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

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Abstract
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. Clof (>0.5 mM) released Ca2+ from the SR under Ca2+‐free conditions buffered with 10 mM EGTA (pCa >8). 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). 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). In addition to this unique mode of opening, Clof also enhanced the CICR mode of opening of RyR‐Ca2+ release channels. Apart from CICR, a high concentration of Ca2+ might also enhance the unique mode of opening by Clof. 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. British Journal of Pharmacology (2001) 134, 719–728; doi:10.1038/sj.bjp.0704306