title: Elevated ventricular wall stress disrupts cardiomyocyte t-tubule structure and calcium homeostasis.
abstract: Invaginations of the cellular membrane called t-tubules are essential for maintaining efficient excitation-contraction coupling in ventricular cardiomyocytes. Disruption of t-tubule structure during heart failure has been linked to dyssynchronous, slowed Ca(2+) release and reduced power of the heartbeat. The underlying mechanism is, however, unknown. We presently investigated whether elevated ventricular wall stress triggers remodelling of t-tubule structure and function.
  
  
  
  MRI and blood pressure measurements were employed to examine regional wall stress across the left ventricle of sham-operated and failing, post-infarction rat hearts. In failing hearts, elevated left ventricular diastolic pressure and ventricular dilation resulted in markedly increased wall stress, particularly in the thin-walled region proximal to the infarct. High wall stress in this proximal zone was associated with reduced expression of the dyadic anchor junctophilin-2 and disrupted cardiomyocyte t-tubular structure. Indeed, local wall stress measurements predicted t-tubule density across sham and failing hearts. Elevated wall stress and disrupted cardiomyocyte structure in the proximal zone were also associated with desynchronized Ca(2+) release in cardiomyocytes and markedly reduced local contractility in vivo. A causative role of wall stress in promoting t-tubule remodelling was established by applying stretch to papillary muscles ex vivo under culture conditions. Loads comparable to wall stress levels observed in vivo in the proximal zone reduced expression of junctophilin-2 and promoted t-tubule loss.
  
  
  
  Elevated wall stress reduces junctophilin-2 expression and disrupts t-tubule integrity, Ca(2+) release, and contractile function. These findings provide new insight into the role of wall stress in promoting heart failure progression.
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Ullevål, Kirkeveien 166, 0424 Oslo, Norway K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway michael.frisk@medisin.uio.no.
authors.forename: Michael
authors.initials: M
authors.lastname: Frisk
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Ullevål, Kirkeveien 166, 0424 Oslo, Norway K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway.
authors.forename: Marianne
authors.initials: M
authors.lastname: Ruud
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Ullevål, Kirkeveien 166, 0424 Oslo, Norway K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway.
authors.forename: Emil K S
authors.initials: EK
authors.lastname: Espe
authors.affiliation: Bjørknes College, Oslo, Norway.
authors.forename: Jan Magnus
authors.initials: JM
authors.lastname: Aronsen
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Ullevål, Kirkeveien 166, 0424 Oslo, Norway K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway.
authors.forename: Åsmund T
authors.initials: ÅT
authors.lastname: Røe
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Ullevål, Kirkeveien 166, 0424 Oslo, Norway K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Ullevål, Kirkeveien 166, 0424 Oslo, Norway K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway.
authors.forename: Per Andreas
authors.initials: PA
authors.lastname: Norseng
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Ullevål, Kirkeveien 166, 0424 Oslo, Norway K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway.
authors.forename: Ole M
authors.initials: OM
authors.lastname: Sejersted
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Ullevål, Kirkeveien 166, 0424 Oslo, Norway K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway.
authors.forename: Geir A
authors.initials: GA
authors.lastname: Christensen
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Ullevål, Kirkeveien 166, 0424 Oslo, Norway K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway.
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Ullevål, Kirkeveien 166, 0424 Oslo, Norway K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, 0316 Oslo, Norway.
authors.forename: William E
authors.initials: WE
authors.lastname: Louch
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D056966:Excitation Contraction Coupling; D006333:Heart Failure / Q000378:metabolism* / Q000469:parasitology / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006706:Homeostasis; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D017208:Rats, Wistar; D013314:Stress, Mechanical; D013997:Time Factors; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D008565:Membrane Proteins; C412507:junctophilin; D002118:Calcium
keywords: Ca2+ homeostasis; Heart failure; Junctophilin-2; Left ventricular wall stress; T-tubules