Abstract
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.
Highlights
Triplet repeat expansions in myotonic dystrophy reduce muscle expression of myotonic dystrophy protein kinase (DMPK)
We found that tight regulation of DMPK levels is necessary to maintain nuclear envelope (NE) stability in C2C12 myoblasts
Our studies have identified a novel role for DMPK in maintenance of NE stability
Summary
Triplet repeat expansions in myotonic dystrophy reduce muscle expression of myotonic dystrophy protein kinase (DMPK). DMPK is a nuclear envelope (NE) protein that promotes myogenic gene expression in skeletal myoblasts. 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. DMPK mRNA transcripts containing CUG expansions accumulate as nuclear foci [5], reducing the expression of DMPK in affected skeletal muscle and altering trans mRNA processing (6 – 8). DMPK RNA transcripts containing CUG expansions accumulate as nuclear foci [5], reducing the expression of DMPK in affected skeletal muscle. Our data demonstrate that DMPK is a critical component of the NE and that reduced DMPK may contribute to skeletal muscle wasting in DM1
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