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Cronos Titin Is Expressed in Human Cardiomyocytes and Necessary for Normal Sarcomere Function
Rebecca J Zaunbrecher1,2,3, Ashley N Abel2,3, Kevin Beussman4,2,3
1Department of Bioengineering (R.J.Z., J.M., D.-H.K., M.R., C.E.M.), University of Washington, Seattle.
Circulation
|October 8, 2019
Summary
The giant sarcomere protein titin is crucial for heart health. A newly discovered titin isoform, Cronos, supports sarcomere formation and function in cardiomyocytes, especially during development.
Area of Science:
- Cardiovascular biology
- Muscle physiology
- Genetics
Background:
- Titin (TTN) is a giant sarcomere protein vital for cardiac function.
- Mutations in TTN are a primary cause of familial dilated cardiomyopathy.
- Understanding TTN isoforms is key to comprehending cardiomyocyte development and disease.
Purpose of the Study:
- To investigate the role of TTN isoforms in human cardiomyocyte (CM) sarcomere formation and function.
- To elucidate the function of the Cronos titin isoform in CMs.
Main Methods:
- CRISPR/Cas9 gene editing to create TTN truncations (TTN-Z-/- and TTN-A-/-) in human induced pluripotent stem cells.
- Characterization of resulting CMs using immunostaining, engineered heart tissue, and single-cell force/calcium measurements.
- Development and use of a custom Cronos antibody for isoform detection.
Main Results:
- TTN-Z-/- CMs formed sarcomeres and contracted, unlike TTN-A-/- CMs, due to Cronos titin expression.
- Cronos titin, expressed in TTN-Z-/- CMs, supports partial sarcomere formation but results in reduced contractile force and myofibril disarray.
- Cronos titin is highly expressed in fetal cardiac tissue and is necessary for proper sarcomere function in iPSC-CMs.
Conclusions:
- Cronos titin is expressed in developing human CMs and can facilitate sarcomere formation without full-length titin.
- Cronos titin is essential for optimal sarcomere function in human iPSC-derived CMs.
- Further research is needed to clarify Cronos titin's mechanisms and role in cardiac disease.
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