AICAR might protect against heat stress in MH-susceptible individuals

MH and Heat Stroke- Similar Symptoms
Malignant hyperthermia (MH) is a life-threatening genetic muscle disorder, most commonly triggered in those at risk by certain types of drugs used during anesthesia. Heat stroke, on the other hand, most commonly occurs in individuals in response to physical exertion in hot/humid environments. While their common triggers may differ, the signs associated with MH and heat stroke are remarkably similar - uncontrolled muscle contractions, dangerous increases in body temperature, and muscle breakdown leading to the release of toxins in the blood which may cause cardiac arrhythmias and death. Immediate treatment for these conditions is crucial.

Treatments for MH and Heat Stroke
The treatment for anesthesia-induced MH is a drug called dantrolene. For heat stroke, options are limited to symptomatic treatment, such as vigorous cooling and hydration. Now, researchers at Baylor College of Medicine (Houston, TX), the University of Rochester (Rochester, NY), and the Joslin Diabetes Center (Boston, MA) have shown that a compound called AICAR, previously shown to slow muscle fatigue and increase muscle endurance, is effective in preventing heat stroke in an animal model of the disorder. This animal model is the same one utilized for MH, though the drug did not protect the mice from anesthetic-induced MH.

A Genetic Link
Not only are the signs of MH and heat stroke similar, but there is also a genetic link. Recent studies have shown that genetically engineered 'MH mice' not only develop MH on exposure to anesthesia but also develop an MH-like response similar to heat stroke on exposure to high temperatures. These 'MH mice' harbor a mutation in the ryanodine receptor gene (RYR1) which codes for an important protein, the ryanodine receptor, which controls the level of calcium in the muscle cell. Mutations in RYR1 have also been identified in some humans who suffered from heat stroke.

What were the key findings of this study?
In these mice, AICAR prevented increased calcium leak in the muscle cell through the ryanodine receptor during heat challenge, thereby blocking the initiation of abnormal muscle contractions, an initial step in the heat stroke response. AICAR was 100% effective in preventing heat-induced sudden death, or heat stroke in these mice.

Why is this study important?
Each year many individuals die or suffer consequences of heat stroke. Heat stroke is not uncommon in the military as well as in athletic competitions. This would be the first demonstration that a medication can be effective in preventing certain forms of heat stroke.

What are the implications of this study for MH-susceptible (MHS) individuals?
As we have previously reported, individuals who harbor certain RYR1 mutations may not only be susceptible to anesthetic-induced MH events, but may also be heat sensitive. "In these individuals, AICAR might serve an important protective role against heat stress," notes Susan Hamilton, Ph.D., lead investigator for the study (Baylor College of Medicine).

According to Dr. Henry Rosenberg, President of MHAUS, this study emphasizes the connection between anesthesia-induced MH and environmental heat stroke, and enhances our understanding of the connection between ryanodine receptor genes and many other disorders. It also opens up the possibility for development of other compounds that might be useful in the treatment of MH and other drug-induced disorders characterized by muscle abnormality and elevated body temperature.

Source: Baylor College of Medicine