The number of heat-related injuries in the U.S. more than doubled from 1997 to 2006. In that 10-year period, an estimated 55,000 people were treated for the condition in emergency rooms across the country.
AICAR made a big splash in 2008 when a study published in Cell, a prestigious scientific journal, found that the drug built muscle and increased endurance in completely inactive mice. As additional studies further established AICAR’s ability to improve muscle function, the team grew curious to test how it might influence the whole-body muscle contractions characteristic of RYR1-associated heat stroke in mice.
Not only did they discover the unanticipated protective effect of the drug, but that it worked in a completely different way than they originally thought.
AICAR normally works by activating the body’s metabolic “master switch,” an enzyme called AMPK that, among other things, influences muscle activity. However, researchers found that the ability of the drug to protect the mice from heat stroke was unrelated to its effects on this master switch. Rather, it directly influenced RYR1.
RYR1, or the type 1 ryanodine receptor, is a protein that plays an essential role in muscle contraction. It is responsible for releasing positively charged calcium ions from storage compartments within cells, which then combine with muscle proteins to trigger contraction. In response to heat, mutations in RYR1 cause excessive amounts of calcium to leak from the storage compartment and trigger uncontrolled muscle contractions. The team found that AICAR reduces calcium leakage from RYR1, thus diminishing heat-induced contractions, muscle damage, and death.
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