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

Abstract

Despite limited regenerative capacity as we age, cardiomyocytes maintain their function in part through compensatory mechanisms, e.g., Vinculin reinforcement of intercalated discs in aged organisms. This mechanism, which is conserved from flies to non-human primates, creates a more crystalline sarcomere lattice that extends lifespan, but systemic connections between the cardiac sarcomere structure and lifespan extension are not apparent. Using the rapidly aging fly system, we found that cardiac-specific Vinculin-overexpression [Vinculin heart-enhanced (VincHE)] increases heart contractility, maximal cardiac mitochondrial respiration, and organismal fitness with age. Systemic metabolism also dramatically changed with age and VincHE; steady state sugar concentrations, as well as aerobic glucose metabolism, increase in VincHE and suggest enhanced energy substrate utilization with increased cardiac performance. When cardiac stress was induced with the complex I inhibitor rotenone, VincHE hearts sustain contractions unlike controls. This work establishes a new link between the cardiac cytoskeleton and systemic glucose utilization and protects mitochondrial function from external stress.

Mechanical Forces Regulate Cardiomyocyte Myofilament Maturation via the VCL-SSH1-CFL Axis

“…It was reported that increased Vinculin (Vinc) expression in Drosophila cardiac muscle cells improves cardiac function and extends lifespan (Kaushik et al, 2015). Cardiac-muscle-specific Vinc overexpression increases fractional shortening and regulates mitochondrial respiration and glucose metabolism, both of which improve cardiac function in the aging fly (Kaushik et al, 2015;Sessions et al, 2018). These data suggest that regulation of VCL expression or function may be a therapeutic target to improve cardiac function in heart failure patients.…”

A Review of in vitro Platforms for Understanding Cardiomyocyte Mechanobiology

“…This study suggested that cardiomyocytes are sensitive to N-cadherin mediated mechanical signaling and possibly also cell-cell mechanical signaling through the intercalated discs. Other studies have suggested that the loss of intercalated disks plays a role in age-related loss of cardiac function and that reinforcement of the intercalated disks may help preserve cardiac function (Kaushik et al, 2015; Sessions et al, 2018).…”