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Focal adhesion kinase regulates early steps of myofibrillogenesis in cardiomyocytes

Nilay Taneja, Abigail C Neininger, Matthew R Bersi, W David Merryman, Dylan T Burnette

Preprint posted on February 07, 2018 https://www.biorxiv.org/content/early/2018/02/07/261248.

Broken hearts: FAK orchestrates force balance in the heart.

Selected by Vassilis Papalazarou

Background

Myofibrils are the foundational functional units within cardiomyocytes. They regulate the generation of contractile forces that form the basis of proper heart function. Myofibrils are essentially a series of sarcomeres that consist of ‘thick’ myosin and ‘thin’ actin filaments. Contact sites between cells and their environment that are known as focal adhesion complexes are not only necessary for the growth and assembly of myofibrils, but also for their physical coupling with their extracellular substrate. This generates a force balance between contractile and adhesive forces that drives normal heart muscle tension and contraction. Collapse of this force balance could be the basis of many cardiomyopathies. Focal adhesion kinase (FAK) has already been established as a major actor that is recruited to focal adhesion complexes. FAK triggers a series of signalling events, which regulate cell proliferation, survival and migration. However, its role in cardiac myocytes, especially during the de novo myofibril assembly, is not completely understood.

Novelty and Findings

By directing the differentiation of human-induced pluripotent stem cells (iPSCs) into human cardiomyocytes (hCMs), the authors were able to study the role of FAK in de novo assembly and maturation of myofibrils. Specifically, the inhibition of FAK to delay adhesion turnover resulted in a more stable coupling of myofibrils to their extracellular environment. This accelerated myofibrillogenesis and increased the viscosity of the filaments, indicating elevated force production. Therefore, FAK appears to be a key molecule that orchestrates the coupling of adhesion complexes to fibre force production during the maturation of myofibrils.

Outstanding Questions

How do sarcomeres get generated and grow within cardiomyocytes? Different models have been suggested for their formation and orientation within the cell; this difference, however, appears to stem mainly from the different experimental settings (1, 2). However, by following the de novo assembly of myofibrils, the authors of this study were able to demonstrate that coupling of cardiomyocytes to their substrate is crucial for this process. This suggests that mechanical uncoupling could severely affect the pathophysiology of cardiac muscles. Future research will shed more light on the mechanisms that regulate these procedures.

References

  1. Chopra, A., M.L. Kutys, K. Zhang, W.J. Polacheck, C.C. Sheng, R.J. Luu, J. Eyckmans, J.T. Hinson, J.G. Seidman, C.E. Seidman, and C.S. Chen. 2018. Force Generation via beta- Cardiac Myosin, Titin, and alpha-Actinin Drives Cardiac Sarcomere Assembly from Cell- Matrix Adhesions. Dev Cell. 44:87-96 e85.
  2. Fenix, A.M., N Taneja, A.C. Neininger, M.R. Visetsouk, B.R. Nixon, A.E. Manalo, J.R. Becker, S.W. Crawley, D.M. Bader, M.J. Tyska, J.H. Gutzman, and D.T. Burnette. 2017. Muscle specific stress fibers give rise to sarcomeres and are mechanistically distinct from stress fibers in non-muscle cells. bioRxiv 235424.

 

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