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Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition

The purpose of our study was to compare two acquired muscle atrophies and the use of myostatin inhibition for their treatment. Myostatin naturally inhibits skeletal muscle growth by binding to ActRIIB, a receptor on the cell surface of myofibers. Because blocking myostatin in an adult wild-type mous...

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Autores principales: MacDonald, Elizabeth M., Andres-Mateos, Eva, Mejias, Rebeca, Simmers, Jessica L., Mi, Ruifa, Park, Jae-Sung, Ying, Stephanie, Hoke, Ahmet, Lee, Se-Jin, Cohn, Ronald D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Limited 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974457/
https://www.ncbi.nlm.nih.gov/pubmed/24504412
http://dx.doi.org/10.1242/dmm.014126
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author MacDonald, Elizabeth M.
Andres-Mateos, Eva
Mejias, Rebeca
Simmers, Jessica L.
Mi, Ruifa
Park, Jae-Sung
Ying, Stephanie
Hoke, Ahmet
Lee, Se-Jin
Cohn, Ronald D.
author_facet MacDonald, Elizabeth M.
Andres-Mateos, Eva
Mejias, Rebeca
Simmers, Jessica L.
Mi, Ruifa
Park, Jae-Sung
Ying, Stephanie
Hoke, Ahmet
Lee, Se-Jin
Cohn, Ronald D.
author_sort MacDonald, Elizabeth M.
collection PubMed
description The purpose of our study was to compare two acquired muscle atrophies and the use of myostatin inhibition for their treatment. Myostatin naturally inhibits skeletal muscle growth by binding to ActRIIB, a receptor on the cell surface of myofibers. Because blocking myostatin in an adult wild-type mouse induces profound muscle hypertrophy, we applied a soluble ActRIIB receptor to models of disuse (limb immobilization) and denervation (sciatic nerve resection) atrophy. We found that treatment of immobilized mice with ActRIIB prevented the loss of muscle mass observed in placebo-treated mice. Our results suggest that this protection from disuse atrophy is regulated by serum and glucocorticoid-induced kinase (SGK) rather than by Akt. Denervation atrophy, however, was not protected by ActRIIB treatment, yet resulted in an upregulation of the pro-growth factors Akt, SGK and components of the mTOR pathway. We then treated the denervated mice with the mTOR inhibitor rapamycin and found that, despite a reduction in mTOR activation, there is no alteration of the atrophy phenotype. Additionally, rapamycin prevented the denervation-induced upregulation of the mTORC2 substrates Akt and SGK. Thus, our studies show that denervation atrophy is not only independent from Akt, SGK and mTOR activation but also has a different underlying pathophysiological mechanism than disuse atrophy.
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spelling pubmed-39744572014-04-04 Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition MacDonald, Elizabeth M. Andres-Mateos, Eva Mejias, Rebeca Simmers, Jessica L. Mi, Ruifa Park, Jae-Sung Ying, Stephanie Hoke, Ahmet Lee, Se-Jin Cohn, Ronald D. Dis Model Mech Research Articles The purpose of our study was to compare two acquired muscle atrophies and the use of myostatin inhibition for their treatment. Myostatin naturally inhibits skeletal muscle growth by binding to ActRIIB, a receptor on the cell surface of myofibers. Because blocking myostatin in an adult wild-type mouse induces profound muscle hypertrophy, we applied a soluble ActRIIB receptor to models of disuse (limb immobilization) and denervation (sciatic nerve resection) atrophy. We found that treatment of immobilized mice with ActRIIB prevented the loss of muscle mass observed in placebo-treated mice. Our results suggest that this protection from disuse atrophy is regulated by serum and glucocorticoid-induced kinase (SGK) rather than by Akt. Denervation atrophy, however, was not protected by ActRIIB treatment, yet resulted in an upregulation of the pro-growth factors Akt, SGK and components of the mTOR pathway. We then treated the denervated mice with the mTOR inhibitor rapamycin and found that, despite a reduction in mTOR activation, there is no alteration of the atrophy phenotype. Additionally, rapamycin prevented the denervation-induced upregulation of the mTORC2 substrates Akt and SGK. Thus, our studies show that denervation atrophy is not only independent from Akt, SGK and mTOR activation but also has a different underlying pathophysiological mechanism than disuse atrophy. The Company of Biologists Limited 2014-04 2014-02-06 /pmc/articles/PMC3974457/ /pubmed/24504412 http://dx.doi.org/10.1242/dmm.014126 Text en © 2014. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Articles
MacDonald, Elizabeth M.
Andres-Mateos, Eva
Mejias, Rebeca
Simmers, Jessica L.
Mi, Ruifa
Park, Jae-Sung
Ying, Stephanie
Hoke, Ahmet
Lee, Se-Jin
Cohn, Ronald D.
Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition
title Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition
title_full Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition
title_fullStr Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition
title_full_unstemmed Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition
title_short Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition
title_sort denervation atrophy is independent from akt and mtor activation and is not rescued by myostatin inhibition
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974457/
https://www.ncbi.nlm.nih.gov/pubmed/24504412
http://dx.doi.org/10.1242/dmm.014126
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