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UT Southwestern Team Reports on Link Between miR-133a and Rare Muscle Condition

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By Doug Macron

Researchers from the University of Texas Southwestern Medical Center and Miragen Therapeutics this month reported that a single microRNA has been found to play a key role in the maintenance of adult skeletal muscle, and that it may be a therapeutic target for a rare muscle condition.

Specifically, the team found that mice lacking miR-133a developed adult-onset centronuclear myopathy, a congenital disease characterized by muscle weakness and abnormal centralization of nuclei in muscle myofibers, suggesting the miRNA may be a “potent modulator” of the disease, according to Miragen.

The findings appear in the August issue of the Journal of Clinical Investigation.

In the study, which was led by UT Southwestern researcher and Miragen co-founder Eric Olson, the investigators focused on the miR-133 family, which contains three highly homologous members: miR-133a-1, miR-133a-2, and miR-133b. The first two are identical and differ from the third only by two nucleotides at the 3' terminus.

In a paper published in late 2008, Olson and colleagues showed that miR-133a-1 and miR-133a-2 are only expressed in cardiac and skeletal muscle and that they are important in “orchestrating cardiac development, gene expression, and function.”

In that work, the investigators knocked out the two copies of miR-133a in mice and found that about half of the animals developed lethal ventricular septal defects as embryos or neonates. The double-knockout mice that survived into adulthood eventually died due to dilated cardiomyopathy and heart failure.

According to Ning Liu, lead author of both papers, the work detailed in JCI was an effort to extend these findings to determine what role miR-133a may have in skeletal muscle after determining its effects in cardiac muscle.

In the latest paper, Olson's lab generated additional double-knockout mice and examined those that survived beyond birth. Those that did “began to develop skeletal muscle myopathy,” he told Gene Silencing News.

Histological analysis revealed “a very dramatic phenotype [that] was remarkably similar to that of” human CNM, he said. The researchers then "analyzed these animals functionally and molecularly on many different levels to document the phenotype and understand how this phenotype could arise from the removal” of just the one miRNA.

They discovered that a major target of miR-133a is dynamin 2, a protein implicated in human CNM. Additionally, they found that elevated levels of the protein in skeletal muscle, at levels comparable to those in the knockout mice, caused the condition, “which indicates that skeletal muscle function depends on a precise level of dynamin 2 expression … although the exact mechanism is unknown,” they wrote in JCI.

“That was interesting because there [are] a multitude of mutations in the dynamin 2 protein that have been shown to cause centronuclear myopathy in humans,” Olson explained. “So we felt we were on to something very important with respect to the underlying mechanism of this type of skeletal muscle disorder.”

According to Liu, there is currently no animal model for CNM, and Olson said that the double-knockout mice may ultimately prove “very useful with respect to exploring the underlying mechanisms responsible for [various] centronuclear myopathies,” a direction his lab is planning to take.

Additionally, the findings described in JCI suggest that miR-133a may be a therapeutic target for the condition.

“We're very interested in the possibility that you could influence centronuclear myopathy and progression of the disease by manipulating this microRNA,” Olson said. “Because [it's] muscle specific, that type of approach is quite attractive because it doesn't suffer from off-target effects in tissues where the microRNA is not expressed.”

“The realization that miRNAs such as miR-133a influence muscle structure and function, and interface with human disease mechanisms, underscores the potential insights that may be gleaned from the analysis of miRNA targets involved in disease,” the paper's authors conclude. “In the future, it will be of interest to explore the potential involvement of other miRNAs in human muscle disease.”

Such work is already underway at Miragen, which currently has a miRNA mimic of miR-29 under early-stage development as a treatment for cardiac fibrosis. Nearer term, the company continues to advance an miRNA inhibitor of miR-208 for chronic heart failure.

Work from Olson's lab has shown that miR-208 is associated with cardiomyocyte hypertrophy, which frequently leads to heart failure. Miragen expects that an investigational new drug application for the miR-208 agent could be ready as soon as next year.

“We are very excited by the publication of these results [in JCI] that further demonstrate the important role of miR-133a in maintaining normal structure and function of adult skeletal muscle,” Miragen President and CEO William Marshall said in a statement. “These findings ultimately enhance our commitment to developing ... microRNA-based therapeutics to treat patients with debilitating muscle diseases.”


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