Specific targeting of TGF-β family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease

Justin Chen, Kelly L Walton, Adam George Hagg, Timothy D Colgan, Katharine Elizabeth Johnson, Hongwei Qian, Paul Gregorevic, Craig A. Harrison

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The transforming growth factor-β (TGF-β) network of ligands and intracellular signaling proteins is a subject of intense interest within the field of skeletal muscle biology. To define the relative contribution of endogenous TGF-β proteins to the negative regulation of muscle mass via their activation of the Smad2/3 signaling axis, we used local injection of adeno-associated viral vectors (AAVs) encoding ligand-specific antagonists into the tibialis anterior (TA) muscles of C57BL/6 mice. Eight weeks after AAV injection, inhibition of activin A and activin B signaling produced moderate (-20%), but significant, increases in TA mass, indicating that endogenous activins repress muscle growth. Inhibiting myostatin induced a more profound increase in muscle mass (-45%), demonstrating a more prominent role for this ligand as a negative regulator of adult muscle mass. Remarkably, codelivery of activin and myostatin inhibitors induced a synergistic response, resulting in muscle mass increasing by as much as 150%. Transcription and protein analysis indicated that this substantial hypertrophy was associated with both the complete inhibition of the Smad2/3 pathway and activation of the parallel bone morphogenetic protein (BMP)/Smad1/5 axis (recently identified as a positive regulator of muscle mass). Analyses indicated that hypertrophy was primarily driven by an increase in protein synthesis, but a reduction in ubiquitin-dependent protein degradation pathways was also observed. In models of muscular dystrophy and cancer cachexia, combined inhibition of activins and myostatin increased mass or prevented muscle wasting, respectively, highlighting the potential therapeutic advantages of specifically targeting multiple Smad2/3-activating ligands in skeletal muscle.

Original languageEnglish
Pages (from-to)E5266-E5275
Number of pages10
JournalProceedings of the National Academy of Sciences
Volume114
Issue number26
DOIs
Publication statusPublished - 27 Jun 2017

Cite this

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title = "Specific targeting of TGF-β family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease",
abstract = "The transforming growth factor-β (TGF-β) network of ligands and intracellular signaling proteins is a subject of intense interest within the field of skeletal muscle biology. To define the relative contribution of endogenous TGF-β proteins to the negative regulation of muscle mass via their activation of the Smad2/3 signaling axis, we used local injection of adeno-associated viral vectors (AAVs) encoding ligand-specific antagonists into the tibialis anterior (TA) muscles of C57BL/6 mice. Eight weeks after AAV injection, inhibition of activin A and activin B signaling produced moderate (-20{\%}), but significant, increases in TA mass, indicating that endogenous activins repress muscle growth. Inhibiting myostatin induced a more profound increase in muscle mass (-45{\%}), demonstrating a more prominent role for this ligand as a negative regulator of adult muscle mass. Remarkably, codelivery of activin and myostatin inhibitors induced a synergistic response, resulting in muscle mass increasing by as much as 150{\%}. Transcription and protein analysis indicated that this substantial hypertrophy was associated with both the complete inhibition of the Smad2/3 pathway and activation of the parallel bone morphogenetic protein (BMP)/Smad1/5 axis (recently identified as a positive regulator of muscle mass). Analyses indicated that hypertrophy was primarily driven by an increase in protein synthesis, but a reduction in ubiquitin-dependent protein degradation pathways was also observed. In models of muscular dystrophy and cancer cachexia, combined inhibition of activins and myostatin increased mass or prevented muscle wasting, respectively, highlighting the potential therapeutic advantages of specifically targeting multiple Smad2/3-activating ligands in skeletal muscle.",
author = "Justin Chen and Walton, {Kelly L} and Hagg, {Adam George} and Colgan, {Timothy D} and Johnson, {Katharine Elizabeth} and Hongwei Qian and Paul Gregorevic and Harrison, {Craig A.}",
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doi = "10.1073/pnas.1620013114",
language = "English",
volume = "114",
pages = "E5266--E5275",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
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Specific targeting of TGF-β family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease. / Chen, Justin; Walton, Kelly L; Hagg, Adam George; Colgan, Timothy D; Johnson, Katharine Elizabeth; Qian, Hongwei; Gregorevic, Paul; Harrison, Craig A.

In: Proceedings of the National Academy of Sciences, Vol. 114, No. 26, 27.06.2017, p. E5266-E5275.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Specific targeting of TGF-β family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease

AU - Chen, Justin

AU - Walton, Kelly L

AU - Hagg, Adam George

AU - Colgan, Timothy D

AU - Johnson, Katharine Elizabeth

AU - Qian, Hongwei

AU - Gregorevic, Paul

AU - Harrison, Craig A.

PY - 2017/6/27

Y1 - 2017/6/27

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AB - The transforming growth factor-β (TGF-β) network of ligands and intracellular signaling proteins is a subject of intense interest within the field of skeletal muscle biology. To define the relative contribution of endogenous TGF-β proteins to the negative regulation of muscle mass via their activation of the Smad2/3 signaling axis, we used local injection of adeno-associated viral vectors (AAVs) encoding ligand-specific antagonists into the tibialis anterior (TA) muscles of C57BL/6 mice. Eight weeks after AAV injection, inhibition of activin A and activin B signaling produced moderate (-20%), but significant, increases in TA mass, indicating that endogenous activins repress muscle growth. Inhibiting myostatin induced a more profound increase in muscle mass (-45%), demonstrating a more prominent role for this ligand as a negative regulator of adult muscle mass. Remarkably, codelivery of activin and myostatin inhibitors induced a synergistic response, resulting in muscle mass increasing by as much as 150%. Transcription and protein analysis indicated that this substantial hypertrophy was associated with both the complete inhibition of the Smad2/3 pathway and activation of the parallel bone morphogenetic protein (BMP)/Smad1/5 axis (recently identified as a positive regulator of muscle mass). Analyses indicated that hypertrophy was primarily driven by an increase in protein synthesis, but a reduction in ubiquitin-dependent protein degradation pathways was also observed. In models of muscular dystrophy and cancer cachexia, combined inhibition of activins and myostatin increased mass or prevented muscle wasting, respectively, highlighting the potential therapeutic advantages of specifically targeting multiple Smad2/3-activating ligands in skeletal muscle.

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U2 - 10.1073/pnas.1620013114

DO - 10.1073/pnas.1620013114

M3 - Article

VL - 114

SP - E5266-E5275

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 26

ER -