title: A critical role for Telethonin in regulating t-tubule structure and function in the mammalian heart.
abstract: The transverse (t)-tubule system plays an essential role in healthy and diseased heart muscle, particularly in Ca(2+)-induced Ca(2+) release (CICR), and its structural disruption is an early event in heart failure. Both mechanical overload and unloading alter t-tubule structure, but the mechanisms mediating the normally tight regulation of the t-tubules in response to load variation are poorly understood. Telethonin (Tcap) is a stretch-sensitive Z-disc protein that binds to proteins in the t-tubule membrane. To assess its role in regulating t-tubule structure and function, we used Tcap knockout (KO) mice and investigated cardiomyocyte t-tubule and cell structure and CICR over time and following mechanical overload. In cardiomyocytes from 3-month-old KO (3mKO), there were isolated t-tubule defects and Ca(2+) transient dysynchrony without whole heart and cellular dysfunction. Ca(2+) spark frequency more than doubled in 3mKO. At 8 months of age (8mKO), cardiomyocytes showed progressive loss of t-tubules and remodelling of the cell surface, with prolonged and dysynchronous Ca(2+) transients. Ca(2+) spark frequency was elevated and the L-type Ca(2+) channel was depressed at 8 months only. After mechanical overload obtained by aortic banding constriction, the Ca(2+) transient was prolonged in both wild type and KO. Mechanical overload increased the Ca(2+) spark frequency in KO alone, where there was also significantly more t-tubule loss, with a greater deterioration in t-tubule regularity. In conjunction, Tcap KO showed severe loss of cell surface ultrastructure. These data suggest that Tcap is a critical, load-sensitive regulator of t-tubule structure and function.
authors.affiliation: Laboratory of Cell Electrophysiology, Heart Science Centre, Harefield Hospital, London UB9 6JH, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Ibrahim
authors.forename: Urszula
authors.initials: U
authors.lastname: Siedlecka
authors.forename: Byambajav
authors.initials: B
authors.lastname: Buyandelger
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Harada
authors.forename: Christopher
authors.initials: C
authors.lastname: Rao
authors.forename: Alexey
authors.initials: A
authors.lastname: Moshkov
authors.forename: Anamika
authors.initials: A
authors.lastname: Bhargava
authors.forename: Michael
authors.initials: M
authors.lastname: Schneider
authors.forename: Magdi H
authors.initials: MH
authors.lastname: Yacoub
authors.forename: Julia
authors.initials: J
authors.lastname: Gorelik
authors.forename: Ralph
authors.initials: R
authors.lastname: Knöll
authors.forename: Cesare M
authors.initials: CM
authors.lastname: Terracciano
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D064211:Connectin; D006321:Heart / Q000502:physiology* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism* / Q000473:pathology
chemical_list: D064211:Connectin; D009124:Muscle Proteins; C577294:Tcap protein, mouse; D002118:Calcium