Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy
| Autor: | Steven A. Bullard, Daryl J. Murry, Daniel K. Fox, Jason M. Dierdorff, Christopher M. Adams, Kale S. Bongers, Michael C. Dyle, David K. Meyerholz, John J. Talley, Scott M. Ebert, Vitor A. Lira |
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| Rok vydání: | 2015 |
| Předmět: |
muscle atrophy
Male Aging Sarcopenia medicine.medical_specialty Weakness protein synthesis skeletal muscle metabolism Gene Expression ursolic acid Biology Biochemistry Mice Tomatine 03 medical and health sciences chemistry.chemical_compound skeletal muscle atrophy 0302 clinical medicine Atrophy Ursolic acid Internal medicine medicine Animals ATF4 RNA Messenger skeletal muscle Muscle Skeletal Molecular Biology 030304 developmental biology 2. Zero hunger 0303 health sciences Skeletal muscle Muscle weakness Molecular Bases of Disease Cell Biology medicine.disease Activating Transcription Factor 4 Triterpenes Muscle atrophy Mice Inbred C57BL medicine.anatomical_structure Endocrinology chemistry medicine.symptom tomatidine 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | Background: Aging reduces skeletal muscle strength and mass. Results: The transcription factor ATF4 is required for age-related muscle weakness and atrophy, and the small molecules ursolic acid and tomatidine reduce ATF4 activity, weakness, and atrophy in aged skeletal muscle. Conclusion: ATF4 is an essential mediator of muscle aging. Significance: These results identify new strategies for reducing weakness and muscle loss during aging. 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. |
| Databáze: | OpenAIRE |
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