Editors' ChoiceCachexia

Act-ing Against Muscle Loss in Cachexia

See allHide authors and affiliations

Science Translational Medicine  08 Sep 2010:
Vol. 2, Issue 48, pp. 48ec139
DOI: 10.1126/scitranslmed.3001654

Cachexia is defined as a loss of body mass, mostly fat and muscle, that cannot be reversed by eating more calories. Cachexia is commonly seen in patients with end-stage diseases such as cancer, chronic obstructive lung disease, and congestive heart failure, and its presence hastens death considerably. There is no effective treatment for cachexia as of yet, but knowledge of growth factors that regulate muscle mass could help in the quest to prevent muscle wasting. One such signaling pathway implicated in muscle wasting is initiated by the ActRIIB receptor, a high-affinity activin type 2 receptor that binds several transforming growth factor–β (TGF-β) family ligands, such as myostatin and activin. Myostatin is a negative regulator of muscle growth; null mutations lead to dramatic muscle hypertrophy in animals and humans. In mice that lack the hormone inhibin, which antagonizes both myostatin and activin, myostatin and activin probably cause cachexia. Now, Zhou et al. show that a decoy receptor of ActRIIB (sActRIIB) reverses cachexia and markedly improves survival in mouse models of cancer.

These authors demonstrate that in mice with cancer-induced cachexia and in mice lacking inhibin, sActRIIB completely reversed muscle loss, increasing its mass even beyond that of cancer-free control mice. This treatment did not prevent the loss of adiposity (something a cancer patient can live with), nor did it reduce tumor mass, although it did markedly increase survival, possibly because sActRIIB completely blocked the atrophy of cardiac muscle. ActRIIB signaling appears to activate the transcription factor Smad2, which triggers FOXO3a to move to the nucleus, where it induces atrogin-1 and MuRF1, important intracellular mediators of muscle breakdown. Because sActRIIB treatment had no effect on other cytokines commonly believed to be critical mediators in cancer cachexia [such as interleukin-6 (IL6) or tumor necrosis factor–α] and IL6 infusion did not induce cachexia, these cytokines may in fact not contribute to cachexia. Thus, this study provides proof of principle that the loss of muscle mass causally contributes to the mortality of cancer cachexia and demonstrates that sActRIIB prevents muscle wasting by decreasing protein degradation. Inhibition of ActRIIB may be a promising pharmacological strategy in battling cancer cachexia in humans.

X. Zhou et al., Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142, 531–543 (2010).[Abstract]

Navigate This Article