Journal article
DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging
Cell metabolism, Vol.25(5), pp.1135-1146.e7
05/02/2017
DOI: 10.1016/j.cmet.2017.04.008
PMCID: PMC5485859
PMID: 28467930
Abstract
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.
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•Aging increases DNA DSBs and DNA-PK phosphorylation of HSP90α in skeletal muscle•HSP90α phosphorylation disrupts HSP90α chaperone function for the AMPK pathway•Inhibiting HSP90α phosphorylation prevents loss of AMPK activity and mitochondria•Inhibiting DNA-PK ameliorates obesity, type 2 diabetes and physical decline
Park et al. show that metabolic and fitness decline with age is mediated by a genetic program, not simply “wear and tear.” Increased DNA breaks in aged skeletal muscle induce DNA-PK phosphorylation of HSP90α, which decreases AMPK activity and mitochondrial function. Inhibiting DNA-PK ameliorates obesity, T2DM, and physical decline.
Details
- Title: Subtitle
- DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging
- Creators
- Sung-Jun Park - Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USAOksana Gavrilova - Mouse Metabolism Core, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USAAlexandra L Brown - Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USAJamie E Soto - Program in Molecular Medicine and Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT 84112, USAShannon Bremner - Department of Orthopedic Surgery, University of California and V.A. Medical Centers, San Diego, La Jolla, CA 92093, USAJeonghan Kim - Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USAXihui Xu - Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USAShutong Yang - Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USAJee-Hyun Um - Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USALauren G Koch - Department of Anesthesiology, The University of Michigan, Ann Arbor, MI 48109, USASteven L Britton - Department of Anesthesiology, The University of Michigan, Ann Arbor, MI 48109, USARichard L Lieber - Department of Orthopedic Surgery, University of California and V.A. Medical Centers, San Diego, La Jolla, CA 92093, USAAndrew Philp - Department of Physiology and Membrane Biology, University of California Davis, Davis, CA USA 95616Keith Baar - Department of Physiology and Membrane Biology, University of California Davis, Davis, CA USA 95616Steven G Kohama - Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Sciences University, Portland, OR 97239, USAE. Dale Abel - Program in Molecular Medicine and Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT 84112, USAMyung K Kim - Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USAJay H Chung - Laboratory of Obesity and Aging Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.25(5), pp.1135-1146.e7
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.cmet.2017.04.008
- PMID
- 28467930
- PMCID
- PMC5485859
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Grant note
- name: NIH, award: HL73167; name: Office of Research Infrastructure Programs, award: P40OD021331; DOI: 10.13039/501100003710, name: Korea Health Industry Development Institute, award: HI14C1176
- Language
- English
- Date published
- 05/02/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024551802771
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