# MBNL loss of function in visceral smooth muscle as a model of myotonic dystrophy type 1

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2024 · $48,974

## Abstract

ABSTRACT
 One in 8500 individuals are affected by myotonic dystrophy type 1 (DM1), the most common adult onset
muscular dystrophy. Those affected suffer from multisystemic symptoms affecting the brain, heart, and skeletal
muscle, which are active areas of investigation. DM1 patient surveys have identified gastrointestinal (GI)
disturbances as a predominant patient complaint that affects daily life and well-being and include difficulty
swallowing, pseudo-obstruction, and constipation. The cause of DM1 GI pathology is currently unknown and
evidence supports a role for visceral smooth muscle dysfunction. The goal of this proposal is to determine the
specific molecular mechanisms by which loss of MBNL function affects smooth muscle activity.
 DM1 is caused by a CTG trinucleotide repeat expansion, ranging between 50 to >4000 repeats, in the 3'
untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. DM1 pathology results from a toxic
gain of function of the expanded DMPK RNA [(CUG)exp RNA]. (CUG)exp RNA sequesters and prevents activity of
the muscleblind-like (MBNL) family of RNA binding proteins that regulate postnatal RNA processing networks
and maintain adult RNA expression patterns. In DM1, loss of MBNL activity predominantly affects alternative
splicing, leading to the expression of fetal protein isoforms in adult tissues, causing disease features. The role
of two Mbnl paralogs in DM1 pathology is demonstrated by mouse Mbnl1 and/or Mbnl2 knockout (KO) that
recapitulate DM1 phenotypes in brain, heart, and skeletal muscle. I am using tamoxifen inducible, conditional
double KO of Mbnl1 and Mbnl2 in mice to determine the impact of MBNL loss of function in visceral smooth
muscle. This will be the first investigation into the molecular mechanisms of DM1 GI features utilizing MBNL loss
as previously established for other DM1 affected tissues. The sponsor’s lab generated homozygous floxed Mbnl1
and Mbnl2 alleles that were combined with a smooth muscle specific CreERT2 (smoCRE;dHOM mice). Five-
week old smoCRE;dHOM mice exhibit delayed upper GI motility and known DM1-associated alternative splicing
events after Mbnl knock out. Optimized dKO mice will be used to: (1) determine what GI phenotypes result from
loss of MBNL, then (2) identify molecular mechanisms for smooth muscle dysfunction. In aim 1, lower GI motility
will be assessed by bead expulsion assays and ex vivo assays will identify perturbations of muscle contractility
and peristaltic patterning across intestinal segments. In aim 2, RNA sequencing data from both experimental
mice and tissues from DM1 affected individuals will be used to identify conserved alternative splicing events,
differentially expressed genes, and predominately affected gene ontologies. I anticipate identifying
transcriptomic changes affecting calcium dynamics and will perform in vitro investigations of calcium handling in
mouse primary smooth muscle cells and immortalized human smooth muscle cells. Togethe...

## Key facts

- **NIH application ID:** 10757336
- **Project number:** 5F31DK132935-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Janel Ann Merkel Peterson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2022-12-15 → 2025-12-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757336

## Citation

> US National Institutes of Health, RePORTER application 10757336, MBNL loss of function in visceral smooth muscle as a model of myotonic dystrophy type 1 (5F31DK132935-02). Retrieved via AI Analytics 2026-06-05 from https://api.ai-analytics.org/grant/nih/10757336. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*