DOI: 10.1152/ajpheart.00602.2009. Hypersensitivity of excitation-contraction coupling in dystrophic cardiomyocytes

Hypersensitivity of excitation-contraction coupling in dystrophic cardiomyocytes

10.1152/ajpheart.00602.2009

Crossref journal-article

American Physiological Society

American Journal of Physiology-Heart and Circulatory Physiology (24)

Abstract

Duchenne muscular dystrophy represents a severe inherited disease of striated muscle. It is caused by a mutation of the dystrophin gene and characterized by a progressive loss of skeletal muscle function. Most patients also develop a dystrophic cardiomyopathy, resulting in dilated hypertrophy and heart failure, but the cellular mechanisms leading to the deterioration of cardiac function remain elusive. In the present study, we tested whether defective excitation-contraction (E-C) coupling contributes to impaired cardiac performance. “E-C coupling gain” was determined in cardiomyocytes from control and dystrophin-deficient mdx mice. To this end, L-type Ca2+currents ( ICaL) were measured with the whole cell patch-clamp technique, whereas Ca2+transients were simultaneously recorded with confocal imaging of fluo-3. Initial findings indicated subtle changes of E-C coupling in mdx cells despite matched Ca2+loading of the sarcoplasmic reticulum (SR). However, lowering the extracellular Ca2+concentration, a maneuver used to unmask latent E-C coupling problems, was surprisingly much better tolerated by mdx myocytes, suggesting a hypersensitive E-C coupling mechanism. Challenging the SR Ca2+release by slow elevations of the intracellular Ca2+concentration resulted in Ca2+oscillations after a much shorter delay in mdx cells. This is consistent with an enhanced Ca2+sensitivity of the SR Ca2+-release channels [ryanodine receptors (RyRs)]. The hypersensitivity could be normalized by the introduction of reducing agents, indicating that the elevated cellular ROS generation in dystrophy underlies the abnormal RyR sensitivity and hypersensitive E-C coupling. Our data suggest that in dystrophin-deficient cardiomyocytes, E-C coupling is altered due to potentially arrhythmogenic changes in the Ca2+sensitivity of redox-modified RyRs.

Bibliography

Ullrich, N. D., Fanchaouy, M., Gusev, K., Shirokova, N., & Niggli, E. (2009). Hypersensitivity of excitation-contraction coupling in dystrophic cardiomyocytes. American Journal of Physiology-Heart and Circulatory Physiology, 297(6), H1992âH2003.

Authors 5

Nina D. Ullrich (first)
Mohammed Fanchaouy (additional)
Konstantin Gusev (additional)
Natalia Shirokova (additional)
Ernst Niggli (additional)

References 45 Referenced 45

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Dates

Type	When
Created	15 years, 11 months ago (Sept. 25, 2009, 9:53 p.m.)
Deposited	6 months, 2 weeks ago (Feb. 12, 2025, 6:01 a.m.)
Indexed	4 months, 1 week ago (April 22, 2025, 2:27 a.m.)
Issued	15 years, 8 months ago (Dec. 1, 2009)
Published	15 years, 8 months ago (Dec. 1, 2009)
Published Print	15 years, 8 months ago (Dec. 1, 2009)

Funders 0

None

BibTeX

@article{Ullrich_2009, title={Hypersensitivity of excitation-contraction coupling in dystrophic cardiomyocytes}, volume={297}, ISSN={1522-1539}, url={http://dx.doi.org/10.1152/ajpheart.00602.2009}, DOI={10.1152/ajpheart.00602.2009}, number={6}, journal={American Journal of Physiology-Heart and Circulatory Physiology}, publisher={American Physiological Society}, author={Ullrich, Nina D. and Fanchaouy, Mohammed and Gusev, Konstantin and Shirokova, Natalia and Niggli, Ernst}, year={2009}, month=dec, pages={H1992–H2003} }

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  "abstract": "<jats:p>Duchenne muscular dystrophy represents a severe inherited disease of striated muscle. It is caused by a mutation of the dystrophin gene and characterized by a progressive loss of skeletal muscle function. Most patients also develop a dystrophic cardiomyopathy, resulting in dilated hypertrophy and heart failure, but the cellular mechanisms leading to the deterioration of cardiac function remain elusive. In the present study, we tested whether defective excitation-contraction (E-C) coupling contributes to impaired cardiac performance. \u201cE-C coupling gain\u201d was determined in cardiomyocytes from control and dystrophin-deficient mdx mice. To this end, L-type Ca<jats:sup>2+</jats:sup>currents ( I<jats:sub>CaL</jats:sub>) were measured with the whole cell patch-clamp technique, whereas Ca<jats:sup>2+</jats:sup>transients were simultaneously recorded with confocal imaging of fluo-3. Initial findings indicated subtle changes of E-C coupling in mdx cells despite matched Ca<jats:sup>2+</jats:sup>loading of the sarcoplasmic reticulum (SR). However, lowering the extracellular Ca<jats:sup>2+</jats:sup>concentration, a maneuver used to unmask latent E-C coupling problems, was surprisingly much better tolerated by mdx myocytes, suggesting a hypersensitive E-C coupling mechanism. Challenging the SR Ca<jats:sup>2+</jats:sup>release by slow elevations of the intracellular Ca<jats:sup>2+</jats:sup>concentration resulted in Ca<jats:sup>2+</jats:sup>oscillations after a much shorter delay in mdx cells. This is consistent with an enhanced Ca<jats:sup>2+</jats:sup>sensitivity of the SR Ca<jats:sup>2+</jats:sup>-release channels [ryanodine receptors (RyRs)]. The hypersensitivity could be normalized by the introduction of reducing agents, indicating that the elevated cellular ROS generation in dystrophy underlies the abnormal RyR sensitivity and hypersensitive E-C coupling. Our data suggest that in dystrophin-deficient cardiomyocytes, E-C coupling is altered due to potentially arrhythmogenic changes in the Ca<jats:sup>2+</jats:sup>sensitivity of redox-modified RyRs.</jats:p>",
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