triggered by inflammation [38], inflammatory cytokines were not shown in this report. There has been increasing reports of HIF-1 inhibitor [39-41] being a novel target for anti-cachexia drugs. 2.5

Cancer cachexia-induced cardiomyopathy models As loss of skeletal muscle is a main finding of cachexia, cardiac muscle atrophy also has considered to be seen in cancer cachexia [42]. Although in several animal studies cancer cachexia was associated with loss of heart muscle mass [43,44], little was known about the precise cardiac function and whether cardiac wasting worsens survival. A recent study demonstrated cardiac wasting in AH-130 hepatoma rat model and the effect of treatment with the b-adrenoceptor antagonist (bisoprolol), the angiotensin converting enzyme inhibitor (imidapril) and the aldosterone antagonist (spironolactone), all of which are commonly used in heart failure treatment. Bisoprolol and spironolactone attenuated tumor-induced cardiac dysfunction (2 and 9% increase in left ventricular mass, respectively, whereas 21% decrease with placebo 11 days post inoculation), body wasting and improved survival but imidapril did not [45]. These results indicated that cardiac 2.6

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wasting by cancer is associated with the increased mortality in cachexia. Inflammation was assessed only by plasma fibrinogen in this study, but in another study of the same model, xanthine oxidase inhibition by oxypurinol suppressed inflammatory cytokines and attenuated cardiac/systemic wasting [46,47]. A selective 5-hydroxytryptamine 1 A receptor partial agonist tandospirone [48] also reversed cardiac/systemic wasting and this effect may be mediated by the reduction of sympathetic tone, as suggested by lower noradrenalin levels. Cardiac wasting in cancer cachexia was also shown in a mouse model using the colon 26 adenocarcinoma cell line [43,49-51]. 3.

Cardiac cachexia

While cancer patients are known to be prone to develop cachexia, cardiac cachexia due to chronic heart failure takes the lead in terms of absolute patient numbers because of high population burden [52]. Although a large amount of animal studies were performed to investigate novel treatment for heart failure, few of them have been utilized for the research of cardiac cachexia [53]. The most widely used in vivo models of cardiac cachexia were myocardial infarction and aortic banding, both of which, however, can have variable phenotype depending on surgical techniques to induce either infarction or dysfunctional myocardium. These two models have been presented and summarized in a previous paper [14]. Cardiac-specific calsequestrin overexpression mouse model

3.1

Li et al. demonstrated that cardiac-specific overexpression of calsequestrin, a sarcoplasmic reticulum Ca2+ storage protein, resulted in chronic heart failure as evidenced by decreased fractional shortening (51% decrease in comparison with wild-type mice at 8 weeks old) and cachexia (38% decrease in weight) [54]. This mouse line was then crossbred with transgenic mice overexpressing muscle-specific proliferator-activated receptor-g coactivator-1a (PGC-1a) under the promoter of muscle creatine kinase. PGC-1a overexpression in skeletal muscle significantly attenuated body wasting in chronic heart failure (27% weight loss in calsequestrin-PGC-1a double-transgenic mice at 8 weeks old compared with 39% in calsequestrin transgenic mice, p < 0.05) [55]. PGC-1a in skeletal muscle may be a potential target of drug discovery for skeletal muscle wasting induced by chronic diseases including heart failure. On the other hand, Okutsu et al. crossbred the calsequestrin overexpression mice with muscle-specific extracellular superoxide dismutase transgenic mice. These double transgenic mice at 7 weeks old showed a significantly attenuated cachectic phenotype with preserved whole body muscle strength in comparison to the calsequestrin transgenic mice, suggesting extracellular superoxide dismutase might be a new target for drug discovery [56]. The underlying mechanisms of this model of cachexia seem to be the increased production of reactive oxygen species and subsequent activation of atrogin-1. Although increased reactive 4

oxygen species led to systemic inflammation [47], no inflammatory responses were assessed in these studies. Dahl salt-sensitive rat model Cardiac cachexia is associated with abnormal energy metabolism in extracardiac tissues. Although the liver plays a central role in the systemic regulation of catabolism and anabolism, few studies had been designed to clarify the change in hepatic metabolism in congestive heart failure. Kato et al. used the Dahl salt-sensitive rat, which shows decreased fractional shortening when fed a high-salt diet after 6 weeks old [57], as a model of cardiac cachexia [58]. These rats showed a failure to grow (assessed at 17 weeks old), increased blood proinflammatory cytokine levels, and reduced food intake in comparison with controls. The pro-inflammatory response was associated with the paradoxical production of triglycerides synthesis. Altered gene expression related to gluconeogenesis and lipogenesis was also observed in the liver. Pharmacological intervention designed to modulate not only inflammation but also liver metabolism may contribute to ameliorating cardiac cachexia. 3.2

4.

