title: Shortening of the elastic tandem immunoglobulin segment of titin leads to diastolic dysfunction.
abstract: BACKGROUND
  Diastolic dysfunction is a poorly understood but clinically pervasive syndrome that is characterized by increased diastolic stiffness. Titin is the main determinant of cellular passive stiffness. However, the physiological role that the tandem immunoglobulin (Ig) segment of titin plays in stiffness generation and whether shortening this segment is sufficient to cause diastolic dysfunction need to be established.
  
  
  RESULTS
  We generated a mouse model in which 9 Ig-like domains (Ig3-Ig11) were deleted from the proximal tandem Ig segment of the spring region of titin (IG KO). Exon microarray analysis revealed no adaptations in titin splicing, whereas novel phospho-specific antibodies did not detect changes in titin phosphorylation. Passive myocyte stiffness was increased in the IG KO, and immunoelectron microscopy revealed increased extension of the remaining titin spring segments as the sole likely underlying mechanism. Diastolic stiffness was increased at the tissue and organ levels, with no consistent changes in extracellular matrix composition or extracellular matrix-based passive stiffness, supporting a titin-based mechanism for in vivo diastolic dysfunction. Additionally, IG KO mice have a reduced exercise tolerance, a phenotype often associated with diastolic dysfunction.
  
  
  CONCLUSIONS
  Increased titin-based passive stiffness is sufficient to cause diastolic dysfunction with exercise intolerance.
authors.affiliation: Department of Physiology, University of Arizona, PO Box245051, Tucson AZ 85724, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Chung
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Hutchinson
authors.forename: Mei
authors.initials: M
authors.lastname: Methawasin
authors.forename: Chandra
authors.initials: C
authors.lastname: Saripalli
authors.forename: John E
authors.initials: JE
authors.lastname: Smith
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Hidalgo
authors.forename: Xiuju
authors.initials: X
authors.lastname: Luo
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.forename: Caiying
authors.initials: C
authors.lastname: Guo
authors.forename: Henk L
authors.initials: HL
authors.lastname: Granzier
mesh_terms: D000367:Age Factors; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology; D003971:Diastole / Q000502:physiology*; D004195:Disease Models, Animal; D004548:Elasticity; D017079:Exercise Tolerance / Q000502:physiology; D054144:Heart Failure, Diastolic / Q000235:genetics* / Q000503:physiopathology*; D007136:Immunoglobulins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016253:Microscopy, Immunoelectron; D010641:Phenotype; D010766:Phosphorylation / Q000502:physiology; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary; D012518:Sarcomeres / Q000502:physiology
chemical_list: D007136:Immunoglobulins; D011494:Protein Kinases; C579730:titin protein, mouse
keywords: elasticity; exercise; extracellular matrix; hypertrophy; vascular stiffness