# Mechanisms of NAD+ action during muscle development and homeostasis in a zebrafish dystroglycanopathy model

> **NIH NIH R01** · UNIVERSITY OF MAINE ORONO · 2021 · $311,564

## Abstract

ABSTRACT
Congenital muscular dystrophies (CMDs) are progressive debilitating diseases without cures. Many CMDs
disrupt the adhesion of muscle cells to their surrounding extracellular matrix (ECM). Muscle-ECM adhesion is
critical for muscle development, homeostasis, regeneration, and resilience to stress. Mutations in genes that
modulate muscle-ECM adhesion frequently lead to CMDs. For example, Dystroglycan (DG) and Integrin
alpha7 (Itga7) are transmembrane ECM receptors that, when mutated, result in CMDs. Whether and/or how
these transmembrane receptors interact during muscle development/homeostasis is not known. In addition, the
roles that post-translational modification of DG plays in modulating both the ECM proper and muscle-ECM
adhesion are not known. We previously found that exogenous NAD+ potentiates ECM deposition and that
NAD+ improves dystrophic phenotypes in zebrafish lacking either DG or Itga7. The basic cell biological
mechanisms that underlie NAD+-mediated improvement in muscle-ECM adhesion are not well understood.
Our long-term goal is to understand how signaling between muscle cells and their ECM mediates muscle
health. Secondary Dystroglycanopathies are a subset of CMDs that result from mutations in genes that are
necessary for glycosylation of DG, which is necessary for muscle-ECM adhesion. GDP-mannose, synthesized
by GMPPB, is essential for glycosylation reactions. Mutations in GMPPB result in GMPPB-associated
Dystroglycanopathy. Preliminary data show that muscle development, homeostasis, and regeneration are
disrupted in gmppb mutants. In contrast to our previous data showing NAD+ improves ECM deposition in dg-
deficient zebrafish, preliminary data show that NAD+ does not improve muscle structure in gmppb mutants. In
this grant, we will compare and contrast the mechanisms underlying the effects of DG glycosylation and NAD+
on muscle development, homeostasis, and regeneration. Our central hypothesis is that both NAD+ and gmppb
regulate muscle cell adhesion by altering sarcolemma architecture and ECM organization. In Aim 1 we will test
the hypothesis that NAD+ increases cell adhesion in DG mutant zebrafish by increasing Itga7 clustering; and
that hypoglycosylated DG disrupts sarcolemma architecture and prevents NAD+-mediated Itga7 clustering and
increased cell adhesion. We will do this with a combination of longitudinal light sheet microscopy studies and
super-resolution microscopy. In Aim 2 we will identify new muscle cell adhesion regulators through
comparative studies of dysregulated muscle development in three zebrafish models of muscular dystrophy. We
will take an unbiased approach to identify ECM regulatory nodes by using network modeling and network
resilience analysis of co-expressed coding and non-coding genes. Completion of this grant will provide new
insight into how cell-ECM adhesion mediates muscle development and homeostasis in vertebrate models of
CMDs. These basic in vivo cell biological studies are crucial to pro...

## Key facts

- **NIH application ID:** 10241349
- **Project number:** 5R01AR075836-03
- **Recipient organization:** UNIVERSITY OF MAINE ORONO
- **Principal Investigator:** Clarissa A Henry
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $311,564
- **Award type:** 5
- **Project period:** 2019-08-02 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241349

## Citation

> US National Institutes of Health, RePORTER application 10241349, Mechanisms of NAD+ action during muscle development and homeostasis in a zebrafish dystroglycanopathy model (5R01AR075836-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10241349. Licensed CC0.

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