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TMEPAI/PMEPA1 Is a Positive Regulator of Skeletal Muscle Mass

Inhibition of myostatin- and activin-mediated SMAD2/3 signaling using ligand traps, such as soluble receptors, ligand-targeting propeptides and antibodies, or follistatin can increase skeletal muscle mass in healthy mice and ameliorate wasting in models of cancer cachexia and muscular dystrophy. How...

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Autores principales: Hagg, Adam, Kharoud, Swati, Goodchild, Georgia, Goodman, Craig A., Chen, Justin L., Thomson, Rachel E., Qian, Hongwei, Gregorevic, Paul, Harrison, Craig A., Walton, Kelly L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672205/
https://www.ncbi.nlm.nih.gov/pubmed/33250771
http://dx.doi.org/10.3389/fphys.2020.560225
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author Hagg, Adam
Kharoud, Swati
Goodchild, Georgia
Goodman, Craig A.
Chen, Justin L.
Thomson, Rachel E.
Qian, Hongwei
Gregorevic, Paul
Harrison, Craig A.
Walton, Kelly L.
author_facet Hagg, Adam
Kharoud, Swati
Goodchild, Georgia
Goodman, Craig A.
Chen, Justin L.
Thomson, Rachel E.
Qian, Hongwei
Gregorevic, Paul
Harrison, Craig A.
Walton, Kelly L.
author_sort Hagg, Adam
collection PubMed
description Inhibition of myostatin- and activin-mediated SMAD2/3 signaling using ligand traps, such as soluble receptors, ligand-targeting propeptides and antibodies, or follistatin can increase skeletal muscle mass in healthy mice and ameliorate wasting in models of cancer cachexia and muscular dystrophy. However, clinical translation of these extracellular approaches targeting myostatin and activin has been hindered by the challenges of achieving efficacy without potential effects in other tissues. Toward the goal of developing tissue-specific myostatin/activin interventions, we explored the ability of transmembrane prostate androgen-induced (TMEPAI), an inhibitor of transforming growth factor-β (TGF-β1)-mediated SMAD2/3 signaling, to promote growth, and counter atrophy, in skeletal muscle. In this study, we show that TMEPAI can block activin A, activin B, myostatin and GDF-11 activity in vitro. To determine the physiological significance of TMEPAI, we employed Adeno-associated viral vector (AAV) delivery of a TMEPAI expression cassette to the muscles of healthy mice, which increased mass by as much as 30%, due to hypertrophy of muscle fibers. To demonstrate that TMEPAI mediates its effects via inhibition of the SMAD2/3 pathway, tibialis anterior (TA) muscles of mice were co-injected with AAV vectors expressing activin A and TMEPAI. In this setting, TMEPAI blocked skeletal muscle wasting driven by activin-induced phosphorylation of SMAD3. In a model of cancer cachexia associated with elevated circulating activin A, delivery of AAV:TMEPAI into TA muscles of mice bearing C26 colon tumors ameliorated the muscle atrophy normally associated with cancer progression. Collectively, the findings indicate that muscle-directed TMEPAI gene delivery can inactivate the activin/myostatin-SMAD3 pathway to positively regulate muscle mass in healthy settings and models of disease.
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spelling pubmed-76722052020-11-26 TMEPAI/PMEPA1 Is a Positive Regulator of Skeletal Muscle Mass Hagg, Adam Kharoud, Swati Goodchild, Georgia Goodman, Craig A. Chen, Justin L. Thomson, Rachel E. Qian, Hongwei Gregorevic, Paul Harrison, Craig A. Walton, Kelly L. Front Physiol Physiology Inhibition of myostatin- and activin-mediated SMAD2/3 signaling using ligand traps, such as soluble receptors, ligand-targeting propeptides and antibodies, or follistatin can increase skeletal muscle mass in healthy mice and ameliorate wasting in models of cancer cachexia and muscular dystrophy. However, clinical translation of these extracellular approaches targeting myostatin and activin has been hindered by the challenges of achieving efficacy without potential effects in other tissues. Toward the goal of developing tissue-specific myostatin/activin interventions, we explored the ability of transmembrane prostate androgen-induced (TMEPAI), an inhibitor of transforming growth factor-β (TGF-β1)-mediated SMAD2/3 signaling, to promote growth, and counter atrophy, in skeletal muscle. In this study, we show that TMEPAI can block activin A, activin B, myostatin and GDF-11 activity in vitro. To determine the physiological significance of TMEPAI, we employed Adeno-associated viral vector (AAV) delivery of a TMEPAI expression cassette to the muscles of healthy mice, which increased mass by as much as 30%, due to hypertrophy of muscle fibers. To demonstrate that TMEPAI mediates its effects via inhibition of the SMAD2/3 pathway, tibialis anterior (TA) muscles of mice were co-injected with AAV vectors expressing activin A and TMEPAI. In this setting, TMEPAI blocked skeletal muscle wasting driven by activin-induced phosphorylation of SMAD3. In a model of cancer cachexia associated with elevated circulating activin A, delivery of AAV:TMEPAI into TA muscles of mice bearing C26 colon tumors ameliorated the muscle atrophy normally associated with cancer progression. Collectively, the findings indicate that muscle-directed TMEPAI gene delivery can inactivate the activin/myostatin-SMAD3 pathway to positively regulate muscle mass in healthy settings and models of disease. Frontiers Media S.A. 2020-11-04 /pmc/articles/PMC7672205/ /pubmed/33250771 http://dx.doi.org/10.3389/fphys.2020.560225 Text en Copyright © 2020 Hagg, Kharoud, Goodchild, Goodman, Chen, Thomson, Qian, Gregorevic, Harrison and Walton. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Hagg, Adam
Kharoud, Swati
Goodchild, Georgia
Goodman, Craig A.
Chen, Justin L.
Thomson, Rachel E.
Qian, Hongwei
Gregorevic, Paul
Harrison, Craig A.
Walton, Kelly L.
TMEPAI/PMEPA1 Is a Positive Regulator of Skeletal Muscle Mass
title TMEPAI/PMEPA1 Is a Positive Regulator of Skeletal Muscle Mass
title_full TMEPAI/PMEPA1 Is a Positive Regulator of Skeletal Muscle Mass
title_fullStr TMEPAI/PMEPA1 Is a Positive Regulator of Skeletal Muscle Mass
title_full_unstemmed TMEPAI/PMEPA1 Is a Positive Regulator of Skeletal Muscle Mass
title_short TMEPAI/PMEPA1 Is a Positive Regulator of Skeletal Muscle Mass
title_sort tmepai/pmepa1 is a positive regulator of skeletal muscle mass
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672205/
https://www.ncbi.nlm.nih.gov/pubmed/33250771
http://dx.doi.org/10.3389/fphys.2020.560225
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