Histopathology of gastrocnemius muscle from patient who died of Duchenne muscular dystrophy. Jeffrey Molkentin from HHMI is using engineered transgenic mice and golden retrievers to develop a drug to treat MD.
Credit: Wikimedia
Necrosis is not subtle. One of the body’s natural forms of cell death, it can be likened to a ship hitting an iceberg, exploding the boiler, and capsizing, all at once. Cell necrosis occurs as a result of sudden death by trauma, by pathogenic infection, or by the proverbial last straw laid on accumulated damage.
Underneath all that seeming chaos, however, cell necrosis is actually an ordered chain of steps, says Jeffery Molkentin, an HHMI investigator at Cincinnati Children’s Hospital Medical Center. Moreover, Molkentin and others are crafting treatments for several ‘untreatable’ degenerative diseases by uncoupling key steps that drive necrosis forward.
Although he made his first discovery in the field of necrosis while studying damaged heart cells, Molkentin is focusing on Duchenne muscular dystrophy (MD). The most common form of the genetic muscle-wasting disease affects one in every 3,500 males born in the United States; boys with Duchenne MD typically live only into their late teens and early 20s.
Molkentin has used engineered transgenic mice to show how the relentless muscle damage that drives Duchenne MD can be interrupted. Now, he has a ‘proof of principle’ drug study underway in Brazil, using a small colony of golden retriever dogs that spontaneously develop an aggressive form of MD similar to human Duchenne MD.
The drug is related to the immune suppressant cyclosporine, but instead of targeting the immune system it blocks a crucial step in the cell necrosis pathway in skeletal muscles, according to Molkentin.
This drug does not correct the genetic defect that drives MD - mistakes in a giant muscle-connecting protein called dystrophin - so it is no cure for the disease.
But stopping cell necrosis could curtail MD’s crippling effects. Though results are not in, Molkentin believes that “if this drug fixes the golden retrievers, it’s going to work in kids.”
The Mitochondrial Link
Molkentin came to the idea of blocking cell necrosis through his earlier studies of cardiac hypertrophy, the enlargement of heart muscle cells, or cardiomyocytes, that follows an ischemic event - a short cut-off of blood to the heart. Cardiomyocytes can’t renew themselves, so cellular necrosis after ischemia leads to heart dysfunction and failure.
The tipping point in the cardiomyocyte is the sudden swelling of mitochondria, the cell’s internal power plants. Excess calcium floods in through a regulated pore, finally bursting the organelles, blacking out energy production and spewing toxic proteins.
Molkentin discovered that he could stop mitochondrial swelling by blocking the action of cyclophilin D, a protein that controls the so-called mitochondrial permeability transition pore, or MPTP. Without cyclophilin D, the MPTP stayed firmly shut.
