Properties of Ca2+ release induced by clofibric acid from the sarcoplasmic reticulum of mouse skeletal muscle fibres

1 To characterize the effect of clofibric acid (Clof) on the Ca2+ release mechanism in the sarcoplasmic reticulum (SR) of skeletal muscle, we analysed the properties of Clof-induced Ca2+ release under various conditions using chemically skinned skeletal muscle fibres of the mouse. 2 Clof (>0.5 mM) released Ca2+ from the SR under Ca2+-free conditions buffered with 10 mm EGTA (pCa > 8). 3 Co-application of ryanodine and Clof at pCa > 8 but not ryanodine alone reduced the Ca2+ uptake capacity of the SR. Thus, Ca2+ release induced by Clof at pCa > 8 must be a result of the activation of the ryanodine receptor (RyR). 4 At pCa > 8, (i) Clof-induced Ca2+ release was inhibited by adenosine monophosphate (AMP), (ii) the inhibitory effect of Mg2+ on the Clof-induced Ca2+ release was saturated at about 1 mm, and (iii) Clof-induced Ca2+ release was not inhibited by procaine (10 mm). These results indicate that Clof may activate the RyR-Ca2+ release channels in a manner different from Ca2+-induced Ca2+-release (CICR). 5 In addition to this unique mode of opening, Clof also enhanced the CICR mode of opening of RYR-Ca2+ release channels. 6 Apart from CICR, a high concentration of Ca2+ might also enhance the unique mode of opening by Clof. 7 These results suggest that some features of Ca2+ release activated by Clof are similar to those of physiological Ca2+ release (PCR) in living muscle cells and raise the possibility that Clof may be useful in elucidating the mechanism of PCR in skeletal muscle.