Novel Role for Vinculin in Ventricular Myocyte Mechanics and Dysfunction

Abstract

Vinculin (Vcl) plays a key structural role in ventricular myocytes that, when disrupted, can lead to contractile dysfunction and dilated cardiomyopathy. To investigate the role of Vcl in myocyte and myocardial function, cardiomyocyte-specific Vcl knockout mice (cVclKO) and littermate control wild-type mice were studied with transmission electron microscopy (TEM) and in vivo magnetic resonance imaging (MRI) tagging before the onset of global ventricular dysfunction. MRI revealed significantly decreased systolic strains transverse to the myofiber axis in vivo, but no changes along the muscle fibers or in fiber tension in papillary muscles from heterozygous global Vcl null mice. Myofilament lattice spacing from TEM was significantly greater in cVclKO versus wild-type hearts fixed in the unloaded state. AFM in Vcl heterozygous null mouse myocytes showed a significant decrease in membrane cortical stiffness. A multiscale computational model of ventricular mechanics incorporating cross-bridge geometry and lattice mechanics showed that increased transverse systolic stiffness due to increased lattice spacing may explain the systolic wall strains associated with Vcl deficiency, before the onset of ventricular dysfunction. Loss of cardiac myocyte Vcl may decrease systolic transverse strains in vivo by decreasing membrane cortical tension, which decreases transverse compression of the lattice thereby increasing interfilament spacing and stress transverse to the myofibers.

Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin 43 containing gap junctions in cardiac Myocytes

“…This is relevant because a significant reduction of Vcl expression at costameres, as well as irregular alignment of Vcl at intercalated discs has been observed after Trypanosoma cruzi infection (Melo et al, 2004). Recently, it has been shown that Vcl deficiency increased systolic stiffness, by increasing interfilament spacing, and thereby could induce mechanical stress in sarcomeres (Tangney et al, 2013). These reports all illustrate the role of Vcl as a cardiomyopathy-linked gene.…”

Vinculin network–mediated cytoskeletal remodeling regulates contractile function in the aging heart

“…Computational studies have suggested a role for vinculin in regulating sarcomere lattice spacing and contractility (28). Therefore, electron micrographs of cross sections through VincHE and control cardiac myofibrils were examined to investigate alterations in ultrastructure (Fig.…”

Preserved cardiac function by vinculin enhances glucose oxidation and extends health- and life-span

“…Since alterations to the cardiac sarcomere lattice structure have been postulated to change the contractile efficiency, 27 we next determined whether VincHE flies had altered cardiomyocyte bioenergetics by adapting the Seahorse XF24 extracellular flux analyzer to measure respiration of individual, surgically exposed and contracting hearts. Oxygen consumption rate (OCR) was proportional to the number of hearts assayed, though we obtained sufficient signal with a single heart, allowing us to measure fly-to-fly variation [Fig.…”

“…27 Better cycling alters energy requirements in the heart, but it was uncertain if similar changes could be observed systemically. Untargeted whole fly GC-MS revealed significant energy metabolite accumulation for VincHE flies in all ontological clusters with age.…”

“…S2R+ cells contain focal adhesions, not sarcomeres, and so, these data are consistent with similar observations of disassembly 62 but with Vinculin overexpression to compensate for rotenone treatment. 63 Thus, in myocytes, it may be plausible that protection may be due to improved cross-bridge cycling, 27 i.e., lower ATP demands, and a more stabilized cytoskeleton.…”