Deficiency in nebulin repeats of sarcomeric nebulette is detrimental for cardiomyocyte tolerance to exercise and biomechanical stress

Abstract

We demonstrate that ablation of first nebulin-repeats of sarcomeric nebulette ( Nebl) causes diastolic dysfunction in Neblex3-/ex3- mice. Exercise-induced development of diastolic dysfunction, cardiac hypertrophy and ventricular dilation in knockouts. This was associated with sarcomere disturbance, intercalated disks disruption, and mitochondrial distortion upon stress and altered expression of genes involved in Nebl-based stress network. We demonstrate that G202R and A592 mutations alter actin and desmin expression causing disorganization of desmin filaments upon cyclic strain.