Role of Oxidative Stress, Autophagy and Apoptosis in the I4895T RyR1 Knockin Mice

Abstract

I4898T mutation in the skeletal muscle ryanodine receptor (RyR1) in humans has been suggested to underlie Central Core Disease (CCD). CCD is the congenital myopathy characterized by muscle weakness of lower extremities leading to delayed attainment of motor skill milestones. We created mice with a corresponding RyR1 I4895T mutation. Although no central cores were observed in the muscle of these mice, this uncoupling mutation dramatically reduces voluntary running. The soleus muscle from the I4895T mice displays decreased ability to generate force, increased oxidative stress, decreased antioxidant capacity and decreased cytochrome c oxidase activity (suggesting mitochondrial damage). We also find evidence of both autophagy and apoptosis in the mutant muscle since Atg5, Atg6 (Beclin1), Atg9, Atg12, Bcl2, caspase family members, C/EBP homologous protein (CHOP) are all upregulated in the soleus. Upregulation of several ER stress related proteins (BiP, IRE1α, and PDI) was also observed. We propose that the I4895 mutation is associated with the oxidative stress, an unfolded protein response (UPR), autophagy and apoptosis, all of which may contribute to mitochondrial destruction associated with this disease.