Epigenetic Mechanisms for Klotho Gene Silencing in Dystrophic Muscle

Duchenne muscular dystrophy (DMD) is an X-linked disease characterized by muscle membrane damage and muscle wasting that eventually causes death of the afflicted. Klotho is a powerful longevity protein that has been linked to lifespan and kidney function; in recent years, Klotho's role in muscle growth has been reported. Previous findings in our lab showed that Klotho expression is suppressed in DMD patients and mdx mice, an animal model of muscular dystrophy. In this study, we investigate the epigenetic mechanisms that regulate Klotho expression in dystrophic muscle. Our data suggest DNA hypermethylation and histone 3 lysine 9 dimethylation at the Klotho transcriptional start site are involved in the transcriptional suppression under oxidative stress. Furthermore, our data also show disrupted demethylation in oxidatively stressed muscle cells during differentiation that may also contribute to the hypermethylation seen in muscle.