Phosphoproteomics reveals conserved exercise-stimulated signaling and AMPK regulation of store-operated calcium entry

Marin E Nelson, Benjamin L Parker, James G Burchfield, Nolan J Hoffman, Elise J Needham, Kristen C Cooke, Timur Naim, Lykke Sylow, Naomi X Y Ling, Deanne Francis, Dougall M Norris, Rima Chaudhuri, Jonathan S Oakhill, Erik A Richter, Gordon S Lynch, Jacqueline Stöckli, David E James*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

43 Citations (Scopus)

Abstract

Exercise stimulates cellular and physiological adaptations that are associated with widespread health benefits. To uncover conserved protein phosphorylation events underlying this adaptive response, we performed mass spectrometry-based phosphoproteomic analyses of skeletal muscle from two widely used rodent models: treadmill running in mice and in situ muscle contraction in rats. We overlaid these phosphoproteomic signatures with cycling in humans to identify common cross-species phosphosite responses, as well as unique model-specific regulation. We identified > 22,000 phosphosites, revealing orthologous protein phosphorylation and overlapping signaling pathways regulated by exercise. This included two conserved phosphosites on stromal interaction molecule 1 (STIM1), which we validate as AMPK substrates. Furthermore, we demonstrate that AMPK-mediated phosphorylation of STIM1 negatively regulates store-operated calcium entry, and this is beneficial for exercise in Drosophila. This integrated cross-species resource of exercise-regulated signaling in human, mouse, and rat skeletal muscle has uncovered conserved networks and unraveled crosstalk between AMPK and intracellular calcium flux.

Original languageEnglish
Article numbere102578
JournalE M B O Journal
Volume38
Issue number24
Number of pages20
ISSN0261-4189
DOIs
Publication statusPublished - 2019

Keywords

  • Faculty of Science
  • AMPK
  • Calcium
  • Exercise
  • Phosphorylation
  • STIM1

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