Rapamycin Nanoparticles Correct Autophagy Defects in Mouse Muscular Dystrophy Model

Nanoparticles coated with rapamycin were found to improve strength and heart function in a mouse model for Duchenne muscular dystrophy.

Duchenne muscular dystrophy in boys progresses rapidly to severe impairment of muscle function and death in the second or third decade of life. Current supportive therapy with corticosteroids results in a modest increase in strength as a consequence of a general reduction in inflammation, but with potential untoward long-term side effects and ultimate failure of the agent to maintain strength.


The primary molecular factor responsible for Duchenne muscular dystrophy is a mutation that prevents the body from producing dystrophin, a protein crucial for maintaining muscle cell integrity and function. In addition, studies with the mdx mouse model of Duchenne muscular dystrophy have shown that defective autophagy is involved in the pathology of the disease.

Investigators at Washington University School of Medicine (St. Louis, MO, USA) looked for ways to correct the autophagy defects. To this end, they developed a class of perfluorocarbon nanoparticles coated with the drug rapamycin. Rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. The drug prevents activation of T-cells and B-cells by inhibiting their response to interleukin-2 (IL-2). It is also used as a coronary stent coating. Rapamycin works, in part, by eliminating old and abnormal white blood cells and is effective in mice with autoimmunity and in children with the rare condition autoimmune lymphoproliferative syndrome (ALPS).

The investigators reported in the February 5, 2014, online edition of the FASEB Journal that following injection, the nanoparticles collected at sites of inflammation, allowing the drug to penetrate muscle tissue. Treated mice showed a 30% increase in grip strength and a significant improvement in cardiac function, based on an increase in the volume of blood the heart pumped. This increase in physical performance occurred in both young and adult mdx mice, and even in aged wild-type mice, which sets the stage for consideration of systemic therapies to facilitate improved cell function by autophagic disposal of toxic byproducts of cell death and regeneration.

“Autophagy plays a major role in disposing of cellular debris,” said senior author Dr. Samuel A. Wickline, professor of medicine at Washington University School of Medicine. “If it does not happen, you might say the cell chokes on its own refuse. In muscular dystrophy, defective autophagy is not necessarily a primary source of muscle weakness, but it clearly becomes a problem over time. If you solve that, you can help the situation by maintaining more normal cellular function.”

“An important aspect of our study is that we are treating both skeletal muscle and heart muscle with the same drug,” said Dr. Wickline. “The heart is a difficult organ to treat in muscular dystrophy. But even in older animals, this regimen works well to recover heart function, and it is effective over a short period of time and after only a few doses.”

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Washington University School of Medicine