Interstitial K⁺ concentration increases up to ~10 mM during a muscle activity leading to fatigue. It is well known that increases in extracellular K⁺ concentration depolarize cell membrane. As the membrane depolarizes more Na⁺ channels become inactivated resulting in lower action potential amplitudes. It was believed that lower action potential amplitude results in lower amount of Ca²⁺ release and force development. However, recent studies have demonstrated that at 37°C twitch and tetanic force is depressed only if the extracellular K⁺ concentration exceeds 12 mM, a concentration usually not observed during exercise. More importantly, increases in extracellular K⁺ up to 12 mM from control level (4.7 mM) potentiate twitch force. Force-frequency relationship shows that the K⁺-induced force potentiation also occurs at stimulation frequencies up to 100 Hz in mouse EDL and up to 30 Hz in soleus muscle. Action potential durations are longer at 9 mM compared with those at 4.7 mM K⁺. In mouse EDL muscle, mimicking the change in action potential with TTX does not give rise to twitch potentiation, suggesting that the mechanisms of action for the potentiation is downstream of action potential. In EDL muscle, the potentiation is also not related to longer contraction time, albeit it is in soleus muscle. K⁺-induced and post-tetanic twitch potentiation are additive in EDL muscle, suggesting that the K⁺ induced twitch potentiation is not due to a phosphorylation of myosin light chain. V_MAX is also unaffected at 9 mM K⁺. The experiments involving post-tetanic twitch potentiation and V_MAX suggest that the K⁺-induced potentiation may not involve an effect at the level of the contractile apparatus. The next question is whether or not K⁺ is an important factor contributing to the decrease in force during fatigue. While the concentration of K⁺ must exceed 12 mM before it depresses force under resting conditions, a decrease in Na⁺ concentration gradient, involving a decrease in extracellular Na⁺ as small as 20 mM, is large enough to switch the potentiating effect of K⁺ to a depressing effect at 12 mM. In summary, increases in extracellular K⁺ concentration during exercise does not necessarily lead to force depression as it can also potentiate force. However, the capacity of K⁺ to potentiate and depress force appears to depend on the physiological state of muscles. Muscles were removed from mice under terminal sodium pentobarbitone anaesthesia.