دورية أكاديمية
Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy.
| العنوان: | Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy. |
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| المؤلفون: | Ebert SM; 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., Dyle MC; 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., Bullard SA; 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., Dierdorff JM; 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., Murry DJ; the College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242., Fox DK; 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., Bongers KS; 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., Lira VA; the Fraternal Order of Eagles Diabetes Research Center, and Health and Human Physiology, and., Meyerholz DK; Pathology., Talley JJ; Emmyon, Inc., Coralville, Iowa 52241., Adams CM; 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. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2015 Oct 16; Vol. 290 (42), pp. 25497-511. Date of Electronic Publication: 2015 Sep 03. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Activating Transcription Factor 4/*antagonists & inhibitors , Aging/*pathology , Muscle, Skeletal/*metabolism , Sarcopenia/*metabolism, Activating Transcription Factor 4/genetics ; Activating Transcription Factor 4/physiology ; Animals ; Gene Expression/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Muscle, Skeletal/pathology ; RNA, Messenger/genetics ; Sarcopenia/pathology ; Sarcopenia/prevention & control ; Tomatine/analogs & derivatives ; Tomatine/pharmacology ; Triterpenes/pharmacology ; Ursolic Acid |
| مستخلص: | 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. (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.) |
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| معلومات مُعتمدة: | I01 BX000976 United States BX BLRD VA; R43 AG044898 United States AG NIA NIH HHS; 1R43AG044898 United States AG NIA NIH HHS; 1F31AG04603801 United States AG NIA NIH HHS; 1R01AR059115 United States AR NIAMS NIH HHS; P30 DK054759 United States DK NIDDK NIH HHS; T32 GM007337 United States GM NIGMS NIH HHS; I01 RX001477 United States RX RRD VA; R01 AR059115 United States AR NIAMS NIH HHS; F30 AG044964 United States AG NIA NIH HHS |
| فهرسة مساهمة: | Keywords: ATF4; aging; muscle atrophy; protein synthesis; sarcopenia; skeletal muscle; skeletal muscle atrophy; skeletal muscle metabolism; tomatidine; ursolic acid |
| المشرفين على المادة: | 0 (Atf4 protein, mouse) 0 (RNA, Messenger) 0 (Triterpenes) 145891-90-3 (Activating Transcription Factor 4) 2B73S48786 (tomatidine) 31U6547O08 (Tomatine) |
| تواريخ الأحداث: | Date Created: 20150905 Date Completed: 20160216 Latest Revision: 20231213 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC4646196 |
| DOI: | 10.1074/jbc.M115.681445 |
| PMID: | 26338703 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1083-351X |
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| DOI: | 10.1074/jbc.M115.681445 |