Cellular Biomechanic Impairment in Cardiomyocytes Carrying the Progeria Mutation: An Atomic Force Microscopy Investigation

Abstract

Given the clinical effect of progeria syndrome, understanding the cell mechanical behavior of this pathology could benefit the patient's treatment. Progeria patients show a point mutation in the lamin A/C gene (LMNA), which could change the cell's biomechanical properties. This paper reports a mechano-dynamic analysis of a progeria mutation (c.1824 C > T, p.Gly608Gly) in neonatal rat ventricular myocytes (NRVMs) using cell indentation by atomic force microscopy to measure alterations in beating force, frequency, and contractile amplitude of selected cells within cell clusters. Furthermore, we examined the beating rate variability using a time-domain method that produces a Poincaréplot because beat-tobeat changes can shed light on the causes of arrhythmias. Our data have been further related to our cell phenotype findings, using immunofluorescence and calcium transient analysis, showing that mutant NRVMs display changes in both beating force and frequency. These changes were associated with a decreased gap junction localization (Connexin 43) in the mutant NRVMs even in the presence of a stable cytoskeletal structure (microtubules and actin filaments) when compared with controls (wild type and nontreated cells). These data emphasize the kindred between nucleoskeleton (LMNA), cytoskeleton, and the sarcolemmal structures in NRVM with the progeria Gly608Gly mutation, prompting future mechanistic and therapeutic investigations.

Effects of targeted lung cancer drugs on cardiomyocytes studied by atomic force microscopy

“…28 The mechanical properties of myocardial cells have been found to affect substantially several important factors of cell functions, such as the shape, contraction force, rate, duration, adhesion and stiffness. [29][30][31][32] Therefore, analyzing the mechanical behaviors of cardiomyocytes affected by EGFR-TKIs is of great signicance to understand the pathogenesis and the treatment of patient. In order to provide guidance for evaluating the effects of EGFR-TKIs on myocardial cells, getinib, afatinib and osimertinib were selected and represented the three different generations of drugs, respectively.…”