Excess mechanical stress on cardiac muscle cells can lead to dilated cardiomyopathy, a type of heart failure where an enlarged heart loses its ability to pump blood. In the December 27 Cell, Ralph Knöll, Masahiko Hoshijima and colleagues pinpoint the major components of the mechanical sensor that controls normal cardiac muscle growth and survival. The investigators describe how cytoskeletal defects in the Z disc, which defines the lateral boundaries of the sarcomere, can lead to an inherited form of dilated cardiomyopathy.

Credit: Reprinted with permission from Elsevier Science

The Z disc serves as an anchoring site for actin filaments (red) and telethonin (green), components that sense stretch during normal cardiac contraction and relaxation. The authors investigated a mouse model with a defect in the Z disc protein MLP (muscle-specific LIM protein), and observed a selective loss of telethonin (merged). In mice with defective MLP, the Z disc complex could not sense changes in stretch or trigger critical growth and survival signals. Ultimately, these defects led to contractile dysfunction and dilated cardiomyopathy.

The study also identified a group of humans with mutations in the MLP gene. Using genetic fingerprinting techniques to test 526 Germans with dilated cardiomyopathy, the investigators identified ten individuals with identical MLP mutations. However, no cases of mutant MLP were found in 285 Japanese patients. The researchers also identified mutant MLP in cardiomyopathy patients of Northern European descent from England, France and the United States, indicating that this mutation has been passed down through several generations of Northern Europeans.