Mechanisms underlying the reduction of isometric force in skeletal muscle fatigue

A decline of isometric force production is one characteristic of skeletal muscle fatigue. In fatigue produced by repeated short tetani, this force decline can be divided into two components: a reduction of the cross-bridges' ability to generate force, which comes early; and a reduction of the sarcoplasmic reticulum Ca²⁺ release, which develops late in fatigue. Acidification due to lactic acid accumulation has been considered as an important cause of the reduced cross-bridge force production. However, in mammalian muscle it has been shown that acidification has little effect on isometric force production at physiological temperatures. By exclusion, in mammalian muscle fatigue, the reduction of force due to impaired cross-bridge function would be caused by accumulation of inorganic phosphate ions, which results from phosphocreatine breakdown. The reduction of sarcoplasmic reticulum Ca²⁺ release in late fatigue correlates with a decline of ATP and we speculate that the reduced Ca²⁺ release is caused by a local increase of the ADP/ATP ratio in the triads.