Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy

Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two s...

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Autores principales: Ebert, Scott M., Dyle, Michael C., Bullard, Steven A., Dierdorff, Jason M., Murry, Daryl J., Fox, Daniel K., Bongers, Kale S., Lira, Vitor A., Meyerholz, David K., Talley, John J., Adams, Christopher M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646196/
https://www.ncbi.nlm.nih.gov/pubmed/26338703
http://dx.doi.org/10.1074/jbc.M115.681445
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author Ebert, Scott M.
Dyle, Michael C.
Bullard, Steven A.
Dierdorff, Jason M.
Murry, Daryl J.
Fox, Daniel K.
Bongers, Kale S.
Lira, Vitor A.
Meyerholz, David K.
Talley, John J.
Adams, Christopher M.
author_facet Ebert, Scott M.
Dyle, Michael C.
Bullard, Steven A.
Dierdorff, Jason M.
Murry, Daryl J.
Fox, Daniel K.
Bongers, Kale S.
Lira, Vitor A.
Meyerholz, David K.
Talley, John J.
Adams, Christopher M.
author_sort Ebert, Scott M.
collection PubMed
description Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle.
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spelling pubmed-46461962015-11-18 Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy Ebert, Scott M. Dyle, Michael C. Bullard, Steven A. Dierdorff, Jason M. Murry, Daryl J. Fox, Daniel K. Bongers, Kale S. Lira, Vitor A. Meyerholz, David K. Talley, John J. Adams, Christopher M. J Biol Chem Molecular Bases of Disease Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle. American Society for Biochemistry and Molecular Biology 2015-10-16 2015-09-03 /pmc/articles/PMC4646196/ /pubmed/26338703 http://dx.doi.org/10.1074/jbc.M115.681445 Text en © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0) .
spellingShingle Molecular Bases of Disease
Ebert, Scott M.
Dyle, Michael C.
Bullard, Steven A.
Dierdorff, Jason M.
Murry, Daryl J.
Fox, Daniel K.
Bongers, Kale S.
Lira, Vitor A.
Meyerholz, David K.
Talley, John J.
Adams, Christopher M.
Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy
title Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy
title_full Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy
title_fullStr Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy
title_full_unstemmed Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy
title_short Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy
title_sort identification and small molecule inhibition of an activating transcription factor 4 (atf4)-dependent pathway to age-related skeletal muscle weakness and atrophy
topic Molecular Bases of Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646196/
https://www.ncbi.nlm.nih.gov/pubmed/26338703
http://dx.doi.org/10.1074/jbc.M115.681445
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