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

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

Skeletal Muscle Susceptibility to Clofibrate Induction of Lesions in Rats

“…Recently, it was reported that clofibrate-induced myopathy is related to carcium influx (Ikemoto and Endo, 2001;Matzno et al, 2006). Hodel briefly reviewed clofibrate-induced 520 OKADA ET AL.…”

Effects of dantrolene and its derivatives on Ca2+ release from the sarcoplasmic reticulum of mouse skeletal muscle fibres

“…D-tubocurarine chloride was purchased from Nacalai Tesque, Inc. All the other chemicals were as described in the previous paper (Ikemoto & Endo, 2001, accompanying study).…”

“…The muscle preparation was immersed in PSS. Preparation of skinned ®bres was described previously (Ikemoto & Endo, 2001, accompanying study). All experiments were carried out at room temperature (21 ± 238C).…”

“…The Ca 2+ released from the skinned ®bres was quanti®ed using Fura-2 as described previously (Ikemoto & Endo, 2001, accompanying study). Brie¯y, the protocol for the measurement of the Ca 2+ release rate consisted of (1) loading the SR with Ca 2+ , (2) test (Ca 2+ -releasing stimuli are given), and (3) determination of the Ca 2+ remaining in the SR. During the test period, various concentrations of Ca 2+ buered with 10 mM EGTA, sometimes together with Clof or CICR activators (caeine or AMP), were given, and the eects of further addition of Dan or its derivatives were examined.…”

“…We tested these agents for inhibition of twitch tension of intact muscle ®bres and inhibition of CICR in saponin-treated skinned muscle ®bres. We also tested for their eects on clo®bric acid (Clof)-induced Ca 2+ release, which has certain characteristics similar to those of PCR (Ikemoto & Endo, 2001, accompanying study). We found that some Dan derivatives indeed distinguish PCR from CICR more clearly than Dan itself.…”