MLP, muscle lim protein is a component of a mechano-sensor pathway in cardiac myocytes

Genetically engineered mice which harbor a deficiency in MLP (muscle lim protein) display cardiac pump failure with chamber dilation and extensive disorganization of myocyte cytoarchitecture. To identify the pathways by which mechanical stress leads to heart failure in the MLP deficient mice (MLPKO), cross-breeding was performed with phospholamban deficient mice (PLBKO), that have the enhanced cardiac performance with positive inotropy and markedly accelerated relaxation. Releasing mechanical stress by PLB ablation resulted in dramatic improvement of functional abnormalities, as well as reversal of histological defects and the induction of embryonic gene markers observed in MLPKO animals. Direct mechanical strain was applied to isolated cardiac myocytes from MLPKO animals using a stretch device equipped with a silicon elastic membrane, revealing that mechanical stress-induced hypertrophic response is selectively blunted in MLPKO cells, while responses to agonists such as endothelin-1 are preserved. These observations strongly support the concept that MLP is an essential molecular component of a mechanosensor pathway in cardiomyocytes.