Modulation of force development by Na+, K+, Na+ K+ pump and KATP channel during muscular activity.

Extracellular K+ concentration increases during exercise and especially during fatigue development. It has been proposed that K+ is an important factor in the etiology of skeletal muscle fatigue because it suppresses membrane excitability and eventually force development. Based on the effect of K+, it has then been proposed the Na+ K+ pump reduces increases in extracellular K+ concentration while the ATP-sensitive K+ channel (KATP channel) allows for rapid increases in extracellular K+ to suppress force development when ATP levels start to fall or when the levels of metabolic end-products become high. However, recent studies have now demonstrated that an increase in extracellular K+ concentration can be advantageous to muscle during exercise because it not only stimulates vasodilation and the exercise pressor reflex, but it also potentiates force development when the Na+ concentration gradient is maintained. A new hypothesis is therefore proposed in which the Na+ K+ pump is important in maintaining the Na+ concentration gradient (and not the K+ concentration gradient as previously suggested), while the activation of KATP channels is important to increase the K+ efflux and extracellular concentration. This situation then optimizes the development of force during exercise. Another hypothesis is proposed in which more KATP channels are activated while the activity of the Na+ K+ pump is reduced when ATP levels start to decrease to allow for an accumulation of intracellular Na+ and further increases in extracellular K+ concentration. These concentration changes then reduce membrane excitability and force development (i.e., fatigue) to protect muscle against large ATP depletion and function impairment.