Elevated expression of activins promotes muscle wasting and cachexia

Justin L Chen, Kelly Walton, Catherine E Winbanks, Kate T Murphy, Rachel E Thomson, Yogeshwar Makanji, Hongwei Qian, Gordon S Lynch, Craig A Harrison, Paul Gregorevic

Research output: Contribution to journalArticleResearchpeer-review

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-beta 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.
Original languageEnglish
Pages (from-to)1711 - 1723
Number of pages13
JournalFASEB Journal
Volume28
Issue number4
DOIs
Publication statusPublished - 2014

Cite this

Chen, J. L., Walton, K., Winbanks, C. E., Murphy, K. T., Thomson, R. E., Makanji, Y., ... Gregorevic, P. (2014). Elevated expression of activins promotes muscle wasting and cachexia. FASEB Journal, 28(4), 1711 - 1723. https://doi.org/10.1096/fj.13-245894
Chen, Justin L ; Walton, Kelly ; Winbanks, Catherine E ; Murphy, Kate T ; Thomson, Rachel E ; Makanji, Yogeshwar ; Qian, Hongwei ; Lynch, Gordon S ; Harrison, Craig A ; Gregorevic, Paul. / Elevated expression of activins promotes muscle wasting and cachexia. In: FASEB Journal. 2014 ; Vol. 28, No. 4. pp. 1711 - 1723.
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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-beta 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.",
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Chen, JL, Walton, K, Winbanks, CE, Murphy, KT, Thomson, RE, Makanji, Y, Qian, H, Lynch, GS, Harrison, CA & Gregorevic, P 2014, 'Elevated expression of activins promotes muscle wasting and cachexia' FASEB Journal, vol. 28, no. 4, pp. 1711 - 1723. https://doi.org/10.1096/fj.13-245894

Elevated expression of activins promotes muscle wasting and cachexia. / Chen, Justin L; Walton, Kelly; Winbanks, Catherine E; Murphy, Kate T; Thomson, Rachel E; Makanji, Yogeshwar; Qian, Hongwei; Lynch, Gordon S; Harrison, Craig A; Gregorevic, Paul.

In: FASEB Journal, Vol. 28, No. 4, 2014, p. 1711 - 1723.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Elevated expression of activins promotes muscle wasting and cachexia

AU - Chen, Justin L

AU - Walton, Kelly

AU - Winbanks, Catherine E

AU - Murphy, Kate T

AU - Thomson, Rachel E

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AU - Qian, Hongwei

AU - Lynch, Gordon S

AU - Harrison, Craig A

AU - Gregorevic, Paul

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AB - 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-beta 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.

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U2 - 10.1096/fj.13-245894

DO - 10.1096/fj.13-245894

M3 - Article

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JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

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ER -

Chen JL, Walton K, Winbanks CE, Murphy KT, Thomson RE, Makanji Y et al. Elevated expression of activins promotes muscle wasting and cachexia. FASEB Journal. 2014;28(4):1711 - 1723. https://doi.org/10.1096/fj.13-245894