title: Elevated expression of activins promotes muscle wasting and cachexia.
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 exhibited weight loss in a dose-dependent manner, to a maximum of -12.4% (-4.2±1.1 g). These reductions in body mass in rAAV6:activin-injected mice correlated inversely with elevated serum activin A levels (7- to 24-fold). Mechanistically, we show that activin A reduces muscle mass and function by stimulating the ActRIIB pathway, leading to deleterious consequences, including increased transcription of atrophy-related ubiquitin ligases, decreased Akt/mTOR-mediated protein synthesis, and a profibrotic response. Critically, we demonstrate that the muscle wasting and fibrosis that ensues in response to excessive activin levels is fully reversible. These findings highlight the therapeutic potential of targeting activins in cachexia.
authors.affiliation: 2Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St. Kilda Rd. Central, Melbourne 8008, Australia. paul.gregorevic@bakeridi.edu.au.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Chen
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Walton
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Winbanks
authors.forename: Kate T
authors.initials: KT
authors.lastname: Murphy
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Thomson
authors.forename: Yogeshwar
authors.initials: Y
authors.lastname: Makanji
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qian
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Lynch
authors.forename: Craig A
authors.initials: CA
authors.lastname: Harrison
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D028341:Activins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002100:Cachexia / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics* / Q000378:metabolism; D055435:Myostatin / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C525912:Mstn protein, mouse; D009124:Muscle Proteins; D055435:Myostatin; C422405:activin A; C044147:activin B; D028341:Activins; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B
keywords: adeno-associated virus; atrophy; myostatin