Effects of extracellular potassium on calcium handling and force generation in a model of excitation-contraction coupling in skeletal muscle

Abstract

It is well-established that extracellular potassium (Ko+) accumulation reduces muscle fiber excitability, however the effects of Ko+ on the excitation–contraction coupling (ECC) pathway are less understood. In vivo and in vitro studies following fatiguing stimulation protocols are limited in their ability to capture the effects of Ko+ on force production in combination with other simultaneously changing factors. To address this, a computational model of ECC for slow and fast twitch muscle is presented to explore the relative contributions of excitability-induced and metabolic-induced changes in force generation in response to increasing K+o. The model incorporates mechanisms previously unexplored in modelling studies, including the effects of extracellular calcium on excitability, calcium-dependent inhibition of calcium release, ATP-dependent ionic pumping, and the contribution of ATP hydrolysis to intracellular phosphate accumulation rate. The model was able to capture the frequency-dependent biphasic Force-K+o response observed experimentally. Force potentiation for moderately elevated K+o was driven by increased action potential duration, myoplasmic calcium potentiation, and phosphate accumulation rate, while attenuation of force at higher K+o was due to action potential failure resulting in reduced calcium release. These results suggest that altered calcium release and phosphate accumulation work together with elevated Ko+ to affect force during sustained contractions.