# Mechanisms of Skeletal Muscle Pathogenesis in Myotonic Dystrophy Type 1

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $132,536

## Abstract

Project Summary
Myotonic dystrophy is the second most common cause of muscular dystrophy and the most common cause
of adult onset muscular dystrophy. The primary cause of disease mortality is progressive skeletal muscle
weakness and wasting. The long term goal of this project is to determine the mechanisms that cause skeletal
muscle pathogenesis in myotonic dystrophy type 1 (DM1). DM1 is an autosomal dominant disease caused by
a CTG repeat expansion in the 3’ untranslated region of the DMPK gene. The molecular basis for the disease
is a toxic gain of function of the RNA containing expanded CUG repeats (CUGexp RNA) that is transcribed
from the mutant allele. CUGexp RNA accumulates in nuclear RNA foci and causes loss of function of
Muscleblind like (MBNL) RNA binding proteins that are sequestered on CUGexp RNA within the nuclear foci.
CUGexp RNA also induces upregulation of CELF1 protein that has been shown to be toxic to skeletal
muscle. MBNL and CELF1 proteins regulate alternative splicing transitions of a large number of genes during
skeletal muscle postnatal development. Their altered functions in DM1 skeletal muscle causes misregulated
alternative splicing and inappropriate expression of fetal protein isoforms in adult skeletal muscle that leads to
disease features. While the basis for MBNL loss of function has been established, the mechanisms causing
CELF1 upregulation in skeletal muscle are unknown. We find that Mbnl1/Mbnl2 double knockout in adult
mouse skeletal muscle results in CELF1 protein upregulation, indicating a mechanistic link between MBNL
loss of function and increased CELF1 activity. We also established a transgenic mouse model for DM1 in
which skeletal muscle specific expression of a human DMPK mRNA containing expanded CUG repeats
reproduces DM1 features including CELF1 upregulation. The goals of this proposal are to determine the
molecular mechanisms of CELF1 upregulation in response to Mbnl1/Mbnl2 double knockout and expression
of the toxic CUGexp RNA and to determine the contributions of CELF1 upregulation to skeletal muscle
pathogenesis caused by MBNL loss of function and CUGexp RNA.

## Key facts

- **NIH application ID:** 11075579
- **Project number:** 3R01AR082852-02S1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Thomas A Cooper
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $132,536
- **Award type:** 3
- **Project period:** 2023-09-06 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11075579

## Citation

> US National Institutes of Health, RePORTER application 11075579, Mechanisms of Skeletal Muscle Pathogenesis in Myotonic Dystrophy Type 1 (3R01AR082852-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11075579. Licensed CC0.

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