Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Knöll, R; Linke, WA; Zou, P; Miocic, S; Kostin, S; Buyandelger, B; Ku, CH; Neef, S; Bug, M; Schäfer, K; Knöll, G; Felkin, LE; Wessels, J; Toischer, K; Hagn, F; Kessler, H; Didié, M; Quentin, T; Maier, LS; Teucher, N; Unsöld, B; Schmidt, A; Birks, EJ; Gunkel, S; Lang, P; Granzier, H; Zimmermann, WH; Field, LJ; Faulkner, G; Dobbelstein, M; Barton, PJ; Sattler, M; Wilmanns, M; Chien, KR.
Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart.
Circ Res. 2011; 109(7):758-769
Doi: 10.1161/CIRCRESAHA.111.245787
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- Co-Autor*innen der Med Uni Graz
- Schmidt Albrecht
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- Abstract:
- RATIONALE: Telethonin (also known as titin-cap or t-cap) is a 19-kDa Z-disk protein with a unique ß-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. METHODS AND 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 a-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.
- Find related publications in this database (using NLM MeSH Indexing)
- Adaptation, Physiological -
- Animals -
- Animals, Genetically Modified -
- Apoptosis -
- Biomechanics -
- Cell Line, Tumor -
- Disease Models, Animal -
- Echocardiography -
- Fibrosis -
- Genotype -
- Heart - physiopathology
- Heart Failure - genetics Heart Failure - metabolism Heart Failure - pathology Heart Failure - physiopathology
- Humans -
- Mechanotransduction, Cellular -
- Mice -
- Mice, Knockout -
- Muscle Proteins - deficiency Muscle Proteins - genetics
- Myocardium - metabolism Myocardium - pathology
- Phenotype -
- RNA Interference -
- Rats -
- Sarcomeres - metabolism
- Stress, Mechanical -
- Transfection -
- Tumor Suppressor Protein p53 - metabolism
- Find related publications in this database (Keywords)
- genetics
- mechanosensation
- mechanotransduction
- cardiomyopathy
- heart failure