Acute skeletal muscle contractions orchestrate signaling mechanisms to trigger nuclear NFATc1 shuttling and epigenetic histone modifications

Abstract

Background/Aims: Calcium (Ca2+) coordinates skeletal muscle functions by controlling contractions as well as signaling pathways and transcriptional properties. The ryanodine receptor 1 (RyR1), its phosphorylation site (pRyR1Ser2840) and its stabilizers navigate Ca2+ oscillations to command muscle signaling cascades and transcriptional activities. While chronic exercise increases pRyR1Ser2840, investigations on acute exercise’s effects on RyR1 and Ca2+-dependent modifications of skeletal muscle are rare. The aim of this study was to examine molecular events leading to RyR1 phosphorylation in a physiological model of acute exercise. We hypothesized that exercise-induced RyR1 phosphorylation is associated with altered Ca2+-dependent physiological phenotypes. Methods: We analyzed pRyR1Ser2840, its stabilizers, involved signaling pathways, and Ca2+-sensitive muscle-determining factors (i.e. NFATc1 and epigenetic histone H3 modifications) in rat muscles upon one single running bout of either concentric or eccentric contractions. Results: Both acute exercises significantly increased pRyRSer2840 levels in muscles, which was accompanied by dissociations of stabilizers from RyR1. Additionally, RyR1 phosphorylation-inducing signaling cascades PTEN/CaMKII/PKA were significantly activated upon exercise. Further, RyR1 phosphorylations were associated with increased Ca2+-dependent NFATc1 nuclear abundances as well as increased Ca2+-dependent epigenetic H3 acetylations pointing to a pRyR1Ser2840-dependent rapid and novel Ca2+ equilibrium upon exercise. Conclusion: Our data report synergistic actions of several distinct pathways to modify RyR1 function to govern physiological phenotypes, here expressed as increased nuclear NFATc1 abundances and epigenetic H3 modifications. Therefore, we underscore the potential of acute exercise to rapidly change muscle Ca2+controlling systems and downstream effectors cascades to adjust physiological demands for proper muscle function and phenotype adaptation.