Enhanced capacity for CaMKII signaling mitigates calcium release related contractile fatigue with high intensity exercise

Background: We tested whether enhancing the capacity for calcium/calmodulin-dependent protein kinase type II (CaMKII) signaling would delay fatigue of excitation-induced calcium release and improve contractile characteristics of skeletal muscle during fatiguing exercise.Methods: Fast and slow type muscle, gastrocnemius medialis (GM) and soleus (SOL), of rats and mouse interosseus (IO) muscle fibers, were transfected with pcDNA3-based plasmids for rat alpha and beta CaMKII or empty controls. Levels of CaMKII, its T287-phosphorylation (pT287-CaMKII), and phosphorylation of components of calcium release and re-uptake, ryanodine receptor 1 (pS2843-RyR1) and phospholamban (pT17-PLN), were quantified biochemically. Sarcoplasmic calcium in transfected muscle fibers was monitored microscopically during trains of electrical excitation based on Fluo-4 FF fluorescence (n = 5-7). Effects of low- (n = 6) and high- (n = 8) intensity exercise on pT287-CaMKII and contractile characteristics were studied in situ.Results: Co-transfection with alpha CaMKII-pcDNA3/beta CaMKII-pcDNA3 increased alpha and beta CaMKII levels in SOL (+45.8 %, +250.5 %) and GM (+40.4 %, +89.9 %) muscle fibers compared to control transfection. High-intensity exercise increased pT287-beta CaMKII and pS2843-RyR1 levels in SOL (+269 %, +151 %) and GM (+354 %, +119 %), but decreased pT287-alpha CaMKII and p17-PLN levels in GM compared to SOL (-76 % vs. +166 %; 0 % vs. +128 %). alpha/beta CaMKII overexpression attenuated the decline of calcium release in muscle fibers with repeated excitation, and mitigated exercise-induced deterioration of rates in force production, and passive force, in a muscledependent manner, in correlation with pS2843-RyR1 and pT17-PLN levels (|r| > 0.7).Conclusion: Enhanced capacity for alpha/beta CaMKII signaling improves fatigue-resistance of active and passive contractile muscle properties in association with RyR1- and PLN-related improvements in sarcoplasmic calcium release.

Automated summary

Enhancing CaMKII signaling improves fatigue resistance and contractile characteristics of skeletal muscle by enhancing calcium release.