Reduction of Cellular Nucleic Acid Binding Protein Encoded by a Myotonic Dystrophy Type 2 Gene Causes Muscle Atrophy

Abstract

Myotonic dystrophy type 2 (DM2) is a neuromuscular disease caused by an expansion of intronic CCTG repeats in the <i>CNBP</i> gene, which encodes a protein regulating translation and transcription. To better understand the role of cellular nucleic acid binding protein (CNBP) in DM2 pathology, we examined skeletal muscle in a new model of <i>Cnbp</i> knockout (KO) mice. This study showed that a loss of Cnbp disturbs myofibrillar sarcomeric organization at birth. Surviving homozygous <i>Cnbp</i> KO mice develop muscle atrophy at a young age. The skeletal muscle phenotype in heterozygous <i>Cnbp</i> KO mice was milder, but they developed severe muscle wasting at an advanced age. Several proteins that control global translation and muscle contraction are altered in muscle of <i>Cnbp</i> KO mice. A search for CNBP binding proteins showed that CNBP interacts with the α subunit of the dystroglycan complex, a core component of the multimeric dystrophin-glycoprotein complex, which regulates membrane stability. Whereas CNBP is reduced in cytoplasm of DM2 human fibers, it is a predominantly membrane protein in DM2 fibers, and its interaction with α-dystroglycan is increased in DM2. These findings suggest that alterations of CNBP in DM2 might cause muscle atrophy via CNBP-mediated translation and via protein-protein interactions affecting myofiber membrane function.