@article{MTMT:30482956,
	title = {Functional abnormalities in induced Pluripotent Stem Cell-derived cardiomyocytes generated from titin-mutated patients with dilated cardiomyopathy},
	url = {https://m2.mtmt.hu/api/publication/30482956},
	author = {Schick, Revital and Mekies, Lucy N. and Shemer, Yuval and Eisen, Binyamin and Hallas, Tova and Ben, Jehuda Ronen and Ben-Ari, Meital and Szántai, Ágnes and Willi, Lubna and Shulman, Rita and Gramlich, Michael and Pane, Luna Simona and My, Ilaria and Freimark, Dov and Murgia, Marta and Santamaria, Gianluca and Gherghiceanu, Mihaela and Arad, Michael and Moretti, Alessandra and Binah, Ofer},
	doi = {10.1371/journal.pone.0205719},
	journal-iso = {PLOS ONE},
	journal = {PLOS ONE},
	volume = {13},
	unique-id = {30482956},
	abstract = {Aims Dilated cardiomyopathy (DCM), a myocardial disorder that can result in progressive heart failure and arrhythmias, is defined by ventricular chamber enlargement and dilatation, and systolic dysfunction. Despite extensive research, the pathological mechanisms of DCM are unclear mainly due to numerous mutations in different gene families resulting in the same outcome-decreased ventricular function. Titin (TTN) a giant protein, expressed in cardiac and skeletal muscles, is an important part of the sarcomere, and thus TTN mutations are the most common cause of adult DCM. To decipher the basis for the cardiac pathology in titin-mutated patients, we investigated the hypothesis that induced Pluripotent Stem Cell (iPSC)-derived cardiomyocytes (iPSC-CM) generated from patients, recapitulate the disease phenotype. The hypothesis was tested by 3 Aims: (1) Investigate key features of the excitation-contraction-coupling machinery; (2) Investigate the responsiveness to positive inotropic interventions; (3) Investigate the proteome profile of the AuP cardiomyocytes using mass-spectrometry (MS). Methods and results iPSC were generated from the patients' skin fibroblasts. The major findings were: (1) Sarcomeric organization analysis in mutated iPSC-CM showed defects in assembly and maintenance of sarcomeric structure. (2) Mutated iPSC-CM exhibited diminished inotropic and lusitropic responses to beta-adrenergic stimulation with isoproterenol, increased [Ca2+](out) and angiotensin-II. Additionally, mutated iPSC-CM displayed prolonged recovery in response to caffeine. These findings may result from defective or lack of interactions of the sarcomeric components with titin through its kinase domain which is absent in the mutated cells. Conclusions These findings show that the mutated cardiomyocytes from DCM patients recapitulate abnormalities of the inherited cardiomyopathies, expressed as blunted inotropic response.},
	year = {2018},
	eissn = {1932-6203},
	orcid-numbers = {Eisen, Binyamin/0000-0002-2185-5054}
}

@article{MTMT:3282237,
	title = {The giant protein titin regulates the length of the striated muscle thick filament},
	url = {https://m2.mtmt.hu/api/publication/3282237},
	author = {Tonino, P and Kiss, Balázs and Strom, J and Methawasin, M and Smith, JE rd and Kolb, J and Labeit, S and Granzier, H},
	doi = {10.1038/s41467-017-01144-9},
	journal-iso = {NAT COMMUN},
	journal = {NATURE COMMUNICATIONS},
	volume = {8},
	unique-id = {3282237},
	abstract = {The contractile machinery of heart and skeletal muscles has as an essential component the thick filament, comprised of the molecular motor myosin. The thick filament is of a precisely controlled length, defining thereby the force level that muscles generate and how this force varies with muscle length. It has been speculated that the mechanism by which thick filament length is controlled involves the giant protein titin, but no conclusive support for this hypothesis exists. Here we show that in a mouse model in which we deleted two of titin's C-zone super-repeats, thick filament length is reduced in cardiac and skeletal muscles. In addition, functional studies reveal reduced force generation and a dilated cardiomyopathy (DCM) phenotype. Thus, regulation of thick filament length depends on titin and is critical for maintaining muscle health.},
	year = {2017},
	eissn = {2041-1723},
	orcid-numbers = {Kiss, Balázs/0000-0002-2347-5928}
}

@article{MTMT:1322327,
	title = {Molecular tools for the study of titin's differential expression},
	url = {https://m2.mtmt.hu/api/publication/1322327},
	author = {Centner, T and Fougerousse, F and Freiburg, A and Witt, C and Beckmann, JS and Granzier, H and Trombitás, Károly and Gregorio, CC and Labeit, S},
	doi = {10.1007/978-1-4615-4267-4_3},
	journal-iso = {ADV EXP MED BIOL},
	journal = {ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY},
	volume = {481},
	unique-id = {1322327},
	issn = {0065-2598},
	abstract = {Although vertebrate genomes appear to contain only one titin gene, a large variety of quite distinct titin isoforms are expressed in striated muscle tissues. The isoforms appear to be generated by a series of complex, not yet fully characterized differential splicing mechanisms. Here, we provide an overview of the titin-specific antibodies that have been raised by our laboratory to study individual differentially expressed isoforms of titin. The staining patterns obtained in different tissues will contribute to the identification of both the particular titin isoforms that are expressed in the different tissues, as well as their intracellular distributions. In addition, antibodies to titin that are available are rapidly allowing for the refinement of our knowledge of titin's elastic spring properties. Knowledge of the nature and structure of vertebrate titins that may also be expressed in nonmuscle tissues may be broadened using these antibodies.},
	year = {2000},
	eissn = {2214-8019},
	pages = {35-52}
}