Journal article
Elevated expression of activins promotes muscle wasting and cachexia
JL Chen, KL Walton, CE Winbanks, KT Murphy, RE Thomson, Y Makanji, H Qian, GS Lynch, CA Harrison, P Gregorevic
FASEB Journal | Published : 2014
DOI: 10.1096/fj.13-245894
Abstract
In models of cancer cachexia, inhibiting type IIB activin receptors (ActRIIBs) reverse muscle wasting and prolongs survival, even with continued tumor growth. ActRIIB mediates signaling of numerous TGF-β proteins; of these, we demonstrate that activins are the most potent negative regulators of muscle mass. To determine whether activin signaling in the absence of tumor-derived factors induces cachexia, we used recombinant serotype 6 adeno-associated virus (rAAV6) vectors to increase circulating activin A levels in C57BL/6 mice. While mice injected with control vector gained ̃10% of their starting body mass (3.8±0.4 g) over 10 wk, mice injected with increasing doses of rAAV6:activin A exhibit..
View full abstractGrants
Awarded by National Health and Medical Research Council (NH&MRC) of Australia
Awarded by NHMRC
Funding Acknowledgements
The authors thank Drs. Jonathan Davey and Kevin Watt (Division of Cell Signaling and Metabolism, Baker IDI Heart and Diabetes Institute) and Emily Kelly, Karen Chan, and Enid Prusyers (Prince Henry's Institute) for technical assistance; David de Kretser and Susan Hayward (Monash Institute of Medical Research, Melbourne, VIC, Australia) for assistance with the activin ELISAs; Drs. Mark Ziemann, Ross Lazarus, and Assam El-Osta (Division of Diabetic Complications, Baker IDI Heart and Diabetes Institute) for support with bioinformatics analyses; and Prof. Mark A. Febbraio (Division of Cell Signaling and Metabolism, Baker IDI Heart and Diabetes Institute) for technical advice and assistance concerning measurement of animals' body composition. The human cancer cell lines were a gift from Assoc. Prof. Guiying Nie and Dr. Colin Clyne (Prince Henry's Institute). Myostatin-null mice were a gift of Prof. Se-Jin Lee (Johns Hopkins University, Baltimore, MD, USA). This work was supported by grant funding (526648, 566820, 1006488) from the National Health and Medical Research Council (NH&MRC) of Australia. P.G., C.A.H., and K.T.M. are supported by Career Development Fellowships (1046782, 1013533, and 1023178) from the NH&MRC. P.G. was previously supported by a senior research fellowship, sponsored by Pfizer Australia. The Baker IDI Heart and Diabetes Institute and Prince Henry's Institute are supported in part by the Operational Infrastructure Support Program of the Victorian government. Author contributions: J.L.C., K.L.W., C.A.H. and P.G. designed the research; J.L.C., K.L., K.T.M., R.E.T., Y.M., and H.Q. performed the experimental work; C.E.W., G.S.L., C.A.H., and P.G. contributed reagents and analytical tools and technical advice; J.L.C., C.E.W., K.T.M., and P.G. analyzed the data; J.L.C., G.S.L., C.A.H., and P.G. wrote the manuscript. The authors declare no conflicts of interest.