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Triadopathies: An Emerging Class of Skeletal Muscle Diseases

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Neurotherapeutics

Abstract

The triad is a skeletal muscle substructure responsible for the regulation of excitation–contraction coupling. It is formed by the close apposition of the T-tubule and the terminal sarcoplasmic reticulum. A rapidly growing list of skeletal myopathies, here referred to as triadopathies, are caused by gene mutations in components of the triad. These disorders, at their root, are caused by defects in excitation contraction coupling and intracellular calcium homeostasis. Secondary abnormalities in triad structure and/or function are also reported in several muscle diseases, most notably certain muscular dystrophies. This review highlights the current understanding of both primary and secondary triadopathies, and identifies important concepts yet to be fully addressed in the field. The emphasis of the review is both on the pathogenesis of triadopathies and their potential treatment.

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Acknowledgments

This work was supported by grants from CureCMD (to J.J.D.), muscular dystrophy association (MDA186999 to J.J.D.), and National Institutes of Health (AR053349 to R.T.D.; 1R03AR062810 and 1K08AR054835 to J.J.D.; and 1K08AR059750 to M.W.L.). We thank Carsten Bonnemann and Maria Rita Santi for contributing biopsy photomicrographs and Elizabeth Gibbs for assistance with Figure 1.

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Authors and Affiliations

  1. Division of Neurology and Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, ON, Canada

    James J. Dowling

  2. Department of Paediatrics, University of Toronto, Toronto, ON, Canada

    James J. Dowling

  3. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    James J. Dowling

  4. Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    Michael W. Lawlor

  5. Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA

    Robert T. Dirksen

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  1. James J. Dowling
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Correspondence to James J. Dowling.

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Dowling, J.J., Lawlor, M.W. & Dirksen, R.T. Triadopathies: An Emerging Class of Skeletal Muscle Diseases. Neurotherapeutics 11, 773–785 (2014). https://doi.org/10.1007/s13311-014-0300-3

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