New treatment strategy for muscular dystrophy sound in preclinical phase.
The muscular dystrophies are a group of muscle wasting disorders characterized by progressive weakening and degeneration of striated muscle. The most common form is Duchenne muscular dystrophy (DMD), an X-linked disorder caused by genetic disruption of dystrophin that affects 1 in 3,500–5,000 males. DMD results from disruption of the dystrophin–glycoprotein complex (DGC), a structure that spans the sarcolemma and forms a mechanical linkage between the cytoskeleton and the extracellular matrix via the association of the dystrophin molecule.
When dystrophin is missing from the muscle cell, the function of another protein, known as nNOS, is impaired, resulting in decreased blood flow to the muscles and exaggerated fatigue after exercise. Therefore, manipulating proteins in the body to compensate for the lack of dystrophin is one of many strategies being investigated to halt or reverse the muscle damage caused by DMD. Now, a study from researchers at the University of Michigan has identified a new way of triggering the instructions normally given by the muscle protein dystrophin. The team state that their findings may lead to new therapeutic strategy for patients with Duchene muscular dystrophy which is caused by a lack of dystrophin. The opensource study is published in the journal PNAS.
Previous studies show that in healthy skeletal muscle, neuronal nitric oxide synthase (nNOS) binds to a dystrophin complex. During muscle contraction, nitric oxide (NO) produced from nNOS is thought to signal to arterioles that supply the skeletal muscle with blood, thereby counteracting vasoconstriction induced by exercise. In DMD, genetic loss of dystrophin results in secondary mislocalization of nNOS and impaired muscle NO production is observed. Disrupted muscle NO signaling impairs muscle blood flow regulation in dystrophin-deficient mice and results in markedly exaggerated fatigue after exercise. In addition to weakness of the skeletal muscles, cardiac muscle cells can also weaken and die, preventing the heart from pumping blood efficiently. Dilated cardiomyopathy is a leading cause of death for those with DMD. Therefore, the current study used isolated heart cells from dystrophin-deficient mice to explain this debilitating protein malfunction and a potential way to bypass it.
The current study shows 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. The lab explain that AMPK, or AMP-activated protein kinase, coordinates cellular energy-use. They go on to add that AMPK normally helps to turn on nNOS function in muscle cells, for instance when a person exercises, and when dystrophin is lost, AMPK does not turn on appropriately.
Results show that once AMPK is activated, the nNOS activity that is reduced in muscular dystrophy is restored. Data findings show that the drug worked by bypassing the defective steps in the protein complex pathway and the treatment tested corrected the signaling pathway that is disrupted in muscular dystrophy at an earlier step than has been shown previously. The lab note that they activated AMPK signaling with drugs that have been used medically to protect heart tissue during surgery and in sports to enhance performance because of its blood flow boosting abilities.
The team surmise that their study is an important first step in showing that manipulating AMPK-nNOS signaling has the potential to help muscle function in muscular dystrophy. For the future, the researchers state that more research is needed to determine if the process could be effective in humans.