Perchlorate potentiation of excitation-contraction coupling in mammalian skeletal muscles

Abstract

The action of perchlorate (ClO4-), an agonist of the voltage sensor in excitation-contraction (EC) coupling, has been examined using bundles of intact muscle cells, isolated membrane vesicles [sarcoplasmic reticulum (SR) and transverse tubule (TT)], and cultured myotubes. The effect of ClO4- on mechanical parameters was investigated in isolated murine limb muscles. The presence of ClO4- (5 or 10 mM) greatly increased twitch tension ( > 250%), slightly enhanced tetanic tension, and increased K contracture tension. K contracture thresholds of extensor digitorum longus (EDL, 40 mM K+) and soleus (30 mM K+) muscles were not altered by ClO4-. However, in whole cell patch clamp studies of mouse myotubes, contractile activation was shifted by approximately -10 mV by 10 mM ClO4-. To further define the site of alteration of EC coupling by ClO4-, studies were conducted with isolated porcine SR and TT vesicles and with cultured mouse myotubes. The rate constant of Ca-induced 45Ca release from SR vesicles was significantly increased by ClO4-. However, neither the affinity nor level of [3H]PN200-110 binding to TT vesicles was significantly affected by ClO4- concentrations that increased twitch tension. Furthermore, slow plasmalemmal Ca currents of myotubes recorded in the whole cell patch-clamp mode were enhanced by 10 mM ClO4-, and the current-voltage relationship was shifted approximately -7mV. Thus, in enhancing EC coupling in mammalian muscle, ClO4- may act at multiple sites including the SR Ca release channel and the TT Ca channel-voltage sensor.

Modulation of caffeine contractures in mammalian skeletal muscles by variation of extracellular potassium

“…However, perchlorate also increases the rate of calcium release from isolated SR vesicles (Gallant et al, 1993;Fruen et al, 1994) indicating action on the SR as well. Recently it was suggested that perchlorate acts to enhance charge movement by feedback from SR to the TT possibly via elevated myoplasmic calcium (Pizarro et al, 1991;Gonzales and Rios, 1993).…”

“…Both agents had no significant effect on caffeine contractures at higher [K'lo. Perchlorate enhancement of K-conditioned caffeine contractures Perchlorate (0.1-5 mM) significantly potentiates twitch force of mouse edl (Gallant et al, 1993) and soleus muscles (Dulhunty et al, 1992) in a dose-dependent manner but has little effect on tetanus tension and does not alter twitch time course (Gallant et al, 1993). At 10 mM or greater perchlorate, mouse edl twitch kinetics are markedly altered (Gallant et al, 1993).…”

“…Muscles were obtained from mice and pigs and processed as previously described to obtain bundles of cells intact from tendon-to-tendon with no microscopically observable damaged areas Gallant and Lentz, 1992a;Gallant et al, 1993). In the studies with porcine muscles, bundles of intact cells were dissected from forelimb muscles (lateral head of the common digital extensor) and reduced to a crosssectional area of 5 2 mm2.…”

“…Rodent physiological saline (RPS) (Gallant et al, 1993) and porcine physiological saline (PPS) were aerated with 5% COJ95% 0,. Elevated potassium solutions (K-solutions) were formulated with methanesulfonate substituted for C1-to maintain constant [K+] x [Cl-] and with sodium reduced to maintain osmolarity of 315 mosmol as previously described .…”

The action of perchlorate on malignant-hyperthermia-susceptible muscle

“…Charge movement arises from the transverse (T) tubule dihydropyridine receptor, indicating that perchlorate may act at the T-tubule. Perchlorate also potentiates E-C coupling and increases contracture force, electrically evoked twitches [11,12] and K -contractures [11]. More recently, perchlorate has been shown to activate purified RyR channels in lipid bilayers [21] and to increase Ca 2+ release from native SR vesicles [4,11], leading to the suggestion that the RyR may be the primary site of perchlorate's action in skeletal muscle [21,29].…”