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.
Original language | English (US) |
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Pages (from-to) | 1135-1146.e7 |
Journal | Cell Metabolism |
Volume | 25 |
Issue number | 5 |
DOIs | |
State | Published - May 2 2017 |
Keywords
- AMPK
- DNA-PK
- HSP90α
- aging
- calorie restriction
- exercise
- insulin sensitivity
- mitochondria
- obesity
- skeletal muscle
- type 2 diabetes
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology