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.

Chronic kidney disease (CKD) and several other catabolic conditions are characterized by increased circulating inflammatory cytokines, defects in IGF-1 signaling, abnormal muscle protein metabolism, and progressive muscle atrophy. In these conditions, no reliable treatments successfully block the development of muscle atrophy. In mice with CKD, we found a 2- to 3-fold increase in myostatin expression in muscle. Its pharmacological inhibition by subcutaneous injections of an anti-myostatin peptibody into CKD mice (IC(50) ∼1.2 nM) reversed the loss of body weight (≈5-7% increase in body mass) and muscle mass (∼10% increase in muscle mass) and suppressed circulating inflammatory cytokines vs. results from CKD mice injected with PBS. Pharmacological myostatin inhibition also decreased the rate of protein degradation (16.38 ± 1.29%; P<0.05), increased protein synthesis in extensor digitorum longus muscles (13.21 ± 1.09%; P<0.05), markedly enhanced satellite cell function, and improved IGF-1 intracellular signaling. In cultured muscle cells, TNF-α increased myostatin expression via a NF-κB-dependent pathway, whereas muscle cells exposed to myostatin stimulated IL-6 production via p38 MAPK and MEK1 pathways. Because IL-6 stimulates muscle protein breakdown, we conclude that CKD increases myostatin through cytokine-activated pathways, leading to muscle atrophy. Myostatin antagonism might become a therapeutic strategy for improving muscle growth in CKD and other conditions with similar characteristics.

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BackgroundCachexia is a multiorganic syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting and inflammation.MethodsThe aim of this investigation was to examine the effect of the soluble receptor antagonist of myostatin (sActRIIB) in cachectic tumor-bearing animals analyzing changes in muscle proteolysis and in quality of life.ResultsAdministration of sActRIIB resulted in an improvement in body and muscle weights. Administration of the soluble receptor antagonist of myostatin also resulted in an improvement in the muscle force.ConclusionsThese results suggest that blocking myostatin pathway could be a promising therapeutic strategy for the treatment of cancer cachexia.

Formoterol is a highly potent b 2 -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 b 2 -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 multifactorial syndrome found in 50-80% of cancer patients, 1 particularly at advanced stages of disease, leading to a decrease in quality of life and physical performance. Cancer cachexia is clinically relevant since is considered a predictor of reduced survival, accounting for more than 20% of cancer deaths. 2,3 The pathogenesis of cancer cachexia is characterized by the loss of skeletal muscle mass and fat, often associated with anorexia. However, muscle wasting should be regarded as the most important trait since it is responsible for most of the cancer cachexia-associated symptoms and decreased survival. 4 The competition for nutrients between the tumor and the host and the inflammatory status promote profound metabolic disturbances that include a massive nitrogen flow from the skeletal muscle to the liver. 5 Consequently, muscle plays a central role in whole-body protein metabolism by serving as the principal reservoir for amino acids to maintain protein synthesis in peripheral tissues in the absence of amino acid absorption from the gut and by providing hepatic gluconeogenic precursors. 5,6 The negative protein balance results from altered rates on both sides of muscle protein turnover, reduced synthesis and increased degradation, as revealed by several preclinical studies o...