DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging

• Published in: Cell metabolism 2017-05, Vol.25 (5), p.1135-1146.e7
• Main Authors: Park, Sung-Jun, Gavrilova, Oksana, Brown, Alexandra L., Soto, Jamie E., Bremner, Shannon, Kim, Jeonghan, Xu, Xihui, Yang, Shutong, Um, Jee-Hyun, Koch, Lauren G., Britton, Steven L., Lieber, Richard L., Philp, Andrew, Baar, Keith, Kohama, Steven G., Abel, E. Dale, Kim, Myung K., Chung, Jay H.
• Format: Article
• Language: English
• Subjects: Aging; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Benzofurans; calorie restriction; Diabetes Mellitus, Type 2 - metabolism; DNA-Activated Protein Kinase - metabolism; DNA-PK; Energy Metabolism; exercise; HSP90α; insulin sensitivity; Macaca mulatta; Mice, SCID; mitochondria; Mitochondria, Muscle - metabolism; Muscle, Skeletal - physiology; obesity; Physical Conditioning, Animal; Quinolines; Rats; skeletal muscle; type 2 diabetes
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2017.04.008

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. [Display omitted] •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.