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

TY - JOUR

T1 - Phosphoproteomics reveals conserved exercise-stimulated signaling and AMPK regulation of store-operated calcium entry

AU - Nelson, Marin E

AU - Parker, Benjamin L

AU - Burchfield, James G

AU - Hoffman, Nolan J

AU - Needham, Elise J

AU - Cooke, Kristen C

AU - Naim, Timur

AU - Sylow, Lykke

AU - Ling, Naomi X Y

AU - Francis, Deanne

AU - Norris, Dougall M

AU - Chaudhuri, Rima

AU - Oakhill, Jonathan S

AU - Richter, Erik

AU - Lynch, Gordon S

AU - Stöckli, Jacqueline

AU - James, David E

N1 - CURIS 2019 NEXS 262 © 2019 The Authors.

PY - 2019/12/16

Y1 - 2019/12/16

N2 - 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.

AB - 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.

KW - Faculty of Science

KW - AMPK

KW - Calcium

KW - Exercise

KW - Phosphorylation

KW - STIM1

U2 - 10.15252/embj.2019102578

DO - 10.15252/embj.2019102578

M3 - Journal article

C2 - 31381180

SN - 0261-4189

JO - E M B O Journal

JF - E M B O Journal

M1 - e102578

ER -