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      Concurrent evolution of cancer cachexia and heart failure: bilateral effects exist

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          Abstract

          Cancer cachexia is defined as a multifactorial syndrome of involuntary weight loss characterized by an ongoing loss of skeletal muscle mass and progressive functional impairment. It is postulated that cardiac dysfunction/atrophy parallels skeletal muscle atrophy in cancer cachexia. Cardiotoxic chemotherapy may additionally result in cardiac dysfunction and heart failure in some cancer patients. Heart failure thus may be a consequence of either ongoing cachexia or chemotherapy-induced cardiotoxicity; at the same time, heart failure can result in cachexia, especially muscle wasting. Therefore, the subsequent heart failure and cardiac cachexia can exacerbate the existing cancer-induced cachexia. We discuss these bilateral effects between cancer cachexia and heart failure in cancer patients. Since cachectic patients are more susceptible to chemotherapy-induced toxicity overall, this may also include increased cardiotoxicity of antineoplastic agents. Patients with cachexia could thus be doubly unfortunate, with cachexia-related cardiac dysfunction/heart failure and increased susceptibility to cardiotoxicity during treatment. Cardiovascular risk factors as well as pre-existing heart failure seem to exacerbate cardiac susceptibility against cachexia and increase the rate of cardiac cachexia. Hence, chemotherapy-induced cardiotoxicity, cardiovascular risk factors, and pre-existing heart failure may accelerate the vicious cycle of cachexia-heart failure. The impact of cancer cachexia on cardiac dysfunction/heart failure in cancer patients has not been thoroughly studied. A combination of serial echocardiography for detection of cachexia-induced cardiac remodeling and computed tomography image analysis for detection of skeletal muscle wasting would appear a practical and non-invasive approach to develop an understanding of cardiac structural/functional alterations that are directly related to cachexia.

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          Most cited references 67

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          Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival.

          Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival. Copyright 2010 Elsevier Inc. All rights reserved.
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            Skeletal muscle hypertrophy and atrophy signaling pathways.

            Skeletal muscle hypertrophy is defined as an increase in muscle mass, which in the adult animal comes as a result of an increase in the size, as opposed to the number, of pre-existing skeletal muscle fibers. The protein growth factor insulin-like growth factor 1 (IGF-1) has been demonstrated to be sufficient to induce skeletal muscle hypertrophy. Over the past few years, signaling pathways which are activated by IGF-1, and which are responsible for regulating protein synthesis pathways, have been defined. More recently, it has been show that IGF-1 can also block the transcriptional upregulation of key mediators of skeletal muscle atrophy, the ubiquitin-ligases MuRF1 and MAFbx (also called Atrogin-1). Further, it has been demonstrated recently that activation of the NF-kappaB transcription pathway, activated by cachectic factors such as TNFalpha, is sufficient to induce skeletal muscle atrophy, and this atrophy occurs in part via NF-kappaB-mediated upregulation of MuRF1. Further work has demonstrated a trigger for MAFbx expression upon treatment with TNFalpha--the p38 MAPK pathway. This review will focus on the recent progress in the understanding of molecular signalling, which governs skeletal muscle atrophy and hypertrophy, and the known instances of cross-regulation between the two systems.
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              Cachexia in cancer patients.

               M Tisdale (2002)
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                Author and article information

                Contributors
                +1-780-4328232 , vbaracos@ualberta.ca
                Journal
                J Cachexia Sarcopenia Muscle
                J Cachexia Sarcopenia Muscle
                Journal of Cachexia, Sarcopenia and Muscle
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                2190-5991
                2190-6009
                14 March 2014
                June 2014
                : 5
                : 2
                : 95-104
                Affiliations
                [ ]Department of Oncology, Division of Palliative Care Medicine, University of Alberta, Edmonton, Canada
                [ ]Department of Medicine, Division of Cardiology, Alberta Cardiovascular and Stroke Research Centre, University of Alberta, Edmonton, Canada
                [ ]Department of Oncology, Division of Medical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada
                Article
                137
                10.1007/s13539-014-0137-y
                4053562
                24627226
                © Springer-Verlag Berlin Heidelberg 2014
                Categories
                Review
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2014

                Orthopedics

                cardiac cachexia, cancer cachexia, cardiac atrophy

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