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

It is well-established that extracellular potassium (K+)(o) accumulation reduces muscle fiber excitability, however the effects of K-o(+) 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 K-o(+) 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 K-o(+) to affect force during sustained contractions. (C) 2021 The Author(s). Published by Elsevier Ltd.

Automated summary

A computational model was presented to explore the effects of elevated extracellular potassium on force generation in muscle fibers. The model captured experimental observations of frequency-dependent force response to potassium accumulation, indicating that altered calcium release and phosphate accumulation work together with elevated potassium to affect force production during sustained contractions.