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

Contributed by Bruce D. Hammock, July 13, 2012 (sent for review June 18, 2012)
August 13, 2012
109 (35) 14158-14163

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 L-type 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.

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Acknowledgments

This work was supported by National Institutes of Health Grants 1P01 AR52354 (to I.N.P. and K.G.B.), 2P01 ES011269 (to I.N.P.), P42 ES004699 (to B.D.H., I.N.P., and N.C.), R03 AG038778 (to R.A.B), R01 AR055104 (to K.G.B.), R01 ES002710 (to B.D.H.), and R01 HL85727, R01 HL85844, and VA Merit Grant 5 I01BX000576 (to N.C.); Muscular Dystrophy Association Grants 176448 (to K.G.B.) and T32 HL86350 (to R.Z.); and the J. B. Johnson Foundation (I.N.P.). B.D.H. is a George and Judy Marcus Senior Fellow of the American Asthma Society.

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Information & Authors

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Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 109 | No. 35
August 28, 2012
PubMed: 22891308

Classifications

Submission history

Published online: August 13, 2012
Published in issue: August 28, 2012

Keywords

  1. cachexia
  2. calcium regulation
  3. heart failure
  4. muscle contraction
  5. L-type current

Acknowledgments

This work was supported by National Institutes of Health Grants 1P01 AR52354 (to I.N.P. and K.G.B.), 2P01 ES011269 (to I.N.P.), P42 ES004699 (to B.D.H., I.N.P., and N.C.), R03 AG038778 (to R.A.B), R01 AR055104 (to K.G.B.), R01 ES002710 (to B.D.H.), and R01 HL85727, R01 HL85844, and VA Merit Grant 5 I01BX000576 (to N.C.); Muscular Dystrophy Association Grants 176448 (to K.G.B.) and T32 HL86350 (to R.Z.); and the J. B. Johnson Foundation (I.N.P.). B.D.H. is a George and Judy Marcus Senior Fellow of the American Asthma Society.

Authors

Affiliations

Gennady Cherednichenko1
Department of Molecular Biosciences, School of Veterinary Medicine,
Rui Zhang1
Department of Molecular Biosciences, School of Veterinary Medicine,
Roger A. Bannister1
Cardiology Division, Department of Medicine, and
Valeriy Timofeyev
Division of Cardiovascular Medicine, Department of Internal Medicine, and
Ning Li
Division of Cardiovascular Medicine, Department of Internal Medicine, and
Erika B. Fritsch
Department of Molecular Biosciences, School of Veterinary Medicine,
Wei Feng
Department of Molecular Biosciences, School of Veterinary Medicine,
Genaro C. Barrientos
Department of Molecular Biosciences, School of Veterinary Medicine,
Nils H. Schebb
Department of Entomology and Cancer Center, University of California, Davis, CA 95616;
Bruce D. Hammock2 [email protected]
Department of Entomology and Cancer Center, University of California, Davis, CA 95616;
Kurt G. Beam
Department of Physiology and Biophysics, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO 80045; and
Nipavan Chiamvimonvat
Division of Cardiovascular Medicine, Department of Internal Medicine, and
Department of Veterans Affairs, Northern California Health Care System, Mather, CA 95655
Isaac N. Pessah2 [email protected]
Department of Molecular Biosciences, School of Veterinary Medicine,

Notes

2
To whom correspondence may be addressed. E-mail: [email protected] or [email protected].
Author contributions: G.C., R.Z., R.A.B., V.T., N.L., E.B.F., W.F., G.C.B., N.H.S., B.D.H., K.G.B., N.C., and I.N.P. designed research; G.C., R.Z., R.A.B., V.T., N.L., E.B.F., W.F., G.C.B., and N.H.S. performed research; N.H.S. and B.D.H. contributed new reagents/analytic tools; G.C., R.Z., R.A.B., V.T., N.L., E.B.F., W.F., G.C.B., N.H.S., B.D.H., K.G.B., N.C., and I.N.P. analyzed data; and G.C., R.Z., R.A.B., E.B.F., N.H.S., B.D.H., K.G.B., N.C., and I.N.P. wrote the paper.
1
G.C., R.Z., and R.A.B. contributed equally to this work.

Competing Interests

The authors declare no conflict of interest.

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    Triclosan impairs excitation–contraction coupling and Ca2+ dynamics in striated muscle
    Proceedings of the National Academy of Sciences
    • Vol. 109
    • No. 35
    • pp. 13879-14277

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