Headlines usually tell the story. A young athlete who seems no different from his colleagues on the football field dies suddenly during exercise under the sun on a blistering summer day.
Some of these young, physically fit young people may have a gene mutation that makes them particularly sensitive to heat, and now researchers led by those at Baylor College of Medicine may have identified a molecule that could reduce that threat. A report on their work appears online January 8 in the journal Nature Medicine.
It all begins in the laboratory of Dr. Susan Hamilton, chair of molecular physiology and biophysics at BCM, who studies the ryanodine receptor 1(RyR1) that is implicated in a particularly deadly disorder called malignant hyperthermia.
Slow muscle fatigue
People with this disorder suffer life-threatening elevations of temperature during a particular kind of general anesthesia. When mice with this mutation exercise in a hot room or are even exposed for a short time to the temperatures of a Houston summer, they suffer all the hallmarks of malignant hyperthermia before they die. Recent evidence suggests that this heat sensitivity is also found in humans with comparable RyR1 mutations.
In her studies of muscle fatigue (another focus of the laboratory), Hamilton and her colleagues studied a compound called AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) recently shown by Vihang Narkar, Ronald Evans and colleagues at the Salk Institute to slow muscle fatigue and improve muscle endurance without exercise -- making it popularly known as "exercise in a pill," said Hamilton.
"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," said Hamilton.
Further experiments showed that one target of AICAR is the skeletal muscle calcium release channel, RyR1. In muscle cells from mice with the mutant form of the ryanodine receptor, calcium "leaks" out of intracellular stores into the cytoplasm in response to a elevation in body temperature generating a feed-forward cycle of calcium lead and increased oxidative stress which drives additional calcium leak. Cytoplasmic calcium eventually reaches a level that triggers massive muscle contractions. These sustained muscle contractions lead to muscle breakdown and leakage of potassium and protein from the muscle, causing heart or kidney failure, and ultimately death.
Decreases calcium leak
"AICAR stops the feed forward cycle that triggers these sustained muscle contractions," said Hamilton. "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."
The finding has implications for young athletes and soldiers with abnormal heat sensitivity, especially those who must wear heavy gear that does not allow them to dissipate the heat generated with exercise.
While it would make sense to tell people with the genetic trait to avoid exercise in the heat, Hamilton said that many youngsters might ignore such advice.
Hopes to find intervention
"We were attempting to identify an intervention, something that could be used prophylactically to protect these sensitive individuals without significant side effects," she said.
More work is needed before she can determine if AICAR fits that bill, but the studies in mice are very encouraging.
Hamilton said that this work was a group effort involving the members of her laboratory and a number of critical collaborators, each author contributing an important part of the story.
Those who took part from BCM include Johanna T. Lanner, Dimitra K. Georgiou, Adan Dagnino-Acosta, Qing Cheng, Aditya D. Joshi, Zanwen Chen, Joshua M. Oakes, Chang Seok Lee, Tanner O. Monroe, Arturo Santillan, Keke Dong, Iskander I. Ismailov and George G. Rodney. Laura Goodyear from the Joslin Diabetes Center in Boston and Alina Ainbinder, Viktor Yarotsky, and Robert T. Dirksen of the University of Rochester Medical Center also took part in the research.
Funding came 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.
- Johanna T Lanner, Dimitra K Georgiou, Adan Dagnino-Acosta, Alina Ainbinder, Qing Cheng, Aditya D Joshi, Zanwen Chen, Viktor Yarotskyy, Joshua M Oakes, Chang Seok Lee, Tanner O Monroe, Arturo Santillan, Keke Dong, Laurie Goodyear, Iskander I Ismailov, George G Rodney, Robert T Dirksen, Susan L Hamilton. AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation. Nature Medicine, 2012; DOI: 10.1038/nm.2598
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