Cardiac actin compensated for the loss of skeletal-muscle actin in mice with a disease resembling nemaline myopathy
A protein present in skeletal muscles during fetal development and in the heart after birth can apparently compensate for a similar protein that's missing in a small percentage of patients with the muscle disease known as nemaline myopathy.
MDA research grantee Nigel Laing at the University of Western Australia in Perth was part of a multinational team of scientists, who published their findings May 25, 2009, in the Journal of Cell Biology.
When the investigators bred mice missing the gene for the skeletal-muscle alpha-actin protein but with extra cardiac-muscle alpha-actin protein, they found the cardiac actin compensated well for the loss of the skeletal-muscle actin.
The findings open up the possibility of developing a treatment for some patients with human nemaline myopathy by increasing their own production of cardiac actin or giving them cardiac actin protein or genes.
A muscle cell is stimulated to contract by chemical signals sent from an adjoining nerve cell (1). Those signals open ion channels at the muscle cell's surface, causing an inward/outward flow of ions that acts as an electrical current (2). Inside the muscle cell, the current spreads and causes opening of ion channels that line calcium storage compartments, releasing the calcium ions trapped within (3). The freed calcium ions trigger nearby filament proteins to slide past each other, pulling the Z-discs closer together and shortening the muscle cell (4).
Nemaline myopathy results from defects in a number of different muscle protein genes, all of which have to do with the muscle's contractile filaments. These filaments slide over each other during muscle contraction in both cardiac and skeletal muscle tissue. Actin is a major filament component.
In its severest form, nemaline myopathy results in death in early infancy. In its less severe forms, affected children attain motor milestones slowly and may weaken further at puberty.
Previously, researchers had found mice bred not to produce any skeletal-muscle actin died by 9 days of age. In contrast, in this latest study, mice bred to produce extra cardiac-muscle actin but no skeletal-muscle actin survived into old age and had virtually normal muscle function.
These mice had grip strength and motor activity equal to that of healthy mice, and their muscles displayed a normal appearance, even under an electron microscope.
The researchers say their results show cardiac actin can effectively replace skeletal-muscle actin in muscles after birth, at least in mice and possibly in humans.
Previously, Laing said, it's been shown that higher cardiac actin levels in patients without skeletal-muscle actin correlate with higher levels of function. The present results might indicate that increasing the level of cardiac actin even more in these patients would improve their motor abilities, he said.
The researchers caution that these experiments only showed compensation for a deficiency of the skeletal-muscle actin protein, not an abnormality in the protein. Patients with abnormalities in the skeletal-muscle alpha-actin gene that result in abnormalities of the actin protein, rather than deficiency, might not be helped by extra cardiac actin.
"Our results show that cardiac actin can work remarkably well in skeletal muscle," Laing said. "This means that cardiac actin is a valid target for developing therapies for skeletal-muscle actin disease. However, we have a long way to go to be able to apply this to human patients. We have to find ways to increase cardiac actin in the muscles of human patients. That could take a long time, although we remain hopeful."