Insulin signaling regulates cardiac titin properties in heart development and diabetic cardiomyopathy.

Isoform-switching of the giant elastic protein titin is a main mechanism for adjusting passive myocardial stiffness in perinatal heart development and chronic heart disease. Previous evidence suggested that thyroid-hormone signaling converging onto the phosphoinositol-3-kinase (PI3K)/AKT pathway regulates titin-isoform composition in developing cardiomyocytes. Here we hypothesized that insulin, another activator of PI3K/AKT, alters titin-isoform composition and titin-based stiffness.

A common MLP (muscle LIM protein) variant is associated with cardiomyopathy.

Rationale: We previously discovered the human 10T-->C (Trp4Arg) missense mutation in exon 2 of the muscle LIM protein (MLP, CSRP3) gene.

Objective: We sought to study the effects of this single-nucleotide polymorphism in the in vivo situation.

Methods And Results: We now report the generation and detailed analysis of the corresponding Mlp(W4R/+) and Mlp(W4R/W4R) knock-in animals, which develop an age- and gene dosage-dependent hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost complete loss of contractile reserve under catecholamine induced stress.