University of Minnesota
Horses studied by veterinarian and researcher Molly McCue (foreground) and her colleagues receive state-of-the-art treatment at the University of Minnesota's Equine Center.
Photo: Patrick O'Leary
From horse to human
Molly McCue’s studies with horses shed light on human medical conditions
By Deane Morrison
A model of beauty and speed, the horse also makes a good model of human metabolism.
Humans have bred horses to run hard and pull heavy loads, all on minimal feed. To do that, they must be able to store energy efficiently in their muscles, where it can be quickly tapped.
But storing energy too well can lead to diseases, some of which mirror human conditions. For University of Minnesota researcher Molly McCue, that parallel makes her studies of equine metabolism all the more fascinating.
"I think the horse is underutilized as a metabolic model for humans," says McCue, a veterinarian and assistant professor of veterinary population medicine at the University’s Equine Center. “[T]hey get naturally occurring diseases, which are like what humans get—this makes them a realistic model."
McCue and her colleagues are in the thick of research that may help uncover the genetic underpinnings of human disorders linked to energy storage.
Storing energy to excess
When we digest food, much of it gets converted to glucose. We store the glucose as "animal starch," or glycogen; liver and muscle are major depots.
Molly McCue with Belle, a horse with PSSM. Photo: Patrick O'Leary
In horses with the condition known as PSSM, excess glycogen accumulates in muscle cells and interferes with muscle contraction. Worse, 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 several 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.
In 2008 McCue and her team reported the discovery of a mutation linked to PSSM. The mutation increases the activity of a muscle cell enzyme that makes glycogen, hence its 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 McCue. “Many people with glycogen storage disease have an undiagnosed mutation and a link between excess glycogen and dysfunctional muscle."
She and her colleagues are now beginning to clone the mutated gene inside insect cells. In this simpler system, free of the complex energy environment of a mammalian muscle cell, they can better study exactly how the defective gene works. They're 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 they have discovered a second form of PSSM—that is, 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 our evolutionary past, when we were active hunter-gatherers and it was beneficial to put on fat for the lean months.
That strategy doesn’t work so well, however, in a sedentary modern society brimming with high-calorie food. Nor does it work in some horses, which were subject not only to natural evolutionary pressures but also to intense breeding for efficient fuel storage and related traits.
At the moment, the genes involved in metabolic syndrome aren’t well known, and even the exact nature of the syndrome is poorly defined. McCue and her fellow researchers are addressing both issues in a two-part study.
“The first phase 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,” she says. “In the second half of the study, we’ll look for genes linked to it.”
If such genes—or forms of genes—exist in humans, McCue’s studies could prove invaluable to understanding a human condition implicated in diabetes, heart disease, and other maladies that collectively account for a large share of the nation’s health care budget.