Acute Skeletal Muscle Contractions Orchestrate Signaling Mechanisms to Trigger Nuclear NFATc1 Shuttling and Epigenetic Histone Modifications.

ABSTRACT

BACKGROUND/AIMS: Calcium (Ca²âº) coordinates skeletal muscle functions by controlling contractions as well as signaling pathways and transcriptional properties. The ryanodine receptor 1 (RyR1), its phosphorylation site (pRyR1Ser²84°) and its stabilizers navigate Ca²âº oscillations to command muscle signaling cascades and transcriptional activities. While chronic exercise increases pRyR1Ser²84°, investigations on acute exercise's effects on RyR1 and Ca²âº-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 Ca²âº-dependent physiological phenotypes. METHODS: We analyzed pRyR1Ser²84°, its stabilizers, involved signaling pathways, and Ca²âº-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 pRyRSer²84° 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 Ca²âº-dependent NFATc1 nuclear abundances as well as increased Ca²âº-dependent epigenetic H3 acetylations pointing to a pRyR1Ser²84°-dependent rapid and novel Ca²âº 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.