In summary, our data demonstrate that persistent ER stress/UPR, decreased protein synthesis, mitochondrial ROS production/damage and elevation of proapoptotic markers are defining features of RyR1 myopathy associated with the I4895T mutation in mice, making this myopathy distinct from that of the RyR1 myopathies that arise from Ca2+ leak (model in Fig. 9). This evidence concerns the gene RYR1 and myopathy.