Triclosan impairs excitation–contraction coupling and Ca²⁺ dynamics in striated muscle
2012
Cherednichenko, Gennady | Zhang, Rui | Bannister, Roger A. | Timofeyev, Valeriy | Li, Ning | Fritsch, Erika B. | Feng, Wei | Barrientos, Genaro C. | Schebb, Nils H. | Hammock, Bruce D. | Beam, Kurt G. | Chiamvimonvat, Nipavan | Pessah, Isaac N.
Triclosan (TCS), a high-production-volume chemical used as a bactericide in personal care products, is a priority pollutant of growing concern to human and environmental health. TCS is capable of altering the activity of type 1 ryanodine receptor (RyR1), but its potential to influence physiological excitation–contraction coupling (ECC) and muscle function has not been investigated. Here, we report that TCS impairs ECC of both cardiac and skeletal muscle in vitro and in vivo. TCS acutely depresses hemodynamics and grip strength in mice at doses ≥12.5 mg/kg i.p., and a concentration ≥0.52 μM in water compromises swimming performance in larval fathead minnow. In isolated ventricular cardiomyocytes, skeletal myotubes, and adult flexor digitorum brevis fibers TCS depresses electrically evoked ECC within ∼10–20 min. In myotubes, nanomolar to low micromolar TCS initially potentiates electrically evoked Ca ²⁺ transients followed by complete failure of ECC, independent of Ca ²⁺ store depletion or block of RyR1 channels. TCS also completely blocks excitation-coupled Ca ²⁺ entry. Voltage clamp experiments showed that TCS partially inhibits L-type Ca ²⁺ currents of cardiac and skeletal muscle, and [ ³H]PN200 binding to skeletal membranes is noncompetitively inhibited by TCS in the same concentration range that enhances [ ³H]ryanodine binding. TCS potently impairs orthograde and retrograde signaling between L-type Ca ²⁺ and RyR channels in skeletal muscle, and L-type Ca ²⁺ entry in cardiac muscle, revealing a mechanism by which TCS weakens cardiac and skeletal muscle contractility in a manner that may negatively impact muscle health, especially in susceptible populations.
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