Researchers have discovered the first microRNAs–tiny bits of code that
regulate gene activity–linked to each of 10 major degenerative
muscular disorders, opening doors to new treatments and a better
biological understanding of these debilitating, poorly understood,
often untreatable diseases.
The study, published online by the Proceedings of the National Academy of Sciences, was led by Iris Eisenberg, PhD, and Louis Kunkel, PhD, director of the Program in Genomics at Children’s Hospital Boston and an investigator with the Howard Hughes Medical Institute.
The disorders, which cause muscle weakness and wasting, include the
muscular dystrophies (Duchenne muscular dystrophy, Becker muscular
dystrophy, limb girdle muscular dystrophies, Miyoshi myopathy, and
fascioscapulohumeral muscular dystrophy); the congenital myopathies
(nemaline myopathy); and the inflammatory myopathies (polymyositis,
dermatomyositis, and inclusion body myositis). While past studies have
linked them with an increasing number of genes, it’s still largely
unknown how these genes cause disease, and, more importantly, how to
translate the discoveries into treatments.
For instance, most muscular dystrophies begin with a known mutation in
a “master gene,” leading to damaged or absent proteins in muscle cells.
In Duchenne and Becker muscular dystrophies, the absent protein is
dystrophin, as Kunkel himself discovered in 1987. Its absence causes
muscle tissue to weaken and rupture, and the tissue becomes
progressively nonfunctional through inflammatory attacks and other
damaging events that aren’t fully understood.
“The initial mutations do not explain why patients are losing their
muscle so fast,” says Eisenberg. “There are still many unknown genes
involved in these processes, as well as in the inflammatory processes
taking place in the damaged muscle tissue.”
She and Kunkel believe microRNAs may help provide the missing genetic
links. Their team analyzed muscle tissue from patients with each of the
ten muscular disorders, discovering that 185 microRNAs are either too
abundant or too scarce in wasting muscle, compared with healthy muscle.
Discovered in humans only in the past decade, microRNAs are already
known to regulate major processes in the body. Therefore, Eisenberg
believes microRNAs may be involved in orchestrating the tissue death,
inflammatory response and other major degenerative processes in the
affected muscle tissue. The researchers used bioinformatics to uncover
a list of genes the microRNAs may act on, and now plan to find which
microRNAs and genes actually underlie these processes.
The findings raise the possibility of slowing muscle loss by targeting
the microRNAs that control these “cascades” of damaging events. This
approach is more efficient than targeting individual genes. The team
also defined the abnormal microRNA “signatures” that correspond to each
of the ten wasting diseases. They hope these will shed light on the
genes and disease mechanisms involved in the most poorly understood and
least treatable of the degenerative disorders, such as inclusion body
“At this point, it’s very theoretical, but it’s possible,” says
Eisenberg. The study was funded by the Howard Hughes Medical Institute and also by the National Center for Research Resources, the Associazione Amici del Centro Dino Ferrari, the Telethon Project, the Eurobiobank Project, the Muscular Dystrophy Association, the National Institutes of Health, the Lee and Penny Anderson Family Foundation, and the Joshua Frase Foundation.