The stiffness of the extracellular matrix (ECM) – which varies considerably between tissues – influences cell shape, protein expression and differentiation, and is important for tissue function. In the heart, for instance, the ECM to which cardiomyocytes attach must be sufficiently compliant for the heart to beat in response to actomyosin contraction. Fibrotic scars – which are considerably stiffer than normal myocardium – are present in the heart after myocardial infarction, but how do they affect cardiomyocyte function? On , Dennis Discher and colleagues address this question by culturing embryonic cardiomyocytes on a series of substrates of differing elasticity. The authors show that the transmission of contractile work (cardiomyocyte beating) to the matrix is optimal on matrices that mimic the elasticity of the developing myocardial microenvironment. By contrast, cells growing on stiffer substrates (which mimic a fibrotic scar) transmit little work to the matrix; moreover, they are deficient in myofibril assembly and their beating frequency slows over time. The authors use an in-situ cysteine-shotgun approach to identify several key differences in protein conformation or assembly between cells grown on myocardium- and fibrosis-like substrates. Their data highlight the likely importance of mechanical microenvironments in pathogenesis.
