Page 48 - Rappaport Institute Magazine 2024

PHYSIOLOGY, BIOPHYSICS AND SYSTEMS BIOLOGY
Izhak Kehat MD, PhD Associate Professor of Physiology
MD, 1996 – Technion, Israel PhD, 1999 – Technion, Israel
The maintenance of the sarcomere in the normal, hypertrophic, and failing heart
The sarcomere is the basic contractile unit of heart cells. Each heart cell contains more than a thousand sarcomeric units, and the human heart has about 3 trillion sarcomeres. The sarcomere is built from large contractile proteins, including Titin, the largest protein in the body. We showed that sarcomeric proteins are rapidly and continuously turned over in the heart and we study the mechanisms responsible for this turnover. I investigate how this turnover contributes to hypertrophy and why it fails in failing hearts. Specifically, my lab discovered that each sarcomeric unit contains a ‘nano-factory’ where the mRNA and ribosomes are localized and where proteins are locally translated. W also showed that a network of microtubules is responsible for shuttling these mRNA and ribosome to all the sarcomeres in the cell. My work uses mouse models of cardiomyopathies and heart failure, advanced imaging and proteomic approaches, viral transduction and gene therapy approaches, CRISPR, as well as functional assessments of the heart. I hope these studies will lead to new insights into the mechanism of heart disease and to new therapies.
Selected Publications
ˆ Scarborough EA, Uchida K, Vogel M, Erlitzki N, Iyer m , Phyo S, Bogush A, Kehat I, Prosser BL. Microtubules orchestrate local translation to enable cardiac growth.
Nat Commun. 2021 Mar 11;12(1):1547
ˆ Schlesinger-Laufer M, Douvdevany G, Haimovich-Caspi L, Kehat I. A simple adeno- associated virus-based approach for the generation of cardiac genetic models in rats. F1000Res. 2020 Dec 10;9:ISF-1441
ˆ Lewis YE, Moskovitz A, Mutlak M, Heineke J, Caspi LH, Kehat I. Localization of transcripts, translation, and degradation for spatiotemporal sarcomere maintenance. J Mol Cell Cardiol. 116 (2018) 16–28.
ikehat@technion.ac.il
Izhak Kehat Lab
We discovered that each sarcomere contains a ‘nano-factory’ where mRNA and ribosomes are localized, and proteins are locally translated to continuously maintain the sarcomere.