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.
"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.
"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 truly a group effort involving the members of her laboratory and a number of critical collaborators, each author contributing an important part of the story.
|Contact: Graciela Gutierrez|
Baylor College of Medicine