"couch potato drug" may protect against heat stroke

An experimental drug that once made the headlines as the "couch potato pill", for its capacity to mimic the effects of exercise in sedentary mice, may have another use, as a way to protect against heat stroke. In a new study about to be published in the journal Nature Medicine, scientists describe how the experimental therapy, called AICAR, protected animals with a genetic predisposition to heat stroke. They hope it means the drug holds promise for treating people who are susceptible to heat-induced sudden death.

We have seen headlines about people unexpectedly dying from heat stroke. A physically fit young athlete, seemingly no different from his colleagues, suddenly dies on the football field during a sweltering hot day in August, or the victim could be an elderly woman gardening in the middle of a hot July day.

Heat stroke is a serious, life-threatening condition, and currently we have no treatment for it other than immerse the casualty in ice water or apply ice packs to bring their body temperature down to normal.

Cases of heat stroke are on the rise. According to a recent study in the American Journal of Preventive Medicine, the number of injuries linked to heat stroke in the US more than doubled in the ten years from 1997 to 2006, during which time, an estimated 55,000 people received treatment for the condition in emergency rooms across the US.

One theory is that some of the victims carry a faulty gene that makes them particularly sensitive to heat. And now, the authors of the Nature Medicine study, led by Dr Susan L. Hamilton, chair of molecular physiology and biophysics at Baylor College of Medicine in Houston, Texas, may have found a molecule that could reduce that risk.

Hamilton and colleagues have been studying a gene called ryanodine receptor 1 (RyR1), that is implicated in a particularly deadly disorder called malignant hyperthermia,a life-threatening inherited disorder of skeletal muscle in which commonly used general anesthetics trigger uncontrolled muscle contractions and dangerous increases in body temperature.

When mice that carry the RyR1 mutation exercise in a hot room, they exhibit similar uncontrolled muscle contraction, a classic heat stroke response. This can happen even when they are exposed for a short time to the outside temperatures that develop in Houston in the summer.

There have been suggestions recently that humans carrying equivalent RyR1 mutations may also have the same sensitivity to heat.

Hamilton and colleagues have also been researching muscle fatigue. In that work, which goes on in the same lab, they started looking at the effects of AICAR (5-aminoimidazole-4-carboxamide ribonucleoside), dubbed the "couch potato drug" or "exercise in a pill", because of its apparent ability to slow muscle fatigue and improve muscle endurance without exercise (as demonstrated by Vihang Narkar, Ronald Evans and colleagues at the Salk Institute).

Hamilton told the press:

"When we gave AICAR to the (heat-sensitive) mice, it was 100 percent effective in preventing heat-induced deaths, even when we gave it no more than 10 minutes before the activity."

They found that giving AICAR to the mice protected them from experiencing the muscle contractions under heat stress.

When they experimented further, the researchers found, among other things, that AICAR targets the skeletal muscle calcium release channel, RyR1.

In mice with the RyR1 mutation, the calcium in their muscle cells "leaks" from stores inside the cells into cytoplasm (the fluid that fills the cells). This begins as body temperature rises, which kicks off a "feed forward" cycle that triggers more calcium leakage, and so on.

Eventually, the amount of calcium in the cytoplasm reaches a point where it triggers massive muscle contractions.

If they are not stopped, the muscle contractions cause the muscle tissue to break apart and release their contents, including potassium and proteins, into the bloodstream. Too much potassium in the blood is extremely toxic, and if not treated quickly can lead to heart or kidney failure and eventually, death.

Hamilton said:

"AICAR stops the feed forward cycle that triggers these sustained muscle contractions."

"We have shown that it acts directly on the ryanodine receptor to decrease the calcium leak. It also protects intracellular calcium stores from depletion and this contributes to the ability of this compound to slow muscle fatigue," she added.

The researchers think their findings may help develop a drug that will be useful to young athletes and soldiers with abnormal heat sensitivity, especially those who have to wear heavy gear that prevents them from easily dissipating exercise-induced heat.

Co-author Dr Robert T. Dirksen, professor of Pharmacology and Physiology at the University of Rochester Medical Center in New York, said:

"There is a great need for the training staff of athletic teams, physicians in emergency rooms in places like Phoenix, and soldiers serving in the deserts of the Middle East to have a drug available to give to individuals during a heat stroke event."

"Our study takes an important first step towards developing a new drug therapy that may be part of the standard treatment regimen for heat stroke in the future," he added.

Hamilton said more work is needed before they can say for sure whether AICAR fits that bill, but the studies in mice are very encouraging.

Funds from the National Institutes of Health, the U.S. Department of Defense, the Muscular Dystrophy Association of America, the Swedish Research Council and the Consejo Nacional de Ciencia y Tecnología of Mexico, helped pay for the study.

Jakubi - Couch Potato (Video Medical And Professional 2020).

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