Muscle fatigue due to changes beyond the neuromuscular junction.

: A number of changes in function occur beyond the neuromuscular junction during activity; three main types are described. (a) During high frequency stimulation there is a rapid loss of force accompanied by a slowing of the action potential waveform and an increase in the excitation threshold of the muscle. It is suggested that accumulation of K+ in the extracellular spaces of the muscle may be responsible for these changes. (b) Slowing of relaxation is a feature of fatigued muscle. The slowing allows a reduction in activation frequency (minimizing high frequency fatigue) without resulting in an appreciable loss of force. (c) Changes in shape and amplitude of the twitch have considerable effects on the force generated by low frequencies of stimulation. After a brief tetanus there is a reduction in the width of the twitch which increases the fusion frequency of the muscle and may account for the "sag' seen at the start of low frequency contractions. After a prolonged series of contractions the twitch amplitude is reduced and remains so for several hours. This may be the result of some structural damage to the sarcoplasmic reticulum or transverse tubular system.