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) accumulation reduces muscle fiber excitability, however the effects of K 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 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 [Formula: see text] . 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- [Formula: see text] response observed experimentally. Force potentiation for moderately elevated [Formula: see text] was driven by increased action potential duration, myoplasmic calcium potentiation, and phosphate accumulation rate, while attenuation of force at higher [Formula: see text] 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 to affect force during sustained contractions.