Activin A-Induced Cachectic Wasting Is Attenuated by Systemic Delivery of Its Cognate Propeptide in Male Mice

Kelly L. Walton, Justin L. Chen, Quinn Arnold, Emily Kelly, Mylinh La, Louis Lu, George Lovrecz, Adam Hagg, Timothy D. Colgan, Hongwei Qian, Paul Gregorevic, Craig A. Harrison

Research output: Contribution to journalArticleResearchpeer-review

Abstract

In cancer, elevated activin levels promote cachectic wasting of muscle, irrespective of tumor progression. In excess, activins A and B use the myostatin signaling pathway in muscle, triggering a decrease in protein synthesis and an increase in protein degradation, which ultimately leads to atrophy. Recently, we demonstrated that local delivery of engineered activin and myostatin propeptides (natural inhibitors of these growth factors) could induce profound muscle hypertrophy in healthy mice. Additionally, the expression of these propeptides effectively attenuated localized muscle wasting in models of dystrophy and cancer cachexia. In this study, we examined whether a systemically administered recombinant propeptide could reverse activin A-induced cachectic wasting in mice. Chinese hamster ovary cells stably expressing activin A were transplanted into the quadriceps of nude mice and caused an 85-fold increase in circulating activin A levels within 12 days. Elevated activin A induced a rapid reduction in body mass (-16%) and lean mass (-10%). In agreement with previous findings, we demonstrated that adeno-associated virus-mediated delivery of activin propeptide to the tibialis anterior muscle blocked activin-induced wasting. In addition, despite massively elevated levels of activin A in this model, systemic delivery of the propeptide significantly reduced activin-induced changes in lean and body mass. Specifically, recombinant propeptide reversed activin-induced wasting of skeletal muscle, heart, liver, and kidneys. This is the first study to demonstrate that systemic administration of recombinant propeptide therapy effectively attenuates tumor-derived activin A insult in multiple tissues.

Original languageEnglish
Pages (from-to)2417-2426
Number of pages10
JournalEndocrinology
Volume160
Issue number10
DOIs
Publication statusPublished - 1 Oct 2019

Cite this

Walton, Kelly L. ; Chen, Justin L. ; Arnold, Quinn ; Kelly, Emily ; La, Mylinh ; Lu, Louis ; Lovrecz, George ; Hagg, Adam ; Colgan, Timothy D. ; Qian, Hongwei ; Gregorevic, Paul ; Harrison, Craig A. / Activin A-Induced Cachectic Wasting Is Attenuated by Systemic Delivery of Its Cognate Propeptide in Male Mice. In: Endocrinology. 2019 ; Vol. 160, No. 10. pp. 2417-2426.
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abstract = "In cancer, elevated activin levels promote cachectic wasting of muscle, irrespective of tumor progression. In excess, activins A and B use the myostatin signaling pathway in muscle, triggering a decrease in protein synthesis and an increase in protein degradation, which ultimately leads to atrophy. Recently, we demonstrated that local delivery of engineered activin and myostatin propeptides (natural inhibitors of these growth factors) could induce profound muscle hypertrophy in healthy mice. Additionally, the expression of these propeptides effectively attenuated localized muscle wasting in models of dystrophy and cancer cachexia. In this study, we examined whether a systemically administered recombinant propeptide could reverse activin A-induced cachectic wasting in mice. Chinese hamster ovary cells stably expressing activin A were transplanted into the quadriceps of nude mice and caused an 85-fold increase in circulating activin A levels within 12 days. Elevated activin A induced a rapid reduction in body mass (-16{\%}) and lean mass (-10{\%}). In agreement with previous findings, we demonstrated that adeno-associated virus-mediated delivery of activin propeptide to the tibialis anterior muscle blocked activin-induced wasting. In addition, despite massively elevated levels of activin A in this model, systemic delivery of the propeptide significantly reduced activin-induced changes in lean and body mass. Specifically, recombinant propeptide reversed activin-induced wasting of skeletal muscle, heart, liver, and kidneys. This is the first study to demonstrate that systemic administration of recombinant propeptide therapy effectively attenuates tumor-derived activin A insult in multiple tissues.",
author = "Walton, {Kelly L.} and Chen, {Justin L.} and Quinn Arnold and Emily Kelly and Mylinh La and Louis Lu and George Lovrecz and Adam Hagg and Colgan, {Timothy D.} and Hongwei Qian and Paul Gregorevic and Harrison, {Craig A.}",
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Activin A-Induced Cachectic Wasting Is Attenuated by Systemic Delivery of Its Cognate Propeptide in Male Mice. / Walton, Kelly L.; Chen, Justin L.; Arnold, Quinn; Kelly, Emily; La, Mylinh; Lu, Louis; Lovrecz, George; Hagg, Adam; Colgan, Timothy D.; Qian, Hongwei; Gregorevic, Paul; Harrison, Craig A.

In: Endocrinology, Vol. 160, No. 10, 01.10.2019, p. 2417-2426.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Activin A-Induced Cachectic Wasting Is Attenuated by Systemic Delivery of Its Cognate Propeptide in Male Mice

AU - Walton, Kelly L.

AU - Chen, Justin L.

AU - Arnold, Quinn

AU - Kelly, Emily

AU - La, Mylinh

AU - Lu, Louis

AU - Lovrecz, George

AU - Hagg, Adam

AU - Colgan, Timothy D.

AU - Qian, Hongwei

AU - Gregorevic, Paul

AU - Harrison, Craig A.

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Y1 - 2019/10/1

N2 - In cancer, elevated activin levels promote cachectic wasting of muscle, irrespective of tumor progression. In excess, activins A and B use the myostatin signaling pathway in muscle, triggering a decrease in protein synthesis and an increase in protein degradation, which ultimately leads to atrophy. Recently, we demonstrated that local delivery of engineered activin and myostatin propeptides (natural inhibitors of these growth factors) could induce profound muscle hypertrophy in healthy mice. Additionally, the expression of these propeptides effectively attenuated localized muscle wasting in models of dystrophy and cancer cachexia. In this study, we examined whether a systemically administered recombinant propeptide could reverse activin A-induced cachectic wasting in mice. Chinese hamster ovary cells stably expressing activin A were transplanted into the quadriceps of nude mice and caused an 85-fold increase in circulating activin A levels within 12 days. Elevated activin A induced a rapid reduction in body mass (-16%) and lean mass (-10%). In agreement with previous findings, we demonstrated that adeno-associated virus-mediated delivery of activin propeptide to the tibialis anterior muscle blocked activin-induced wasting. In addition, despite massively elevated levels of activin A in this model, systemic delivery of the propeptide significantly reduced activin-induced changes in lean and body mass. Specifically, recombinant propeptide reversed activin-induced wasting of skeletal muscle, heart, liver, and kidneys. This is the first study to demonstrate that systemic administration of recombinant propeptide therapy effectively attenuates tumor-derived activin A insult in multiple tissues.

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DO - 10.1210/en.2019-00257

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