Related Experiment Video
Updated: Apr 4, 2026
Author Spotlight: A Selective Luciferase-Based Assay for Monitoring ATG4B 27 Activity in Cells
Published on: June 30, 2023
Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to
Scott M Ebert1, Michael C Dyle2, Steven A Bullard3
1From 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.
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.
Insights
Aging causes muscle weakness and atrophy. Ursolic acid and tomatidine, found in apples and green tomatoes, mitigate these age-related muscle deficits by targeting activating transcription factor 4 (ATF4).
Area of Science:
- Gerontology
- Skeletal Muscle Biology
- Molecular Mechanisms of Aging
Background:
- Aging is characterized by a progressive decline in skeletal muscle mass and strength.
- The molecular pathways driving age-related muscle weakness and atrophy are not fully understood.
- Identifying interventions to counteract these age-related changes is crucial for maintaining healthspan.
Purpose of the Study:
- To investigate the molecular mechanisms underlying age-related skeletal muscle decline.
- To identify potential therapeutic compounds for mitigating age-related muscle deficits.
- To elucidate the role of activating transcription factor 4 (ATF4) in muscle aging.
Main Methods:
- Utilized mouse models to study age-related skeletal muscle changes.
- Administered ursolic acid and tomatidine to assess their effects on muscle health.
- Analyzed mRNA expression profiles to understand compound-induced molecular changes.
- Investigated the role of ATF4 by reducing its expression in skeletal muscle.
Main Results:
- Ursolic acid and tomatidine significantly improved age-related skeletal muscle strength, quality, and mass.
- Both compounds induced similar changes in mRNA expression in aged skeletal muscle.
- A subset of genes repressed by these compounds were positively regulated by ATF4.
- Targeted reduction of ATF4 in skeletal muscle mimicked the beneficial effects of ursolic acid and tomatidine.
Conclusions:
- Activating transcription factor 4 (ATF4) is a critical mediator of age-related skeletal muscle weakness and atrophy.
- Ursolic acid and tomatidine show potential as therapeutic agents or lead compounds for combating muscle aging.
- These findings provide a molecular basis for using ursolic acid and tomatidine to improve muscle health in aging individuals.
