EAST LANSING, Mich. — A mouse created by Michigan State University scientists studying a disease thought to be a neurological disorder that weakens men has exposed two surprises: Testosterone appears to be the culprit and it’s attacking muscles, not nerves.
The muscles of male mice genetically engineered in the laboratory of Cynthia Jordan, professor of neuroscience and psychology, have extra receptors that latch onto testosterone – a trick that left researchers anticipating mouse versions of bulked up body builders. Instead, these mice developed into shrunken weaklings. More significantly, their condition precisely imitated a rare human condition called Kennedy’s Disease.
The results, reported in the Oct. 29 online issue of the Proceedings of the National Academy of Sciences, not only directly contradict conventional wisdom about the root of Kennedy’s Disease, but also offer significant hope. Researchers say these new results make a strong case that Kennedy’s Disease is a muscular disease rather than a neurological disease, and put testosterone in the category of cause, not cure.
“When we started studying this little wimp mouse, we were surprised to find that we inadvertently created a model for Kennedy’s Disease,” Jordan said. “Our story provides some hope, because it’s an easier problem to target muscles therapeutically than the motor neurons in the spinal cord. Our sick mice get well when we take testosterone away from them.”
Kennedy’s Disease, also known as spinal bulbar muscular atrophy, is an adult-onset, progressive disease that affects one in 40,000 people. It is marked by muscle weakness and wasting throughout the body. While debilitating, it is not fatal. Women rarely are affected, but can carry the recessive gene.
Jordan’s lab was not looking for a cure for Kennedy’s Disease. For more than 20 years, she has been looking at how hormones lead to changes in behavior by affecting developing and adult nervous systems.
Jamie Johansen, a doctoral student in the MSU Neuroscience Program, was working with the mice created by former postdoctoral fellow Ashley Monks. The research seeks to understand more about a neuromuscular system that is present in adult male rodents, but curiously absent in adult females – a system that also exists in humans.
They knew that the system is actually formed in both sexes, but then dies in females. If an infant female mouse is given a dose of testosterone, the neuromuscular system survives.
These mice engineered with supercharged testosterone receptors in the muscles were created to help understand that system. But their developing into Kennedy’s Disease models is a bit of science serendipity – the right answer to a very different question.
Upon scrutinizing the mice, Johansen discovered that it’s not the motor neurons that first falter in the mice, but the muscles. The damaged muscles then short-circuit the neurons. Kennedy’s Disease, with its tremors and difficulties in speaking and swallowing, is widely viewed as a neurological or motoneuron disease.
“Our work challenges the idea that this is purely a neurological disease and also challenges the way clinicians typically view and treat this disease,” Jordan said.
Over time, human muscle fibers die as do motor neurons. But Johansen’s work shows that this is probably a long-term effect of testosterone that happens very slowly.
“We have a video showing that if testosterone is taken away from these diseased mice, they get better,” Johansen said. “They may not have any lasting damage to their muscles or nerves or they still have enough muscle and nerve to recover. Our results also show that you can lose a fair number of muscle fibers and still be OK.
“The disease can cause permanent damage, but muscle cell death is an end-stage event. We have some really beautiful evidence showing that you can make animals very sick by giving them testosterone, yet they have just as many motor neurons as a normal animal. Muscle changes are what cause the disease, and in the early stages it is completely reversible.”
Jordan said the correlation between their mouse model and humans is strong.
“In terms of both symptoms and microscopically in tissue sections, what we see in mice is also observed in humans,” she said.
The research is funded by the National Institutes of Health and the MSU Foundation.
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