TY - JOUR
T1 - Microtubule-Mediated Misregulation of Junctophilin-2 Underlies T-Tubule Disruptions and Calcium Mishandling in mdx Mice
AU - Prins, Kurt W
AU - Asp, Michelle L.
AU - Zhang, Huiliang
AU - Wang, Wang
AU - Metzger, Joseph M
N1 - Publisher Copyright:
© 2016 The Authors
PY - 2016/4/1
Y1 - 2016/4/1
N2 - Cardiac myocytes from the mdx mouse, 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 (JPH)-2 on an altered microtubule network caused t-tubule derangements and calcium mishandling in a pressure-overload heart failure model. Mdx cardiac myocytes have microtubule abnormalities, but how this may affect JPH-2, t-tubules, and calcium handling has not been established. Here, we investigated the hypothesis that an inverse relationship between microtubules and JPH-2 underlies t-tubule disruptions and calcium mishandling in mdx cardiac myocytes. Confocal microscopy revealed t-tubule disorganization in mdx cardiac myocytes. Quantitative Western blot analysis demonstrated JPH-2 was decreased by 75% and showed an inverse hyperbolic relationship with α- and β-tubulin, the individual components of microtubules, in mdx hearts. Colchicine-induced microtubule depolymerization normalized JPH-2 protein levels and localization, corrected t-tubule architecture, and reduced calcium sparks. In summary, these results suggest microtubule-mediated misregulation of JPH-2 causes t-tubule derangements and altered calcium handling in mdx cardiac myocytes.
AB - Cardiac myocytes from the mdx mouse, 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 (JPH)-2 on an altered microtubule network caused t-tubule derangements and calcium mishandling in a pressure-overload heart failure model. Mdx cardiac myocytes have microtubule abnormalities, but how this may affect JPH-2, t-tubules, and calcium handling has not been established. Here, we investigated the hypothesis that an inverse relationship between microtubules and JPH-2 underlies t-tubule disruptions and calcium mishandling in mdx cardiac myocytes. Confocal microscopy revealed t-tubule disorganization in mdx cardiac myocytes. Quantitative Western blot analysis demonstrated JPH-2 was decreased by 75% and showed an inverse hyperbolic relationship with α- and β-tubulin, the individual components of microtubules, in mdx hearts. Colchicine-induced microtubule depolymerization normalized JPH-2 protein levels and localization, corrected t-tubule architecture, and reduced calcium sparks. In summary, these results suggest microtubule-mediated misregulation of JPH-2 causes t-tubule derangements and altered calcium handling in mdx cardiac myocytes.
KW - Duchenne cardiomyopathy
KW - calcium handling
KW - junctophilin-2
KW - microtubules
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U2 - 10.1016/j.jacbts.2016.02.002
DO - 10.1016/j.jacbts.2016.02.002
M3 - Review article
C2 - 27482548
AN - SCOPUS:85010289802
SN - 2452-302X
VL - 1
SP - 122
EP - 130
JO - JACC: Basic to Translational Science
JF - JACC: Basic to Translational Science
IS - 3
ER -