Changes in the rate of isometric force development with fatigue were measured in vitro (25 degrees C) using mouse soleus and extensor digitorum longus (EDL) muscles. Muscles were fatigued using 30 tetanic contractions. Rate of force development was determined from the rate constant of an exponential curve fitted to the rising force phase of a tetanus. For both muscles, when the intertetanus interval was 3 s, maximum isometric force and relaxation rate were significantly reduced in the final tetanus relative to the values in the first tetanus. Rate of force development in soleus muscles transiently increased and then decreased a small amount. The final rate was 92.7 +/- 3.3% (n = 4) of the initial rate. In contrast, the rate of force development in EDL muscles increased to 133.7 +/- 3.3% (n = 4) of the initial rate. This increased rate was evident from the second tetanus of the series, was fully established after 5 tetani, and the magnitude of the increase in rate was inversely proportional to intertetanus interval and was independent of presumed energy expenditure. The enhanced rate decayed with a time constant of 14.3 +/- 2.0 s and was independent of presumed energy expenditure. Most of these observations can be explained by the effects of P(i) on cross bridge kinetics. Other possible mechanisms, involving more rapid activation, are also suggested.