Muscular Dystrophy: Manipulating Cell Signaling for Better Muscle Function

A team of researchers at the University of Michigan Health System identified a novel method of triggering the "instructions" normally given to cells by the muscle protein dystrophin, which is found in cardiac muscles cells and in muscles used for movement. This new method could produce a key to a breakthrough therapeutic strategy for patients with Duchenne Bekcer muscular dystrophy.

Duchenne/Becker muscular dystrophy (DBMD) is a disease that interferes with the production of dystrophin, which is necessary to form healthy muscle, resulting in the loss of muscle mass. Primarily found in males, many patients develop difficulties swallowing or breathing, and ultimately lose the ability to walk. Currently, 90 percent of the population with DBMD aged 15-24 are subject to the use of a wheelchair, according to the CDC.

When dystrophin is missing from muscle cells, a chain reaction is initiated, causing the protein nNOS to be impaired, which in turn decreases the blood flow to the muscles, leaving patients with extreme fatigue after exercise.

Dr. Daniel Michele and Ph.D. student Joanne Garbincius, of the University of Michigan's Department of Molecular and Integrative Physiology used isolated heart cells from mice that were lacking in dystrophin to unlock the reason for this protein malfunction.

"Our work suggests that AMPK signaling may be one of the links between the loss of dystrophin and the impaired nNOS function that is seen in muscular dystrophy," Michele, the senior study author, said. "AMPK normally helps to turn on nNOS function in muscle cells, for instance when we exercise, and when dystrophin is lost, AMPK does not turn on appropriately."

AMPK is an enzyme that coordinates and organizes energy use in the cells. The team activated AMPK signaling by using drugs normally used in surgery to enhance blood flow to protect heart tissue, which restored the nNOS activity that is reduced in DBMD patients. The drug bypasses the malfunction in the protein complex pathway, according to Garbincius. Manipulating AMPK-nNOS signaling is a strategy that may be able to halt, or even reverse, the effects of muscular dystrophy.

"[It's] an important first step to show that manipulating AMPK-nNOS signaling at least has the potential to help muscle function in muscular dystrophy," Michele said.

The study was published in the journal PNAS.

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