ABSTRACT
mRNA processing is highly regulated during development through changes in RNA-binding protein (RBP) activities. CUG-BP, Elav-like family member 1 (CELF1, also called CUGBP1) is an RBP, the expression of which decreases in skeletal muscle soon after birth. CELF1 regulates multiple nuclear and cytoplasmic RNA processing events. In the nucleus, CELF1 regulates networks of postnatal alternative splicing (AS) transitions, while in the cytoplasm, CELF1 regulates mRNA stability and translation. Stabilization and misregulation of CELF1 has been implicated in human diseases including myotonic dystrophy type 1, Alzheimer's disease and multiple cancers. To understand the contribution of nuclear and cytoplasmic CELF1 activity to normal and pathogenic skeletal muscle biology, we generated transgenic mice for doxycycline-inducible and skeletal muscle-specific expression of active CELF1 mutants engineered to be localized predominantly to either the nucleus or the cytoplasm. Adult mice expressing nuclear, but not cytoplasmic, CELF1 are characterized by strong histopathological defects, muscle loss within 10 days and changes in AS. In contrast, mice expressing cytoplasmic CELF1 display changes in protein levels of targets known to be regulated at the level of translation by CELF1, with minimal changes in AS. These changes are in the absence of overt histopathological changes or muscle loss. RNA-sequencing revealed extensive gene expression and AS changes in mice overexpressing nuclear and naturally localized CELF1 protein, with affected genes involved in cytoskeleton dynamics, membrane dynamics, RNA processing and zinc ion binding. These results support a stronger role for nuclear CELF1 functions as compared to cytoplasmic CELF1 functions in skeletal muscle wasting.
Subject(s)
CELF1 Protein/genetics , Muscular Atrophy/genetics , Myotonic Dystrophy/genetics , RNA Stability/genetics , Alternative Splicing/genetics , Animals , Cell Nucleolus/genetics , Cytoplasm/genetics , Humans , Mice , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscular Atrophy/pathology , Myotonic Dystrophy/pathology , RNA Processing, Post-Transcriptional/genetics , RNA, Messenger/geneticsABSTRACT
INTRODUCTION: Myotonic dystrophy type 1 (DM1) is a multisystemic disease caused by expansion of a CTG repeat in the 3' UTR of the Dystrophia Myotonica-Protein Kinase (DMPK) gene. While multiple organs are affected, more than half of mortality is due to muscle wasting. METHODS: It is unclear whether endurance exercise provides beneficial effects in DM1. Here, we show that a 10-week treadmill endurance exercise program leads to beneficial effects in the HSALR mouse model of DM1. RESULTS: Animals that performed treadmill training displayed reduced CUGexp RNA levels, improved splicing abnormalities, an increase in skeletal muscle weight and improved endurance capacity. DISCUSSION: These results indicate that endurance exercise does not have adverse effects in HSALR animals and contributes to beneficial molecular and physiological outcomes.
Subject(s)
Endurance Training/methods , Muscle, Skeletal/metabolism , Myotonic Dystrophy/metabolism , Physical Conditioning, Animal/methods , Physical Endurance/physiology , Actins/genetics , Adipose Tissue , Alternative Splicing , Animals , Body Composition , Bone Density , Disease Models, Animal , Gene Expression , Humans , Mice , Mice, Transgenic , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Myotonic Dystrophy/pathology , Myotonic Dystrophy/physiopathology , Organ Size , Reverse Transcriptase Polymerase Chain Reaction , Trinucleotide Repeat ExpansionABSTRACT
Repeat expansions cause dominantly inherited neurological disorders. In this issue of Molecular Cell, Kearse et al. (2016) examine the requirements for RAN translation of the CGG repeats that cause fragile X-associated tremor/ataxia syndrome, revealing similarities and differences with canonical translation.
