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[PMID]: | 28467930 |
[Au] Autor: | Park SJ; Gavrilova O; Brown AL; Soto JE; Bremner S; Kim J; Xu X; Yang S; Um JH; Koch LG; Britton SL; Lieber RL; Philp A; Baar K; Kohama SG; Abel ED; Kim MK; Chung JH |
[Ad] Endereço: | Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. |
[Ti] Título: | DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging. |
[So] Source: | Cell Metab;25(5):1135-1146.e7, 2017 May 02. | [Is] ISSN: | 1932-7420 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | Hallmarks of aging that negatively impact health include weight gain and reduced physical fitness, which can increase insulin resistance and risk for many diseases, including type 2 diabetes. The underlying mechanism(s) for these phenomena is poorly understood. Here we report that aging increases DNA breaks and activates DNA-dependent protein kinase (DNA-PK) in skeletal muscle, which suppresses mitochondrial function, energy metabolism, and physical fitness. DNA-PK phosphorylates threonines 5 and 7 of HSP90α, decreasing its chaperone function for clients such as AMP-activated protein kinase (AMPK), which is critical for mitochondrial biogenesis and energy metabolism. Decreasing DNA-PK activity increases AMPK activity and prevents weight gain, decline of mitochondrial function, and decline of physical fitness in middle-aged mice and protects against type 2 diabetes. In conclusion, DNA-PK is one of the drivers of the metabolic and fitness decline during aging, and therefore DNA-PK inhibitors may have therapeutic potential in obesity and low exercise capacity. |
[Mh] Termos MeSH primário: |
Envelhecimento Proteína Quinase Ativada por DNA/metabolismo Metabolismo Energético Músculo Esquelético/fisiologia
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[Mh] Termos MeSH secundário: |
Proteínas Quinases Ativadas por AMP/metabolismo Animais Benzofuranos Diabetes Mellitus Tipo 2/metabolismo Macaca mulatta Camundongos SCID Mitocôndrias Musculares/metabolismo Condicionamento Físico Animal Quinolinas Ratos
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 ((3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide); 0 (Benzofurans); 0 (Quinolines); EC 2.7.11.1 (DNA-Activated Protein Kinase); EC 2.7.11.31 (AMP-Activated Protein Kinases) |
[Em] Mês de entrada: | 1802 |
[Cu] Atualização por classe: | 180219 |
[Lr] Data última revisão:
| 180219 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170504 |
[St] Status: | MEDLINE |
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