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From horses to humans

U researchers explore how horses can
shed light on human disease

 

First, he lost coordination. His legs trembled and jerked when he tried to walk backward, and gradually he had trouble walking forward, too. Medical tests revealed one possible answer: a lesion in his cerebellum.

Though this patient is a horse, University of Minnesota scientists are finding that his condition—known as shivers in the equine population—is remarkably similar to a degenerative brain disease in humans. And, as investigators uncover connections like this one, they are gaining insights likely to improve the health of both species.

Most of the systems that make up the human and horse anatomies are quite similar, says University of Minnesota Leatherdale Equine Center researcher Stephanie Valberg, D.V.M., Ph.D. Although they are quadrupeds, horses have the same muscle groups that people do. That and other similarities make horses an excellent model for studying muscle and metabolic diseases that occur naturally in both species, says U equine genetics expert Molly McCue, D.V.M., Ph.D.

Studies have suggested that dozens of known conditions in horses are genetically similar to disorders seen in humans. So taking the next step—applying knowledge about horse diseases to help humans, and vice versa—only makes sense.

Stephanie Valberg, D.V.M., Ph.D., and her colleagues are now searching the horse genome for a mutation that may lead to shivers. Click here to watch the video on YouTube. (Photo: Brady Willette)

Solving a mystery

Consider shivers, a neuromuscular equine disease that gives horses trouble lifting up their hind legs and walking backward.

“We’re so focused on gait and balance with horses because, as athletes, they need to perform at specific gaits. They are animals that can grow to weigh more than a ton, depending on the breed, so you can’t work around a horse that hasn’t got its balance,” says Valberg. “It’s much too dangerous.”

Valberg and her colleagues suspected that shivers might be a form of dystonia. They just weren’t sure where in the nervous system the disease originated. So when Valberg heard Human Sensorimotor Control Laboratory director Juergen Konczak, Ph.D., lecture at the University’s Paul and Sheila Wellstone Muscular Dystrophy Center, she tracked him down afterward to get his thoughts on what might be causing this movement abnormality in horses.

Meanwhile, College of Veterinary Medicine neuropathologist Anibal Armien, D.V.M., had started to systematically analyze, section by section in microscopic slices, 4 feet of spinal cord and the entire brain from each of five horses with shivers that had been donated to the University when their loss of coordination made them unsafe to be around people. The distal spinal cord was a good place to start, Valberg thought, because it’s responsible for activating the muscles used in walking forward and backward.

Once Konczak learned that walking backward was a learned behavior in horses—“In nature, they don’t do it. They just turn,” he says—he advised Armien to take a close look at the horses’ cerebellums, the part of the brain responsible for regulating movement and learning movement coordination.

And sure enough, Armien discovered a lesion on the cerebellum of each of the five horses he studied.

“We’re wondering now whether this might be more of a form of cerebellar ataxia,” Valberg says.

Konczak, a professor in the School of Kinesiology and a faculty member in the Medical School’s Graduate Program in Neuroscience, agrees with the hypothesis. “In humans you would call this ataxia,” he says, which is generally characterized by poor coordination, loss of balance, and difficulty swallowing.

EMG patterns from a healthy horse (left) and a horse with shivers (right)

EMG patterns from a healthy horse (left) and a horse with shivers (right) show a definitive difference in muscle activity. (Images: Courtesy of Human Sensorimotor Control Laboratory)

Although they are quadrupeds, horses have the same muscle groups that people do. That similarity makes horses an excellent model for studying muscle diseases that occur naturally in both species.

Proving the connection

After finding the cerebellar lesions, Valberg’s team came back to Konczak with a request: Could the Human Sensorimotor Control Laboratory help them functionally prove that this type of lesion could disrupt coordinated movement?

It was a perfect time to apply the lab’s expertise in surface electromyography (EMG), which involves taping small sensors to the skin to measure activity as the muscles contract and relax during activity. The information the sensors gather shows how coordinated the subject is when going backward and forward.

