Cardiac hypertrophy and reduced contractility in hearts deficient in the titin kinase region.

Background— Titin is a giant protein crucial for the assembly and elasticity of the sarcomere. Recently, titin has been linked to signal transduction through its kinase domain, which has been proposed to sense mechanical load. We developed a knockout in which expression of M-line–deficient titin can be induced in adult mice and investigated the role of the titin kinase region in cardiac function. Methods and Results— Isolated heart experiments revealed that in titin M-line–deficient mice, the contractile response to β-adrenergic agonists and extracellular calcium is reduced. However, the Ca2+ sensitivity and cooperativity of activation of skinned cardiac muscle were unchanged. In knockout mice, calcium transients showed a reduced rate of calcium uptake, and expression analysis showed reduced levels of calmodulin, phospholamban, and SERCA2. Ultimately, knockout mice developed cardiac hypertrophy and heart failure, which involves protein kinase C signal transduction but not the mitogen-activated protein kin...