Figure 5. Proposed model of exertional/environmental heat stress and myopathy in RyR1^Y522S/wt mice.

➀ SR Ca²⁺ release channels in RyR1^Y522S/wt mice are more sensitive to voltage, ligand, and Ca²⁺ activation and open more readily, producing small, possibly local, increases in resting Ca²⁺. ➁ Increased cytosolic Ca²⁺ levels enhance ROS/RNS production. Increases in RNS are likely to be produced by nitric oxide synthases (NOS). Possible sources of ROS include mitochondria, xanthine oxidase (XO) and NAD(P)H oxidases (NOX). ➂ Although both S-glutathionylation and S-nitrosylation of RyR1^Y522S/wt occurs, our data suggest that S-nitrosylation alone enhances the temperature sensitivity of RyR1. ➃ S-nitrosylation of RyR1^Y522S/wt increases its sensitivity to temperature and decreases its sensitivity to Ca²⁺ inhibition further promoting SR Ca²⁺ leak. ➄ Ca²⁺ increases further enhance ROS/RNS production. ➅ In response to heat stress, Ca²⁺ release from the modified RyR1^Y522S/wt is greatly and persistently augmented, leading to heat stroke. ➆ and ➇ Chronically-elevated levels of Ca²⁺ and ROS/RNS damage mitochondria and contribute to the development of myopathy.