Nov. 10, 2008

Compound Improves Heart Function in EDMD Mice

Treatment with a compound that blocks a signaling pathway in the hearts of mice with a disease resembling human Emery-Dreifuss muscular dystrophy (EDMD) resulted in markedly improved cardiac function compared to that seen in untreated EDMD mice, say researchers at Columbia University in New York and the Institute of Myology in Paris.

Howard Worman, a professor and MDA grantee at Columbia, coordinated a group of investigators who published their results online Oct. 16 in Human Molecular Genetics.

Previous work by Worman and colleagues has shown that mutations (flaws) in the lamin A/C gene, which cause EDMD in mice and in humans, lead to abnormal activation of a signaling pathway in the heart.

In this new set of experiments, the investigators gave a compound called PD98059, which blocks the ERK signaling pathway, to mice with a lamin A/C gene mutation, while giving other mice with this mutation an inactive substance (placebo) or no treatment at all. They also studied heart function in normal mice.

After eight weeks, the mice that had received injections of PD98059 showed values similar to the normal mice on four measures of heart function. The untreated and the placebo-treated mice, however, showed markedly different values from the normal mice on two of these measures.

In addition to the functional differences, the researchers noted that the nuclei of cardiac muscle cells were different in shape in the different groups of mice.

The normal and PD98059-treated EDMD mice had cardiac muscle cells with well-rounded, oval nuclei, whereas the nuclei in these cells in untreated or placebo-treated EDMD mice had an abnormal, elongated shape.

The lamin A and lamin C proteins are made from the lamin A/C gene's instructions, and they form part of the envelope that surrounds each cell nucleus. Therefore, these nuclear shape differences could reflect lamin abnormalities.

EDMD caused by lamin A/C gene mutations is one of two types of EDMD, the other type being caused by mutations in the gene for emerin, another nuclear envelope protein. The researchers say their findings in a lamin-related EDMD mouse model may also be relevant in emerin-related EDMD, but they have not yet performed any experiments to demonstrate this.

They say their results support the hypothesis that ERK pathway activation caused by lamin abnormalities is an underlying cause of heart-muscle degeneration (cardiomyopathy) in EDMD and that their new results provide evidence that blocking ERK could prevent or delay the onset of heart failure in this disease.

They also note that medications that block ERK have been safely administered to people with cancer.