title: Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart.
abstract: BACKGROUND
  Telethonin (also known as titin-cap or t-cap) is a 19-kDa Z-disk protein with a unique β-sheet structure, hypothesized to assemble in a palindromic way with the N-terminal portion of titin and to constitute a signalosome participating in the process of cardiomechanosensing. In addition, a variety of telethonin mutations are associated with the development of several different diseases; however, little is known about the underlying molecular mechanisms and telethonin's in vivo function.
  
  
  OBJECTIVE
  Here we aim to investigate the role of telethonin in vivo and to identify molecular mechanisms underlying disease as a result of its mutation.
  
  
  RESULTS
  By using a variety of different genetically altered animal models and biophysical experiments we show that contrary to previous views, telethonin is not an indispensable component of the titin-anchoring system, nor is deletion of the gene or cardiac specific overexpression associated with a spontaneous cardiac phenotype. Rather, additional titin-anchorage sites, such as actin-titin cross-links via α-actinin, are sufficient to maintain Z-disk stability despite the loss of telethonin. We demonstrate that a main novel function of telethonin is to modulate the turnover of the proapoptotic tumor suppressor p53 after biomechanical stress in the nuclear compartment, thus linking telethonin, a protein well known to be present at the Z-disk, directly to apoptosis ("mechanoptosis"). In addition, loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure, an effect that may contribute to enhanced rates of apoptosis found in these hearts.
  
  
  CONCLUSIONS
  Telethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress, owing at least in part to apoptosis of cardiomyocytes, an effect that may also play a role in human heart failure.
authors.affiliation: Imperial College, National Heart & Lung Institute, British Heart Foundation, Centre for Research Excellence, Myocardial Genetics, London, UK. r.knoell@imperial.ac.uk
authors.forename: Ralph
authors.initials: R
authors.lastname: Knöll
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.forename: Peijian
authors.initials: P
authors.lastname: Zou
authors.forename: Snjezana
authors.initials: S
authors.lastname: Miocic
authors.forename: Sawa
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authors.lastname: Kostin
authors.forename: Byambajav
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authors.lastname: Buyandelger
authors.forename: Ching-Hsin
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authors.forename: Stefan
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authors.lastname: Neef
authors.forename: Monika
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authors.lastname: Bug
authors.forename: Katrin
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authors.lastname: Schäfer
authors.forename: Gudrun
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authors.lastname: Knöll
authors.forename: Leanne E
authors.initials: LE
authors.lastname: Felkin
authors.forename: Johannes
authors.initials: J
authors.lastname: Wessels
authors.forename: Karl
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authors.lastname: Toischer
authors.forename: Franz
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authors.lastname: Hagn
authors.forename: Horst
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authors.lastname: Kessler
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authors.lastname: Didié
authors.forename: Thomas
authors.initials: T
authors.lastname: Quentin
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Nils
authors.initials: N
authors.lastname: Teucher
authors.forename: Bernhard
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authors.lastname: Unsöld
authors.forename: Albrecht
authors.initials: A
authors.lastname: Schmidt
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Birks
authors.forename: Sylvia
authors.initials: S
authors.lastname: Gunkel
authors.forename: Patrick
authors.initials: P
authors.lastname: Lang
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.forename: Wolfram-Hubertus
authors.initials: WH
authors.lastname: Zimmermann
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Field
authors.forename: Georgine
authors.initials: G
authors.lastname: Faulkner
authors.forename: Matthias
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authors.lastname: Dobbelstein
authors.forename: Paul J R
authors.initials: PJ
authors.lastname: Barton
authors.forename: Michael
authors.initials: M
authors.lastname: Sattler
authors.forename: Matthias
authors.initials: M
authors.lastname: Wilmanns
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D001696:Biomechanical Phenomena; D045744:Cell Line, Tumor; D064211:Connectin; D004195:Disease Models, Animal; D004452:Echocardiography; D005355:Fibrosis; D005838:Genotype; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D040542:Mechanotransduction, Cellular; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference; D051381:Rats; D012518:Sarcomeres / Q000378:metabolism; D013314:Stress, Mechanical; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D064211:Connectin; D009124:Muscle Proteins; C577294:Tcap protein, mouse; C507454:Tcap protein, rat; D016159:Tumor Suppressor Protein p53