Other animal models of cachexia

Other widely used animal models of cachexia include chronic kidney disease models, COPD models and inflammatory models with injected inflammatory cytokines (such as TNF-a or IL-1b) or lipopolysaccharide (bacterial endotoxin) [14]. Chronic kidney disease model is demonstrated by the surgical nephrectomy whereas cigarette smoke exposure is used as chronic pulmonary disease model [14,59]. Neuromuscular disease model Weight loss is a common finding among patients with neuromuscular disease. After stroke, both experimental animals [60] and patients [61] lose weight accompanied by systemic inflammation [62,63]. A recent study demonstrated wasting of muscle and fat tissue irrespective of inactivity (-12% in muscle, -2minus;27% in fat and d -2minus;22% in body weight on the 3rd day) in a mouse model of acute cerebral ischemia with temporal occlusion of the middle cerebral artery. Catabolic signaling and proteasome activity were higher in animal models of stroke in the contralateral and the ipsilateral leg. However, all the three attempted interventions, which included high caloric feeding, b-receptor blockade against sympathetic overactivation, and antibiotic treatment to prevent post-stroke infections, failed to prevent muscle wasting [64]. As preventing muscle wasting after stroke may be important in improving rehabilitation and outcome, additional studies targeting metabolic modification therapeutically are warranted. It is noteworthy that inflammation is fundamental to the pathogenesis of both cachexia and muscular dystrophies [65]. Acharyya et al. reported that muscle wasting was accentuated 2 weeks after C26 and LLC cells injection in mdx mice 4.1

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Developing models for cachexia and their implications in drug discovery

lacking a dystrophin glycoprotein complex but spared in dystrophin transgenic mice [66]. Weight loss resulting from inflammatory response is also ubiquitous among amyotrophic lateral sclerosis (ALS) patients and animal models [67]. Anti-inflammatories [68,69], antioxidants [70-72], mitochondrial protective agents [73,74], antiapoptotic [75,76] and antiexcitotoxic [77] agents have been reported to attenuate weight loss and reduce mortality in SOD1G93A mouse model of ALS. These results also imply that approaches targeted at neuromuscular diseases could also be considered a viable option in designing anti-cachectic therapy. A mouse model of burn cachexia Severe burn injuries are accompanied by significant inflammation and lead to a hypermetabolic state persistent for years [78]. Consequently, patients with severe burn injuries lose weight leading to a cachectic state. Pedroso et al. recapitulated weight loss (-12% in weight and d -3minus;30% in muscle at 14 days after procedure) and accelerated systemic inflammation in mice given full-thickness burns using heated brass plates [79]. Although no therapeutic approach had been attempted in this study, further studies of burn injuryassociated cachexia in evaluating the efficacy of therapeutic drugs are expected. 4.2

Twist mutant mice The transcription factor TWIST was discovered in Drosophila and has been studied for its role in immune and inflammatory responses in rodent models. Sosic et al. showed that twist proteins function downstream of NF-kB and described a cachexia phenotype (threefold underweight by 10 days old) and early death (maximum survival of 15 days) in mice with heterozygous knockout of TWIST1 and TWIST2 due to an increased expression of proinflammatory cytokines such as TNF-a and IL-1b [80]. These mice were similar to mouse models of TNF-a-induced cachexia [81] and showed atrophic hepatocytes, increased number of apoptotic cells and myofiber breakdown in skeletal muscle, as well as abnormalities in glucose metabolism and storage. Baumgarten et al. has also demonstrated that TWIST1 regulates the activity of ubiquitin proteasome system via the miR-199/214 cluster in human cardiomyocytes [82]. 4.3

Angiotensin II infusion model Angiotensin II infusion model of cachexia has been in development based on the notion that cardiac cachexia is associated with activated renin--angiotensin system [83]. Brink et al. reported continuous infusion of angiotensin II via implanted osmotic minipumps induced 18--26% weight loss by 1 week in rats [84]. Angiotensin II induces systemic inflammation [85] and reduces expression of insulin-like growth factor-1 [86], induces sympathetic activation [87] and reduced hypothalamic expression of neuropeptides (neuropeptide Y and orexin) [88]. Ghrelin infusion for 5 days in mice [89] and AT1 receptor antagonist losartan (1 week in rats) restored IGF-1 levels [84], 4.4

candesartan (7 days in mice) and carvedilol (12 days in rats) reduced lipolysis [87], resulting in complete inhibition of weight loss. 5.

Conclusion

In recent years, researchers have been developing several novel animal models in each field of cachexia with the inflammatory response in a central role. The purpose of such developing models is to address more co-morbidities associated with cachexia, reduce the variation of the cachectic phenotype and recapitulate the cachectic status more closely to that of humans. However, no one model is ideal for all the cachectic patients, of course. We have to choose adequate model for each research question. 6.