Doing this for a horse study involved a lot of starting from scratch, Konczak says. No comparison data existed for normal horse EMGs, so the scientists collected their own with some of the College of Veterinary Medicine’s healthy horses. Plus, the standard EMG cables designed for humans were much too short for horses, so they custom-ordered longer cables from England. (Graduate students in the lab summoned their courage before shaving the seven large horses to tape the sensors on them.)

Konczak is wrapping up the EMG analysis and running it like he would for a human study. Just looking at the curves in the EMGs, you wouldn’t know it’s not a human’s, he says.

But the EMG results already are uncovering some intriguing data. “[The horses with shivers] are even abnormal in their forward gait,” Konczak says. “It becomes really eye-opening when they go backward, but the EMG, the muscle pattern, the way they fire—it’s already abnormal in the forward gait.”

This further leads Konczak to believe that shivers is indeed a type of spinocerebellar disease. “In humans there is a disease called Friedreich’s ataxia,” he says. “It may be that shivers is the horse equivalent to Friedreich’s ataxia or some other form of spinocerebellar ataxia.”

Origins of a mutation

What in the horse genome might be causing this dysfunction? Valberg’s colleagues at the College of Veterinary Medicine are working to find out. And what better place to do it: the U of M group, led by Jim Mickelson, D.V.M., Ph.D., and Valberg, contributed to the first published report of the entire horse genome, in 2009.

Few would call any sort of genetic analysis simple. But nailing down the genetic mutation that leads to shivers in horses may be relatively easy compared with identifying the mutations that lead to human ataxia, for instance. Because horses are bred and don’t mate randomly, Valberg explains, many equine diseases likely have one or two responsible genetic mutations; all cases of the disease likely follow the lineage of one popular stallion with the abnormality. Conversely, a similar disease in humans could involve dozens of responsible mutations.

For example, Valberg says there are 24 genetic variations that can lead to the muscle disease hyperkalemic periodic paralysis in humans but just one variant in horses. Similarly, there are 36 known genetic variations that can lead to spinocerebellar ataxias in humans—and many variations that have not yet been discovered.

Therefore, in horses, once the genetic flaw responsible for shivers is identified, breeders can eradicate the disease for future generations of horses by making sure the lines carrying the mutations aren’t bred any further, Konczak says. But it’s not so simple for humans.

Juergen Konczak, Ph.D.

Juergen Konczak, Ph.D., and his Human Sensorimotor Control Laboratory team developed a custom electromyography setup to measure muscle activity in horses. (Photo: Brady Willette)

An informative exchange

Konczak is already thinking about how the shivers study might shed light on treating ataxia in humans. Hereditary ataxias typically start becoming apparent as people reach their 30s. They are neurodegenerative and lead to early death. Today there’s no cure.

“At this point we can’t stop the downhill,” Konczak says. “But you may flatten the slope. And that’s a big deal. If you are thinking that someone in five years is wheelchair-bound versus someone in 10 years is wheelchair-bound … I think everyone would agree that’s a worthwhile goal.”

So far about a dozen horses with shivers have been donated to the University for research. Valberg hopes that postmortem tissue samples from these horses can help the interdisciplinary team further understand the disease and why it occurs.

“I think there will be some back-and-forth information that we can glean from these studies,” she says of working with Konczak. “You take this information to fix people, and I’ll take this information to do what I can to help these horses.”


 

When a ‘thrifty’ genotype becomes a problem

Working at the institution where researchers first sequenced the entire horse genome certainly has its advantages. Molly McCue, D.V.M., Ph.D., says the University of Minnesota’s expertise and resources, namely its Equine Genetics and Genomics Laboratory, allow her team to conduct leading-edge studies—ones that make her collaborators around the world envious.

“[We have] a very large research community,” she says. “Having the Academic Health Center means there’s a lot of expertise, right here at home.”

