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Topic Name: Scientists say, too much of a good thing: When testosterone is bad for muscles

Category: Genetic Engineering

Research persons: Cynthia Jordan, Jamie Johansen

Location: Michigan State University, United States

Details

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.

In figure,
The larger mouse above is a wild type, while the smaller mouse is genetically engineered to have extra testosterone receptors in its muscle tissue. Testosterone causes the altered mouse to be weakened and wasted.

Note for Kennedy's disease

Kennedy's disease (KD) or X-linked spinal-bulbar muscular atrophy (SBMA) is a neuromuscular disease associated with mutations of the androgen receptor (AR). Because of its endocrine manifestations related to the impairment of the AR, it can be viewed as a variation of the disorders of the androgen insensitivity syndrome (AIS). It is named after WR Kennedy, a neurologist who was among the first to describe this disease.

The gene for the androgen receptor is located on the X chromosome (Xq11-q12), making it a sex-linked disease, thus KD generally affects males. Females are rarely affected; female carriers tend to have a relatively mild expression of the disease if they show symptoms at all.

About Researchers:

Jamie Johansen
Faculty Advisor: Drs. S.M. Breedlove and C. Jordan
Entered Program in Fall 2002
Email: johanse8@msu.edu

Selected Publications
Johansen, J. A., et al. (2004). "Steroid hormone masculinization of neural structure in rats: a tale of two nuclei." Physiology & Behavior 83(2): 271-277.

Cynthia Jordan

Neuroscience and Psychology: (517) 355-1722, jordancy@msu.edu; or Sue Nichols, University Relations: (517) 353-8942, cell (517) 282-8472, nichols@msu.edu

Breedlove Jordan Lab 
108 Giltner Hall 
Michigan State University 
East Lansing, MI 48824-1101 
Phone: (517) 432-1674 
Fax: (517) 432-2744

About Fund:

National Institutes of Health

The National Institutes of Health (NIH) is an agency of the United States Department of Health and Human Services and is the primary agency of the United States government responsible for biomedical research.

The Institutes are responsible for 28%—about $28 billion—of the total biomedical research funding spent annually in the U.S., with most of the rest coming from industry.[1] The NIH is divided into two parts: the "Extramural" parts of NIH are responsible for the funding of biomedical research outside of NIH, while the "Intramural" parts of NIH conduct research. Intramural research is primarily conducted at the main campus in Bethesda in unincorporated Montgomery County, Maryland, and the surrounding communities. The National Institute of Aging and the National Institute on Drug Abuse are located in Baltimore, Maryland, and the National Institute of Environmental Health Sciences is in Research Triangle, North Carolina. The NIAID maintains Rocky Mountain Labs in Hamilton, Montana,[2] with an emphasis on virology.

The predecessor of the NIH began in 1887 as the Laboratory of Hygiene. It grew and was reorganized in 1930 by the Ransdell Act into the National Institute of Health (singular at the time). Today it is one of the world's foremost medical research centers, and the Federal focal point for medical research in the U.S. The NIH, comprising 27 separate institutes, centers and the Office of the Director, is part of the United States Department of Health and Human Services. The current NIH Director is Elias Zerhouni.

The goal of NIH research is to acquire new knowledge to help prevent, detect, diagnose, and treat disease and disability, from the rarest genetic disorder to the common cold. The NIH mission is to uncover new knowledge that will lead to better health for everyone. NIH works toward that mission by: conducting research in its own laboratories; supporting the research of non-Federal scientists in universities, medical schools, hospitals, and research institutions throughout the country and abroad; helping in the training of research investigators; and fostering communication of medical and health sciences information.