Myotonic Dystrophy Protein Kinase Is Critical for Nuclear Envelope Integrity

Myotonic dystrophy 1 (DM1) is a multisystemic disease caused by a triplet nucleotide repeat expansion in the 3′ untranslated region of the gene coding for myotonic dystrophy protein kinase (DMPK). DMPK is a nuclear envelope (NE) protein that promotes myogenic gene expression in skeletal myoblasts. Muscular dystrophy research has revealed the NE to be a key determinant of nuclear structure, gene regulation, and muscle function. To investigate the role of DMPK in NE stability, we analyzed DMPK expression in epithelial and myoblast cells. We found that DMPK localizes to the NE and coimmunoprecipitates with Lamin-A/C. Overexpression of DMPK in HeLa cells or C2C12 myoblasts disrupts Lamin-A/C and Lamin-B1 localization and causes nuclear fragmentation. Depletion of DMPK also disrupts NE lamina, showing that DMPK is required for NE stability. Our data demonstrate for the first time that DMPK is a critical component of the NE. These novel findings suggest that reduced DMPK may contribute to NE instability, a common mechanism of skeletal muscle wasting in muscular dystrophies. Background: Triplet repeat expansions in myotonic dystrophy reduce muscle expression of myotonic dystrophy protein kinase (DMPK). Results: DMPK localizes to the nuclear envelope, and DMPK depletion disrupts the nuclear envelope. Conclusion: DMPK is critical to maintain nuclear envelope integrity. Significance: Reduced DMPK expression in myotonic dystrophy could contribute to nuclear instability, a common mechanism of muscle wasting in muscular dystrophies.