Dec. 2, 2008

Muscle May Be First Tissue Damaged in ALS

Damage to muscle fibers may play an earlier and larger role in ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease) than previously believed, according to a multinational team of researchers coordinated by MDA grantee Antonio Musaro at the University of Rome (Italy).

The findings of these investigators, published in the Nov. 5 issue of Cell Metabolism, contradict an assumption ALS researchers have made for decades, which is that the primary targets in the disease process are muscle-controlling nerve cells called motor neurons in the spinal cord and brain.

The new conclusions, if confirmed, would be a positive development for ALS researchers and patients, because muscle tissue is more accessible than the spinal cord or brain and would be easier to reach with therapeutic substances.

However, in a study partially funded by MDA that was published in Proceedings of the National Academy of Sciences in 2006, Timothy Miller and colleagues showed that partially blocking the effects of an ALS-causing genetic mutation in mice in muscle alone, while leaving the mutation in motor neurons, did not slow the course of the disease.

These investigators interpreted their findings to mean that muscle does not play an important role in ALS, at least in the form caused by mutations in the SOD1 gene, and that the problem is primarily one of motor neuron damage.

In their new paper, Gabriella Dobrowolny and colleagues (coordinated by Musaro) report having conducted different experiments, and they come to different conclusions about these earlier findings.

In their experiments, the Musaro group found that when mice were genetically engineered to express mutated SOD1 genes and produce a toxic form of the SOD1 protein in skeletal muscles alone, they developed severe muscle wasting without any loss of motor neurons.

The muscle fibers with the mutated SOD1 genes sustained damage to their protective membranes, showed a change in metabolic activity, and didn't function normally, the investigators say.

"The results of this study challenge the accepted dogma that motor neuron degeneration ... is the primary cause of muscle atrophy [wasting]," they note.

They say their findings don't necessarily contradict the report from Miller and coworkers. Instead, they speculate, the reason that group didn't see any slowing of the ALS disease process after blocking mutated SOD1 in muscle tissue is that the SOD1 wasn't blocked completely and therefore continued to exert its toxic effect on muscle fibers.

They further speculate that toxic signals originating from skeletal muscle fibers may compromise the nerve-to-muscle connections. Damage to these connections, known as neuromuscular junctions, could, in this new way of looking at ALS, contribute to the loss of motor neurons.

"Taken together," Musaro said, "these results support the redefinition of ALS as a multisystem disease in which in structural, physiological and metabolic alterations in different cell types -- muscle cells, motor neurons and motor-neuron support cells -- may act synergistically to exacerbate the disease." He added that, from a therapeutic point of view, "perhaps the most powerful future approach would be to target both spinal cord and muscle."