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

摘要: Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate of age-related weakness atrophy as well new potential interventions for these conditions. We identified two small molecules that significantly reduce deficits in quality, mass: ursolic acid (a pentacyclic triterpenoid found apples) tomatidine steroidal alkaloid derived from green tomatoes). Because molecule inhibitors can sometimes provide mechanistic insight into disease processes, pathogenesis atrophy. generate hundreds positive negative changes mRNA levels aged muscle, expression signatures compounds are remarkably similar. Interestingly, a subset mRNAs repressed by positively regulated activating transcription factor 4 (ATF4). Based on this finding, investigated ATF4 mediator targeted reduction mass, similar tomatidine. These results elucidate critical In addition, identify agents and/or lead reducing activity, weakness, muscle.