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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

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.

The Journal of biological chemistry, 2015-10, Vol.290 (42), p.25497-25511 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy
Autor: 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.
Assuntos: Activating Transcription Factor 4 - antagonists & inhibitors ; Activating Transcription Factor 4 - genetics ; Activating Transcription Factor 4 - physiology ; aging ; Aging - pathology ; Animals ; ATF4 ; Gene Expression - drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Bases of Disease ; muscle atrophy ; Muscle, Skeletal - metabolism ; Muscle, Skeletal - pathology ; protein synthesis ; RNA, Messenger - genetics ; sarcopenia ; Sarcopenia - metabolism ; Sarcopenia - pathology ; Sarcopenia - prevention & control ; skeletal muscle ; skeletal muscle atrophy ; skeletal muscle metabolism ; tomatidine ; Tomatine - analogs & derivatives ; Tomatine - pharmacology ; Triterpenes - pharmacology ; Ursolic Acid
É parte de: The Journal of biological chemistry, 2015-10, Vol.290 (42), p.25497-25511
Descrição: 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. 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.
Editor: United States: Elsevier Inc
Idioma: Inglês

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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

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.

United States: Elsevier Inc

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