Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy.
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.
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.
Scott M
SM
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 Molecular Physiology and Biophysics.
Michael C
MC
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.
Steven A
SA
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
JM
Dierdorff
the College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242.
Daryl J
DJ
Murry
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.
Daniel K
DK
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
KS
Bongers
the Fraternal Order of Eagles Diabetes Research Center, and Health and Human Physiology, and.
Vitor A
VA
Lira
Pathology.
David K
DK
Meyerholz
Emmyon, Inc., Coralville, Iowa 52241.
John J
JJ
Talley
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.
Christopher M
CM
Adams
D051701:Activating Transcription Factor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000375:Aging / Q000473:pathology*; D000818:Animals; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D055948:Sarcopenia / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D014053:Tomatine / Q000031:analogs & derivatives / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology; D000097245:Ursolic Acid
D051701:Activating Transcription Factor 4; D012333:RNA, Messenger; D014053:Tomatine; D014315:Triterpenes; D000097245:Ursolic Acid; C081452:Atf4 protein, mouse; C003677:tomatidine
ATF4; aging; muscle atrophy; protein synthesis; sarcopenia; skeletal muscle; skeletal muscle atrophy; skeletal muscle metabolism; tomatidine; ursolic acid