Changes in force and intracellular metabolites during fatigue of human skeletal muscle.

1. The relationship between intracellular metabolites and the generation of force during fatigue has been examined in the first dorsal interosseous muscle of the hand. With the arm made ischaemic, the muscle was fatigued by three bouts of maximal voluntary contraction, leaving approximately three minutes ischaemic rest between contractions. During one series of experiments intracellular phosphorus metabolites were measured by nuclear magnetic resonance during the intervals between the fatiguing contractions: in the second series contractile properties were tested with brief electrical stimulation during the rest intervals. 2. The relationships between loss of force and change in metabolite concentrations obtained with four normal subjects were compared with those from one subject with myophosphorylase deficiency (MPD) who could not utilize muscle glycogen and therefore produced no hydrogen ion from glycolysis during exercise. 3. For both the MPD and normal subjects the relationship between relative force loss and inorganic phosphate (Pi) concentration was curvilinear, force changing little in the early stages of the contraction when the intracellular Pi was accumulating rapidly but falling faster when the Pi was above 25 mM and increasing relatively slowly. 4. In the normal subjects intracellular pH fell from a mean of 7.03 +/- 0.01 (mean +/- S.E. of mean, n = 19) in the fresh muscle to 6.51 +/- 0.02 at the end of the fatiguing exercise; force, as a percentage of the initial value, fell in proportion to the increase in H+ concentration. In the MPD subject pH did not change and force loss was therefore independent of H+ accumulation. In the normal subjects the force of the fatiguing muscle showed an approximately linear relationship with the concentration of the monobasic form of inorganic phosphate. However, the MPD subject showed a quite different relationship, with force loss being much greater for a given concentration of monobasic phosphate. This result indicates that monobasic phosphate is not a unique determinant of force loss in fatigued muscle. 5. During the first 60 s of recovery in the normal subjects, pH remained low while force recovered, indicating a mechanism of force loss that was independent of H+ accumulation. However, the recovery of force was not complete, so that for comparable phosphocreatine contents the recovering, more acid, muscle generated less force than the muscle that was being fatigued. It was estimated that H(+)-dependent and independent mechanisms contributed roughly equally to the observed force loss. The relationship between force and the concentration of monobasic phosphate differed in fatiguing and recovering muscle.