Összes szerző

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Jámbor András

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Török György
Adaptive changes in the a-band region of the giant protein titin in diseased human cardiac sarcomere

Aug 30 - szerda

15:30 – 17:00

II. Poszterszekció

P32

Adaptive changes in the A-band region of the giant protein titin in diseased human cardiac sarcomere

György Török¹, Iliza Ramazanova¹, Péter Dániel¹, András Jámbor¹, Dalma Kellermayer^1,2, Cristina M. Șulea^1,2, Zoltán Szabolcs², Miklós S. Z. Kellermayer¹ and Balázs Kiss¹

¹Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary

²Heart and Vascular Center, Semmelweis University, Budapest, Hungary

Titin, the largest protein known, spans the half-sarcomere, the contractile unit of skeletal and cardiac muscle through its Z-disk to M-line and interacts with thin and thick filaments in the I- and A-band of the muscle sarcomere, respectively. Titin’s A-band segment is not well understood but is shown to be orders of magnitude less extensible than the I-band region of the molecule. Heterozygous truncating mutations (TTNtv) affecting A-band titin are often associated with dilated cardiomyopathy (DCM). Marfan syndrome (MFS), a connective tissue disorder caused by mutations of the matrix glycoprotein fibrillin is also associated with impaired cardiac contractility but its exact pathomechanism is largely unknown.

Here, we performed STED super-resolution microscopy on sections of stretched and fixed demembranated human cardiac myofibrils carrying heterozygous TTNtv mutations or on samples originated from MFS patients. Sequence-specific anti-titin antibodies included the 1) MIR, which labels titin at the ends of the thick filaments, 2) A170, labeling titin close to the M-line (this epitope is missing in TTNtv+). Sarcomere length-dependent anti-titin epitope position, shape and intensity analysis pointed at structural defects in the I/A junction and the M-band of TTNtv+ sarcomeres. Our experiments indicate that truncated titin is able to integrate into the cardiac sarcomere. We propose that the truncated titin cannot precisely register the ends of the thick filaments, and this can ultimately lead to the manifestation of DCM by disrupting the overlapping of thin and thick filaments. In MFS sarcomeres a pronounced, ~30 nm shift away from the M-line was found in the case of the A170 titin epitope suggesting that alterations in the M-band ultrastructure might be important contributors of the impaired cardiac contractility of MFS patients.