Horses hold clues to human disease

U. MINNESOTA (US) — Horses need to be able to efficiently store energy to do the work they are bred for, but doing so too well can lead to disease—some that mirror human conditions.

The link could be beneficial in understanding and treating a variety of diseases in humans, including diabetes and heart disease.

When humans digest food, much of it gets converted to glucose that is stored as “animal starch,” or glycogen; primarily in the liver and muscle.

In horses with a condition known as PSSM, excess glycogen accumulates in muscle cells and interferes with muscle contraction. Aerobic exercise, which requires oxygen, ruptures the cells and allows their contents to leak into the bloodstream. If one muscle protein—myoglobin—leaks out, it can cause severe kidney damage.

Humans suffer from a variety of glycogen storage diseases and exhibit similar symptoms. Exercise commonly causes muscle cramping, and in some patients myoglobin breaches kidney tissue and appears in the urine.

Researchers previously discovered a mutation linked to PSSM that increases the activity of a muscle cell enzyme that makes glycogen, causing an overabundance. The gene, known as GYS1, is also part of the human genome.

“Potentially, there are mutations in GYS1 that can be linked in humans to glycogen storage diseases,” says Molly McCue, assistant professor of veterinary population medicine at the University of Minnesota.

“Many people with glycogen storage disease have an undiagnosed mutation and a link between excess glycogen and dysfunctional muscle.”

McCue and colleagues are cloning the mutated gene inside insect cells because their simpler system is free of the complex energy environment of a mammalian muscle cell, and is easier to study exactly how the defective gene works. They are also taking a broad look at muscle cells of PSSM horses to see why their aerobic metabolism is abnormal.

The team has already found a separate mutation that makes PSSM worse and have discovered a second form of PSSM—a novel glycogen storage disease of horses—and are close to finding the genes responsible for it.

Like people, domestic horses also get metabolic syndrome, a cluster of symptoms related to type II diabetes that includes obesity, insulin resistance, and high blood lipid levels. In people, it may result from humans’ evolutionary past, when putting on fat for the lean months was beneficial for an active hunter-gatherer population.

That strategy doesn’t work so well in a sedentary modern society brimming with high-calorie food. Nor does it work for some horses, which were subject not only to natural evolutionary pressures but also to intense breeding for efficient fuel storage and related traits.

The genes involved in metabolic syndrome aren’t well known, and even the exact nature of the syndrome is poorly defined.

“The first phase (of a two-part study) is to look at 700 horses from six breeds to more clearly define what constitutes [equine] metabolic syndrome and see if it’s constant across breeds,” McCue says. “In the second half of the study, we’ll look for genes linked to it.”

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Veterinarian Molly McCue believes horses are underutilized as metabolic models for humans. (Credit: Patrick O’Leary)