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

Scott M Ebert; Michael C Dyle; Steven A Bullard; Jason M Dierdorff; Daryl J Murry; Daniel K Fox; Kale S Bongers; Vitor A Lira; David K Meyerholz; John J Talley; Christopher M Adams

doi:10.1074/jbc.M115.681445

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

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

Scott M Ebert, Michael C Dyle, Steven A Bullard, Jason M Dierdorff, Daryl J Murry, Daniel K Fox, Kale S Bongers, Vitor A Lira, David K Meyerholz, John J Talley, …

The Journal of biological chemistry, Vol.290(42), pp.25497-25511

10/16/2015

DOI: 10.1074/jbc.M115.681445

PMCID: PMC4646196

PMID: 26338703

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Abstract

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.

Activating Transcription Factor 4 - antagonists & inhibitors

Triterpenes - pharmacology

Gene Expression - drug effects

Mice, Inbred C57BL

RNA, Messenger - genetics

Activating Transcription Factor 4 - genetics

Male

Muscle, Skeletal - metabolism

Tomatine - analogs & derivatives

Tomatine - pharmacology

Aging - pathology

Animals

Sarcopenia - prevention & control

Sarcopenia - pathology

Mice

Muscle, Skeletal - pathology

Activating Transcription Factor 4 - physiology

Sarcopenia - metabolism

Details

Title: Subtitle: Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy
Creators: Scott M Ebert - From the Departments of Internal Medicine, the Fraternal Order of Eagles Diabetes Research Center, and the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246, and Emmyon, Inc., Coralville, Iowa 52241
Michael C Dyle - From the Departments of Internal Medicine, the Fraternal Order of Eagles Diabetes Research Center, and the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246, and Molecular Physiology and Biophysics
Steven A Bullard - From the Departments of Internal Medicine, the Fraternal Order of Eagles Diabetes Research Center, and the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246, and
Jason M Dierdorff - From the Departments of Internal Medicine, the Fraternal Order of Eagles Diabetes Research Center, and the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246, and
Daryl J Murry - the College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242
Daniel K Fox - From the Departments of Internal Medicine, the Fraternal Order of Eagles Diabetes Research Center, and the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246, and Molecular Physiology and Biophysics
Kale S Bongers - From the Departments of Internal Medicine, the Fraternal Order of Eagles Diabetes Research Center, and the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246, and Molecular Physiology and Biophysics
Vitor A Lira - the Fraternal Order of Eagles Diabetes Research Center, and Health and Human Physiology, and
David K Meyerholz - Pathology
John J Talley - Emmyon, Inc., Coralville, Iowa 52241
Christopher M Adams - From the Departments of Internal Medicine, the Fraternal Order of Eagles Diabetes Research Center, and the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246, and Emmyon, Inc., Coralville, Iowa 52241 Molecular Physiology and Biophysics, christopher-adams@uiowa.edu
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.290(42), pp.25497-25511
DOI: 10.1074/jbc.M115.681445
PMID: 26338703
PMCID: PMC4646196
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: I01 BX000976 / BLRD VA R43 AG044898 / NIA NIH HHS T32 GM007337 / NIGMS NIH HHS 1F31AG04603801 / NIA NIH HHS I01 RX001477 / RRD VA 1R01AR059115 / NIAMS NIH HHS F30 AG044964 / NIA NIH HHS 1R43AG044898 / NIA NIH HHS P30 DK054759 / NIDDK NIH HHS R01 AR059115 / NIAMS NIH HHS
Language: English
Date published: 10/16/2015
Academic Unit: Molecular Physiology and Biophysics; Pathology; Holden Comprehensive Cancer Center; Health, Sport, and Human Physiology ; Internal Medicine
Record Identifier: 9984025478002771

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