Author:

Keywords:

Acute exercise, Calcium/calmodulin-dependent protein kinase II, H3 modifications, NFATc1, Ryanodine receptor 1, Skeletal muscle, Acetylation, Actinin, Animals, Calcium, Catalytic Domain, Cell Nucleus, Cyclic AMP-Dependent Protein Kinases, Female, Histones, Muscle Contraction, Muscle, Skeletal, Phosphorylation, Physical Conditioning, Animal, Rats, Rats, Sprague-Dawley, Ryanodine Receptor Calcium Release Channel, Sarcomeres, Transcription Factors, 0601 Biochemistry and Cell Biology, 1116 Medical Physiology, Physiology, 3101 Biochemistry and cell biology

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.