Lactate inhibits Ca(2+) -activated Ca(2+)-channel activity from skeletal muscle sarcoplasmic reticulum

Sarcoplasmic reticulum (SR) Ca(2+)-release channel function is modified by ligands that are generated during about of exercise. We have examined the effects of lactate on Ca(2+)- and caffeine-stimulated Ca2+ release, [3H]ryanodine binding, and single Ca(2+)-release channel activity of SR isolated from rabbit white skeletal muscle. Lactate, at concentrations from 10 to 30 mM, inhibited Ca(2+)- and caffeine-stimulated nodine binding to and inhibited Ca(2+)- and caffeine-stimulated [3H]ryanodine binding to and inhibited Ca(2+)- and caffeine-stimulated Ca2+ release from SR vesicles. Lactate also inhibited caffeine activation of single-channel activity in bilayer reconstitution experiments. These findings suggest that intense muscle activity, which generates high concentrations of lactate, will disrupt excitation-contraction coupling. This may lead to decreases in Ca2+ transients promoting a decline in tension development and contribute to muscle fatigue.