Triclosan impairs excitation-contraction coupling and Ca2+ dynamics in striated muscle

Gennady Cherednichenko, Rui Zhang, Roger A. Bannister, Valeriy Timofeyev, Ning Li, Erika B. Fritsch, Wei Feng, Genaro C. Barrientos, Nils H. Schebb, Bruce D. Hammock, Kurt G. Beam, Nipavan Chiamvimonvat, Isaac N Pessah

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105 Scopus citations

Abstract

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 Ca2+ transients followed by complete failure of ECC, independent of Ca2+ store depletion or block of RyR1 channels. TCS also completely blocks excitation-coupled Ca2+ entry. Voltage clamp experiments showed that TCS partially inhibits L-type Ca2+ 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 Ltype Ca2+ and RyR channels in skeletal muscle, and L-type Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)14158-14163
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number35
DOIs
StatePublished - Aug 28 2012

Keywords

  • Cachexia
  • Calcium regulation
  • Heart failure
  • L-type current
  • Muscle contraction

ASJC Scopus subject areas

  • General

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    Cherednichenko, G., Zhang, R., Bannister, R. A., Timofeyev, V., Li, N., Fritsch, E. B., Feng, W., Barrientos, G. C., Schebb, N. H., Hammock, B. D., Beam, K. G., Chiamvimonvat, N., & Pessah, I. N. (2012). Triclosan impairs excitation-contraction coupling and Ca2+ dynamics in striated muscle. Proceedings of the National Academy of Sciences of the United States of America, 109(35), 14158-14163. https://doi.org/10.1073/pnas.1211314109