Here, McCue and her team identified a mutation in the enzyme glycogen synthase that resulted in type 1 polysaccharide storage myopathy, a glycogen storage disease in horses. (Glycogen is the storage form of glucose, or blood sugar, in skeletal muscle. If the glycogen synthase enzyme is not working appropriately or is working too fast, the accumulating glycogen can cause muscle damage, in both horses and humans.)

Years ago, it likely wasn’t a problem; when horses were more physically active and had limited feed, the excess sugar accumulation in the muscles may have conferred an advantage, McCue says. Her team has demonstrated that this “thrifty” genotype was used in breeding. But today, as horses aren’t as active and have access to more feed, the mutation can lead to disease. This was the first ever described “gain of function” mutation in glycogen synthase discovered in any species, McCue says.

What McCue finds especially interesting is the location of the mutation on the enzyme. It has been highly conserved across species over time, meaning that researchers have found the same pattern in dogs, cats, monkeys, horses, people — all of the species they’ve studied. “That would suggest that it’s important,” she says. McCue has teamed up with James Ervasti, Ph.D., a professor of biochemistry, molecular biology, and biophysics and faculty member with the Paul and Sheila Wellstone Muscular Dystrophy Center at the University, to try to understand what biochemical change is happening in that particular spot, which may provide clues about why the location of the mutation matters.

And because about half of glycogen storage diseases in people today have no identifiable cause, McCue says, this work may help identify the source and provide a springboard for new treatment strategies.


 
 
 

Web extra—A new look at joint pain

Image: Courtesy of Mikko Nissi, Ph.D.

(Image: Courtesy of Mikko Nissi, Ph.D.)

Before a horse is sold, several of its joints are usually radiographed as part of a health evaluation. Sometimes these scans reveal lesions in the joints that result from a developmental condition known as osteochondrosis, which affects rapidly growing animals such as dogs, pigs, and humans, too.

The ends of adult long bones (in all of these species) are covered with articular cartilage, a permanent tissue. Underneath that, there’s a layer of growth cartilage that has a blood supply while the animal is growing but is converted to bone over time.

College of Veterinary Medicine pathologist Cathy Carlson, D.V.M., Ph.D., says histological studies of horses show that a defect in the growth cartilage’s blood supply can lead to these lesions, resulting in an area of retained dead cartilage in the bone and predisposing it to weakness. If these areas collapse, the result is a painful lesion in the joint and, if left untreated, premature osteoarthritis.

Carlson was determined to prove, using magnetic resonance imaging, that a faulty blood supply was to blame for these lesions across species, including in humans. So she approached Jutta Ellermann, M.D., Ph.D., an assistant professor in the Department of Radiology and part of the University’s world-renowned Center for Magnetic Resonance Research (CMRR), to find out how to do it.

Ellermann knew that blood vessels had been imaged in the brain, but no one had used the technology to image blood vessels in cartilage. “[I]t’s unusual to apply it to the cartilage,” she thought, “but let’s try it. And that was the beginning of a new direction.”

Working with Ellermann, Carlson, and College of Veterinary Medicine large animal surgeon Ferenc Toth, D.V.M., Ph.D., CMRR physicist Mikko Nissi, Ph.D., developed a technique to visualize the blood vessels in animal cartilage using the center’s 9.4 Tesla magnet. Nissi’s initial work was done using tissue specimens, but the technique was quickly applied and demonstrated in vivo as well.

The team now can evaluate the vessels in cartilage in three dimensions and is assessing foals at various ages. The multidisciplinary group has applied the technique to human tissues as well.

“We are the only group in the world who noninvasively images cartilage vessels,” Ellermann says.

This work could lend knowledge about how best to treat joint pain while keeping horses and humans active for as long as possible, Carlson says.

“The horses helped us develop the technique,” she adds. “We can study [the disease] in horses … and then apply the findings to humans.”