Investigación del IIBCE en destaque editorial

La prestigiosa revista American Journal of Physiology – Cell Physiology se dedica a aproximaciones innovadoras en el estudio de la fisiología molecular y celular, incluidas las que se utilizan para aclarar el control fisiológico en niveles más altos de organización.

En su último número, dedicó un foco editorial a una publicación realizada por científicos Uruguayos que trabajan en nuestro instituto. Allí se destaca la elegancia del estudio de Juan Benech y colegas, del Laboratorio de Señalización Celular y Nanobiología del IIBCE, en el que utilizan por primera vez el microscopio de fuerza atómica para dilucidar las propiedades mecánicas y funcionales de células cardíacas, afectadas por la diabetes inducida en ratones.

Ilustramos esta buena noticia con una foto de su investigación, donde se pueden ver los resultados obtenidos en el modelo de cardiomiocitos aislados de corazones de ratones diabéticos (A, vistos con luz transmitida; B, con fluorescencia, C, “cantilever” del Microscopio de Fuerza Atómica (AFM) sobre el miocardiocito,. imagenes de deflexión y altura desde el AFM, F medida de altura).

Fig BlogIIBCE Juan Benech micocardiocitos en ratones c diabetes inducida

Copiamos el destaque editorial en inglés.
Contacto: Juan Claudio Benech, //

Atomic force microscopy (AFM) is proving to be a very useful tool for probing nanoscale and microscale mechanical properties and behavior of cells. A cursory search of the literature reveals that the use of the technique to study various characteristics of myocardial cells dates back to the mid 1990’s (e.g., 1,6). Perhaps more revealing is its ever more frequent application to study myocardial contractile function and dysfunction (e.g., 4,8,9,). The study published in this issue of AJP-Cell by Benech et al., is to my knowledge the first time AFM has been used to study left ventricular myocardial cells in diabetes mellitus in order to gain a deeper understanding of the mechanical and functional events that may underlie heart failure in that disease. Importantly, heart failure is a complication that is frequently associated with the diabetic state and is likely to be of increasing importance with the increased prevalence of Type 2 diabetes and insulin-resistant states.

There are several striking observations made in their elegant study of Benech et al. First they observe that in their streptozotocin model of diabetes that myocytes from the diabetic animals are stiffer when compared to those from control mice. In addition, the increase in stiffness appears associated with decreased expression of the sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA 2) and a disordered cytoskeletal organization within the myocytes. The latter changes appeared to strongly influence the actin cytoskeleton. Although the reduced SERCA 2 expression would make one suspect that a component of the increased stiffness in the diabetic animals was related to intracellular Ca2+, the increase in stiffness was apparent even when intracellular Ca2+ was reduced to low levels in a near Ca2+ free buffer. Again, this appears to strongly indicate that normal regulation of the actin cytoskeleton dynamics are fundamentally disturbed. These changes were accompanied by marked changes in the extracellular matrix as diabetic mice showed increased collagen accumulation between myocytes; in addition, the distribution of myocytes within the myocardium was less orderly compared to controls.

The data presented in this study are, in my opinion, building on an emerging common theme in cardiovascular disease. There appears to be strong evidence accumulating that altered mechanical properties of cardiovascular tissue in disease is not solely attributable to changes in the extracellular matrix protein composition, organization and post-translational modification (including for example, glycation which would be expected in the diabetic model) but also includes significant contributions from changes in the intrinsic mechanical properties of the cells. This appears to be true for myocardial cells, as demonstrated here, but also for vascular smooth muscle cells (e.g., 7,10) and endothelial cells (e.g., 2,3,5). Furthermore, while a common theme appears to be a fundamental change in the actin cytoskeleton, particularly in the cortical regions of the cell, there is also evidence that cellular interactions with the extracellular matrix are fundamentally altered. An immediate, critical question is what is driving what? What are the respective roles of the extracellular matrix changes, the cytoskeletal changes, and the changes in cell adhesion and changes in the mechanical environment? Clearly, for a tissue to function normally it requires a normally structured and functioning matrix. In addition, the cell and its cytoskeleton must relate properly to the external matrix structure for mechanical force to be sensed and transmitted. Disordered cellular attachment and cytoskeletal properties combined with extracellular matrix changes are a formula for dysfunction (Figure 1). It will be exciting to watch this area unfold and in particular, to see what new functional insights and new paradigms emerge in disease.

1. Domke J, Parak WJ, George M, Gaub HE, Radmacher M. Mapping the mechanical pulse of single cardiomyocytes with the atomic force microscope. Eur Biophys J. 1999;28(3):179-86. PMID: 10192933
2. Fels J, Jeggle P, Liashkovich I, Peters W, Oberleithner H. Nanomechanics of vascular endothelium. Cell Tissue Res. 2014 Mar;355(3):727-37. doi: 10.1007/s00441 014-1853-5. Epub 2014 Mar 19. PMID: 24643677
3. Grimm KB, Oberleithner H, Fels J. Fixed endothelial cells exhibit physiologically relevant nanomechanics of the cortical actin web. Nanotechnology. 2014 May 30;25(21):215101. doi: 10.1088/0957-4484/25/21/215101. Epub 2014 May 2. PMID: 2478685
4. Kliche K, Kuhn M, Hillebrand U, Ludwig Y, Stock C, Oberleithner H. Direct aldosterone action
70 on mouse cardiomyocytes detected with atomic force microscopy. Cell Physiol Biochem. 2006;18(4-5):265-74. PMID: 17167231
5. Kusche-Vihrog K, Jeggle P, Oberleithner H. Pflugers The role of ENaC in vascular endothelium. Arch. 2014 May;466(5):851-9. doi: 10.1007/s00424-013-1356-3. Epub 2013 Sep 18. PMID: 24046153
6. Lal R, John SA, Laird DW, Arnsdorf MF. Heart gap junction preparations reveal hemiplaques by atomic force microscopy. Am J Physiol. 1995 Apr;268(4 Pt 1):C968-77. PMID: 7733245
7. Sehgel, N.L., Y. Zhu, Z. Sun, J.P. Trzeciakowski, Z. Hong, W.C. Hunter, D.E. Vatner, G.A. Meininger, S.F. Vatner. Increased vascular smooth muscle cell stiffness: a novel mechanism for increased aortic stiffness in hypertension. American Journal of Physiology: Heart and Circulatory Physiology, 305:H1281-H1287, 2013. DOI: 10.1152, PMID: 23709594, PMCID: PMC3840243
8. Wang L, Chen T, Zhou X, Huang Q, Jin C. Atomic force microscopy observation of lipopolysaccharide-induced cardiomyocyte cytoskeleton reorganization. Micron. 2013 Aug;51:48-53. doi: 10.1016/j.micron.2013.06.008. Epub 2013 Jul 5. PMID: 23906659



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