title: Microtubule-mediated defects in junctophilin-2 trafficking contribute to myocyte transverse-tubule remodeling and Ca2+ handling dysfunction in heart failure.
abstract: BACKGROUND
  Cardiac dysfunction in failing hearts of human patients and animal models is associated with both microtubule densification and transverse-tubule (T-tubule) remodeling. Our objective was to investigate whether microtubule densification contributes to T-tubule remodeling and excitation-contraction coupling dysfunction in heart disease.
  
  
  RESULTS
  In a mouse model of pressure overload-induced cardiomyopathy by transaortic banding, colchicine, a microtubule depolymerizer, significantly ameliorated T-tubule remodeling and cardiac dysfunction. In cultured cardiomyocytes, microtubule depolymerization with nocodazole or colchicine profoundly attenuated T-tubule impairment, whereas microtubule polymerization/stabilization with taxol accelerated T-tubule remodeling. In situ immunofluorescence of heart tissue sections demonstrated significant disorganization of junctophilin-2 (JP2), a protein that bridges the T-tubule and sarcoplasmic reticulum membranes, in transaortic banded hearts as well as in human failing hearts, whereas colchicine injection significantly preserved the distribution of JP2 in transaortic banded hearts. In isolated mouse cardiomyocytes, prolonged culture or treatment with taxol resulted in pronounced redistribution of JP2 from T-tubules to the peripheral plasma membrane, without changing total JP2 expression. Nocodazole treatment antagonized JP2 redistribution. Moreover, overexpression of a dominant-negative mutant of kinesin 1, a microtubule motor protein responsible for anterograde trafficking of proteins, protected against JP2 redistribution and T-tubule remodeling in culture. Finally, nocodazole treatment improved Ca(2+) handling in cultured myocytes by increasing the amplitude of Ca(2+) transients and reducing the frequency of Ca(2+) sparks.
  
  
  CONCLUSIONS
  Our data identify a mechanistic link between microtubule densification and T-tubule remodeling and reveal microtubule-mediated JP2 redistribution as a novel mechanism for T-tubule disruption, loss of excitation-contraction coupling, and heart failure.
authors: Division of Cardiovascular Medicine, Department of Internal Medicine (C.Z., B.C., A.G., Y.Z., S.G., W.K., R.M.W., F.L.J., M.E.A., L.-S.S.) and Department of Molecular Physiology and Biophysics (M.E.A.), University of Iowa Carver College of Medicine, Iowa City, IA; Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China (Y.Z., J.H.); Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN (J.D.M.); Department of Pharmacology, College of Basic Medicine, Anhui Medical University, Hefei, China (S.G.); Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA (C.Y., L.F.S.); Department of Veterans Affairs Medical Center, Iowa City, IA (K.Z.); and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (X.H.T.W.).
authors: Caimei
authors: C
authors: Zhang
authors: Biyi
authors: B
authors: Chen
authors: Ang
authors: A
authors: Guo
authors: Yanqi
authors: Y
authors: Zhu
authors: Jordan D
authors: JD
authors: Miller
authors: Shan
authors: S
authors: Gao
authors: Can
authors: C
authors: Yuan
authors: William
authors: W
authors: Kutschke
authors: Kathy
authors: K
authors: Zimmerman
authors: Robert M
authors: RM
authors: Weiss
authors: Xander H T
authors: XH
authors: Wehrens
authors: Jiang
authors: J
authors: Hong
authors: Frances L
authors: FL
authors: Johnson
authors: Luis F
authors: LF
authors: Santana
authors: Mark E
authors: ME
authors: Anderson
authors: Long-Sheng
authors: LS
authors: Song
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D004195:Disease Models, Animal; D056966:Excitation Contraction Coupling / Q000187:drug effects / Q000502:physiology; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D015739:Nocodazole / Q000494:pharmacology; D012508:Sarcolemma / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D003078:Colchicine; D016547:Kinesins; D008565:Membrane Proteins; D009124:Muscle Proteins; D015739:Nocodazole; D050257:Tubulin Modulators; C000589041:JPH2 protein, human; C488101:KIF5B protein, human; C412507:junctophilin; C000589042:JP2 protein, mouse
keywords: excitation contraction coupling; junctophilin; microtubules; myocytes, cardiac