An alarming increase in the number of exertional heat-related deaths among young, physically fit athletes, soldiers, policemen, and even individuals conducting normal “everyday” activities (e.g. yard work, home maintenance) are reported each year in the mainstream media, raising questions as to whether some individuals are more susceptible to heat and exercise-induced sudden death than others in the population. Recent findings suggest that at least 13 mutations in the skeletal muscle Ca2+
release channel (ryanodine receptor 1, RyR1) are associated with life-threatening responses to exertion, heat challenge and febrile illness [1
]. RyR1 associated disorders are not rare; the prevalence of genetic abnormalities in the RYR1
gene has been suggested to be as great as one in 3,000 individuals [7
]. Mutations in RyR1 are associated with a wide spectrum of human muscle disorders (for review see, [13
]) including malignant hyperthermia (MH), central core disease (CCD), multiminicore disease, core-rod myopathy, atypical periodic paralysis, neonatal hypotonia, idiopathic hyperCKaemia, late-onset axial myopathy, and congenital neuromuscular disease with uniform type 1 fibers.
The life threatening responses to elevated environmental temperatures associated with some RyR1 mutations (which we designate the enhanced heat response, EHR) display many similarities to heat stroke. Although sudden death in response to exertion, stress and/or high environmental temperature in young, apparently fit, adults can arise from pre-existing cardiac abnormalities [14
] or the acute onset of organ failure (e.g., heart, kidney, liver) [15
], it could also arise from organ failure secondary to rhabdomyolysis of skeletal muscle, triggered by exercise induced increases in body temperature. Dantrolene is an effective treatment to reverse anesthetic-induced MH episodes, but there are no FDA approved interventions for the other RyR1 myopathies. Given the severity and life threatening nature of some of the RyR1 myopathies, drugs that can be used prophylactically are greatly needed.
We created a mouse model [16
] by knocking-in a Y522S (Y524S in mice) mutation in RyR1 associated with MH in humans [18
]. The heterozygous mice (RyR1Y524S/WT
or YS) demonstrate typical hallmarks of MH (e.g. whole body contractures, elevated core temperature, rhabdomyolysis and death) upon exposure to inhalation anesthetics [16
]. These mice also display an enhanced susceptibility to a heat stroke-like response leading to sudden death when exposed to elevated environmental temperatures (>37 °C) or when exercising under warm (>25 °C) conditions [16
]. In our search for agents that improve the myopathy [19
] in these mice, we found that AICAR protected the mice against EHR. AICAR is an activator of the AMP-activated protein kinase (AMPK), a kinase that functions as a cellular energy sensor that is activated by increases in the AMP to ATP ratio [20
]. AICAR is converted to 5-aminoimidazole-4-carboxamide ribonucleoside (ZMP) in the cell where it mimics AMP to activate AMPK and improves muscle endurance without exercise [21
]. AMP binding to AMPK increases its phosphorylation at threonine 173, leading to prolonged activation. We now report that acute AICAR treatment prevents the EHR in YS mice, at least partially by directly inhibiting RyR1 Ca2+
leak and reducing oxidative/nitrosative stress.