Faculty Collaboration Database

Proteasome activation by insulin-like growth factor-1/nuclear factor erythroid 2-related factor 2 signaling promotes exercise-induced neurogenesis. Stem Cells 2020 Feb;38(2):246-260

Date

10/28/2019

Pubmed ID

31648402

DOI

10.1002/stem.3102

Scopus ID

2-s2.0-85075204508 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

Physical exercise-induced enhancement of learning and memory and alleviation of age-related cognitive decline in humans have been widely acknowledged. However, the mechanistic relationship between exercise and cognitive improvement remains largely unknown. In this study, we found that exercise-elicited cognitive benefits were accompanied by adaptive hippocampal proteasome activation. Voluntary wheel running increased hippocampal proteasome activity in adult and middle-aged mice, contributing to an acceleration of neurogenesis that could be reversed by intrahippocampal injection of the proteasome inhibitor MG132. We further found that increased levels of insulin-like growth factor-1 (IGF-1) in both serum and hippocampus may be essential for exercise-induced proteasome activation. Our in vitro study demonstrated that IGF-1 stimulated proteasome activity in cultured adult neural progenitor cells (NPCs) by promoting nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), followed by elevated expressions of proteasome subunits such as PSMB5. In contrast, pretreating adult mice with the selective IGF-1R inhibitor picropodophyllin diminished exercise-induced neurogenesis, concurrent with reduced Nrf2 nuclear translocation and proteasome activity. Likewise, lowering Nrf2 expression by RNA interference with bilateral intrahippocampal injections of recombinant adeno-associated viral particles significantly suppressed exercise-induced proteasome activation and attenuated cognitive function. Collectively, our work demonstrates that proteasome activation in hippocampus through IGF-1/Nrf2 signaling is a key adaptive mechanism underlying exercise-related neurogenesis, which may serve as a potential targetable pathway in neurodegeneration.

Author List

Niu X, Zhao Y, Yang N, Zhao X, Zhang W, Bai X, Li A, Yang W, Lu L

Author

Xiaowen Bai PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Exercise
Humans
Insulin-Like Growth Factor I
Male
Mice
NF-E2-Related Factor 2
Neurogenesis
Transfection