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Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates
Hoffman, Nolan John Parker, Benjamin L. Chaudhuri, Rima Fisher-Wellman, Kelsey H. Kleinert, Maximilian Humphrey, Sean J. Yang, Pengyi Holliday, Mira Trefely, Sophie Fazakerley, Daniel J.
Hoffman, Nolan John
Parker, Benjamin L.
Chaudhuri, Rima
Fisher-Wellman, Kelsey H.
Kleinert, Maximilian
Humphrey, Sean J.
Yang, Pengyi
Holliday, Mira
Trefely, Sophie
Fazakerley, Daniel J.
Author
Hoffman, Nolan John
Parker, Benjamin L.
Chaudhuri, Rima
Fisher-Wellman, Kelsey H.
Kleinert, Maximilian
Humphrey, Sean J.
Yang, Pengyi
Holliday, Mira
Trefely, Sophie
Fazakerley, Daniel J.
Stöckli, Jacqueline
Burchfield, James G.
Jensen, Thomas E.
Jothi, Raja
Kiens, Bente
Wojtaszewski, Jørgen F. P.
Richter, Erik A.
James, David E.
Parker, Benjamin L.
Chaudhuri, Rima
Fisher-Wellman, Kelsey H.
Kleinert, Maximilian
Humphrey, Sean J.
Yang, Pengyi
Holliday, Mira
Trefely, Sophie
Fazakerley, Daniel J.
Stöckli, Jacqueline
Burchfield, James G.
Jensen, Thomas E.
Jothi, Raja
Kiens, Bente
Wojtaszewski, Jørgen F. P.
Richter, Erik A.
James, David E.
Abstract
Exercise is essential in regulating energy metabolism and whole-body insulin sensitivity. To explore the exercise signaling network, we undertook a global analysis of protein phosphorylation in human skeletal muscle biopsies from untrained healthy males before and after a single high-intensity exercise bout, revealing 1,004 unique exercise-regulated phosphosites on 562 proteins. These included substrates of known exercise-regulated kinases ( AMPK, PKA, CaMK, MAPK, mTOR ), yet the majority of kinases and substrate phosphosites have not previously been implicated in exercise signaling. Given the importance of AMPK in exercise-regulated metabolism, we performed a targeted in vitro AMPK screen and employed machine learning to predict exercise-regulated AMPK substrates. We validated eight predicted AMPK substrates, including AKAP1, using targeted phosphoproteomics. Functional characterization revealed an undescribed role for AMPK-dependent phosphorylation of AKAP1 in mitochondrial respiration. These data expose the unexplored complexity of acute exercise signaling and provide insights into the role of AMPK in mitochondrial biochemistry.
Keywords
Date
2015
Type
Journal article
Journal
Cell Metabolism
Book
Volume
22
Issue
5
Page Range
922-935
Article Number
ACU Department
Centre for Exercise and Nutrition
Faculty of Health Sciences
Faculty of Health Sciences
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Relation URI
Source URL
Event URL
Open Access Status
License
File Access
Controlled