title: Microtubule-Mediated Misregulation of Junctophilin-2 Underlies T-Tubule Disruptions and Calcium Mishandling inmdxMice.
abstract: Cardiac myocytes from themdxmouse, the mouse model of Duchenne muscular dystrophy, exhibit t-tubule disarray and increased calcium sparks, but a unifying molecular mechanism has not been elucidated. Recently, improper trafficking of junctophilin-2 on an altered microtubule network caused t-tubule derangements and calcium mishandling in a pressure-overload heart failure model.Mdxcardiac myocytes have microtubule abnormalities, but how this may affect junctophilin-2, t-tubules, and calcium handling has not been established. Here, we investigated the hypothesis that an inverse relationship between microtubules and junctophilin-2 underlies t-tubule disruptions and calcium mishandling inmdxcardiac myocytes. Confocal microscopy revealed t-tubule disorganization inmdxcardiac myocytes. Quantitative Western blot analysis demonstrated junctophilin-2 was decreased by 75% and showed an inverse hyperbolic relationship with α- and β-tubulin, the individual components of microtubules, inmdxhearts. Colchicine-induced microtubule depolymerization normalized junctophilin-2 protein levels and localization, corrected t-tubule architecture, and reduced calcium sparks. In summary, these results suggest microtubule-mediated misregulation of junctophilin-2 causes t-tubule derangements and altered calcium handling inmdxcardiac myocytes.
authors.affiliation: Cardiovascular Division, University of Minnesota Medical School, Minneapolis, Minnesota.
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Prins
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Asp
authors.affiliation: Mitochondria and Metabolism Center, University of Washington, Seattle, Washington.
authors.forename: Huiliang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Mitochondria and Metabolism Center, University of Washington, Seattle, Washington.
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
keywords: Duchenne cardiomyopathy; calcium handling; junctophilin-2; microtubules