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

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          Abstract

          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.

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          Author and article information

          Journal
          Cell
          Cell
          Elsevier BV
          1097-4172
          0092-8674
          Aug 20 2010
          : 142
          : 4
          Affiliations
          [1 ] Departments of Metabolic Disorders and Protein Science, Amgen Research, Thousand Oaks, CA 91320, USA.
          Article
          S0092-8674(10)00780-4
          10.1016/j.cell.2010.07.011
          20723755
          a58b4204-7b1a-4304-8c84-21edfe410471
          Copyright 2010 Elsevier Inc. All rights reserved.
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