# The contribution of nuclear and cytoplasmic CELF1 protein functions to muscle wasting in myotonic dystrophy type I

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2020 · $45,520

## Abstract

Abstract
 The goal of this project is to determine how the RNA binding protein CELF1 (also known as CUGBP1)
contributes to skeletal muscle wasting in myotonic dystrophy type 1 (DM1). DM1 is an adult-onset
neuromuscular disorder and more than half of DM1 mortality is due to muscle wasting. The mechanisms
leading to skeletal muscle wasting remain unknown. DM1 is caused by expansion of a CTG repeat in the 3'
UTR of the Dystrophia Myotonica-Protein Kinase (DMPK) gene. The CTG repeats are transcribed and DM1
pathogenesis is due to a gain of function of the expanded CUG repeat mRNA. The expanded repeat RNA
disrupts the function of RNA binding proteins. The RNA sequesters the MBNL family of RNA binding proteins
producing a loss of function which leads to RNA processing abnormalities resulting in disease features. A
second RNA binding protein effected by the repeat RNA is CELF1. CELF1 protein is post-transcriptionally up-
regulated 2-4 fold in DM1 skeletal muscle. The sponsor’s lab previously reported that inducible overexpression
of CELF1 in adult skeletal muscle of transgenic mice reproduces DM1-like defects in muscle function and
histology. CELF1 functions in the nucleus as a splicing regulator and in the cytoplasm as a regulator of mRNA
stability and translation. I have recently generated and tested transgenic mice for skeletal muscle-specific and
tetracycline-inducible expression of active CELF1 derivatives localized exclusively to either the nucleus or the
cytoplasm. These transgenic animals will be used for muscle-specific expression to determine whether a gain
of CELF1 nuclear or cytoplasmic functions contribute to DM1 pathogenesis and muscle wasting.
 I will achieve this through two specific aims. In the first specific aim transgenic mice inducibly expressing
modified versions of mCherry-tagged human CELF1 that localize exclusively to the nucleus or cytoplasm will
be used to determine whether the nuclear and/or cytoplasmic roles of CELF1 leads to pathogenesis. I will
validate effects on CELF1 nuclear and cytoplasmic targets and systematically characterize muscle function
and histology. In the second specific aim I will use RNA-seq to identify CELF1-associated transcriptome
changes likely to contribute to skeletal muscle wasting in DM1. RNA-seq from skeletal muscle of either the
nuclear or cytoplasmic line (or both) will be filtered against available RNA-seq data sets from skeletal muscle of
individuals affected by DM1, a mouse model in the sponsor’s lab that express CUG repeat RNA and show
muscle wasting, as well as models of CELF1 up-regulation. Additionally, I will determine the extent to which the
muscle wasting phenotype of animals that express expanded repeat RNA is rescued by Celf1 loss of function
by AAV-shRNA mediated Celf1 knockdown. RNA-seq from rescued animals will provide an additional data set
to identify the molecular changes that correlate with phenotypic rescue.

## Key facts

- **NIH application ID:** 9872130
- **Project number:** 5F31AR073088-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Diana Cox
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2018-02-27 → 2021-02-26

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872130

## Citation

> US National Institutes of Health, RePORTER application 9872130, The contribution of nuclear and cytoplasmic CELF1 protein functions to muscle wasting in myotonic dystrophy type I (5F31AR073088-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9872130. Licensed CC0.

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