Expert opinion

Through these developing cancer models, researchers have been seeking more targets for intervention (metastasis, dissemination and cancer-cachexia associated cardiomyopathy, etc.). In cardiac cachexia, technical issue, which is one of the most important issue limiting the preciseness and reproducibility in making heart failure models, has been overcome by means of transgenic mice models and Dahl salt-sensitive rats models. In the other types of cachexia, the spectrum of cachexia as research target has been widening and now includes stroke, burn, neuromuscular disease and the other types of chronic disease, which has not been studied so far. Using the developing animal models of cachexia, however, few therapeutic options have been attempted. Many compounds used in human clinical trials in recent years are still presented with the preclinical data using traditional cachexia models [90]. In developing new animal cachexia model, there will be some potential to make progress in research for much more underlying disease causing cachexia, such as metastatic tumors, heart failure, stroke and burn injury. Such progress enables to elucidate further the roles of inflammation, anabolism and catabolism in muscle and fat tissue, and anorexia on cachexia. Inflammation is considered the common pathophysiology in all types of cachexia, whereas anabolism/ catabolism in muscle/fat and anorexia may act differently depending on the underlying diseases. The results of novel studies may impact appropriate anti-cachectic therapeutic strategies in each disease. Another potential of preclinical research is to explore more sensitive means for detecting changes in muscle function. As current clinical methodologies for quantifying physical activity are not sensitive [91], in particular when dealing with severely frail patients, future cachexia animal model should focus on the selection of the best measurement tool to detect functional changes. To discover new compounds, it is important to collaborate with researchers of different specialties. For example, muscle wasting is an important component of cachexia, which can

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result not only from cachexia but also from neuromuscular disease, including ALS, orthopedic disease or peripheral vascular disease. The collaboration within different specialties may also be effective in reducing attrition rate. Kola et al. have given six factors to reduce attrition rate [92], to any of which the collaboration of different specialties may contribute. Especially, comprehensive testing in preclinical setting including detailed cardiac or renal function is essential to avoid unexpected toxicity of a compound and reduce attrition. The three types of potential pathophysiology under cachexia have lately attracted considerable attention in animal researches. These are adipose tissue function in energy expenditure [93,94], roles of myokines [6,95] and gut microbiota [96]. As studies in these mechanisms have made a great progress in terms of physiological or non-cachexia pathological settings, cachexia studies should expand further if they include these mechanisms. For example, the models of gastrointestinal cancer could be used in the context of gut microbiota with the accumulated notion in gastrointestinal oncology. The area of the research we are finding of interest at present is cardiac function in cancer. Although there has been increasing evidence in cardiac function in cancer models [49-51], clinical data is sparse. Recently, some reports [45,97] have shown the characteristics that include reduced wall thickness, relatively preserved systolic function and impaired functional capacity in cancer patients, some of which are also common in heart failure patients. As fatigue, which indeed is a complex symptom with several contributing factors [98], can be the most pronounced symptom both in cachexia and heart failure [97], cardiac function may have potential impact on functional capacity and even on mortality in cancer patients. In addition, the same metabolic and inflammatory pathways altered in cachexia may compromise the cardiac function and that muscle mass derangements involve also cardiac muscle [11]. Therefore, analysis of cardiac function and cardiac tissue alterations may be a component of cachexia common to the different underlying diseases and useful to be investigated.

6

To measure cardiac function properly even in non-cardiac cachexia may pave the way for drug discovery, especially to improve the quality of life in cachexia. Heart failure itself includes common pathophysiology with cancer cachexia, that is, the roles of inflammation, oxidative stress and diseased muscle tissue by mitochondrial dysfunction [11,99]. As many large clinical trials have been conducted in heart failure, some heart failure treatment may turn out to be beneficial for cachexia in the future [45]. Here, we introduce two alternative approaches that are potentially useful in this field. Dyle et al. identified tomatidine, a natural compound from tomato plants, as an inhibitor of skeletal muscle atrophy using systems-based strategy [100]. That is, they compared the mRNA signatures of 1309 small molecules to the mRNA signatures that are altered by fasting and spinal cord injury [101] using the Connectivity Map [102] (mRNA signatures are patterns of positive and negative changes in mRNA levels flustered by conditions such as a disease or small molecule) and found that the mRNA signature of tomatidine negatively correlated to the mRNA signatures that are altered by fasting and spinal cord injury. Using this approach, we can estimate the efficacy of a lot of molecules within a short period. Drug repositioning, which means to use existing drugs for new indication, is another approach to drug discovery also in the field of cachexia models [103]. Repositioning drugs shortens the development times and reduces the risks. So far, drug repositioning has been attempted in traditional cachexia models [17,45,47,48,104,105] but not in developing models of cachexia.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Affiliation

Masaaki Konishi†1 MD PhD, Nicole Ebner1, Stephan von Haehling1,2 MD PhD, Stefan D. Anker1 MD PhD & Jochen Springer1,2 PhD † Author for correspondence 1 University Medical Centre G€ottingen, Institute of Innovative Clinical Trials, Robert-Koch-Str. 40, 37075 G€ottingen, Germany; Tel: +49 0 551 39 6380; Fax: +49 0 551 39 6389; E-mail: [email protected] 2 University Medical Centre G€ottingen, Department of Cardiology and Pneumology, G€ottingen, Germany

Developing models for cachexia and their implications in drug discovery.

Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. Syst...
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