Regulating Muscle Decline: Small molecules linked to degenerative diseases

Deteriorating muscles in people with diseases such as muscular dystrophy have abnormal amounts of important gene-regulating molecules called microRNAs, new research shows.

These microRNAs—snippets of the molecule that copies genetic information from DNA—help regulate the working of cells by silencing as many as hundreds of genes each. Scientists knew that microRNAs play important roles in healthy muscle cells, but the new study is the first comprehensive survey of microRNA activity in these muscle-wasting diseases.

Scientists led by Louis M. Kunkel of Children’s Hospital in Boston measured the activity of several hundred microRNAs in samples of muscle tissue taken from 88 patients with either Duchenne muscular dystrophy or one of nine similar diseases. The researchers found 185 microRNAs that had either elevated or reduced activities in the diseased tissue when compared with healthy muscles.

“These microRNAs are influencing overall gene expression and the progression of the diseases,” Kunkel says. By looking at a subset of 18 microRNAs, Kunkel’s team could identify the disease affecting a particular sample with greater than 90 percent accuracy, the scientists report online and in the Oct. 23 Proceedings of the National Academy of Sciences. “There are unique microRNA-activity profiles specific to each of the diseases,” Kunkel says.

To understand the functional roles played by the affected microRNAs, the scientists checked their list against a database of known types. Of the 145 microRNAs that were listed in the database, about 60 percent regulate genes in muscle cells.

Of the remaining microRNAs, 11 are active in cells of the immune system. While the various forms of muscular dystrophy are primarily caused by inherited mutations in genes that produce muscle proteins, the immune system sometimes contributes to the diseases by attacking muscle cells.

“This research is going to make our view of these diseases more realistic,” comments Francisco H. Andrade of the University of Kentucky Medical Center in Lexington, who has studied microRNAs in mice with a muscular dystrophylike condition. “We’ll have a better sense of how complex the response of the tissue to the genetic defect is,” he says.

John J. McCarthy, a colleague of Andrade’s at the University of Kentucky, points out that while this research shows that certain microRNAs become more or less active in the diseases studied, it does not demonstrate which of those changes are essential for producing the diseases’ symptoms. Future experiments should test whether altering the amounts of these microRNAs affects disease-related genes in ways that improve muscle function, McCarthy says.

If so, the microRNAs identified by Kunkel’s team could eventually provide targets for new drugs that mitigate the diseases’ effects, Andrade says. Drugs that can enhance or reduce microRNA activity are still years away, but developing such drugs is a burgeoning area of research.

“Maybe we couldn’t correct the inherited genetic defect, but maybe we could alter the course of the disease,” McCarthy says. Profiling microRNA activity could also give doctors a new way to diagnose which form of muscular dystrophy a patient has.