# Pathophysiology and Treatment of Recessive RYR1 Related Myopathy

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $416,980

## Abstract

Mutations in the gene that encodes the skeletal muscle type I ryanodine receptor (RYR1) result in a wide range
of muscle disorders that collectively comprise the most common cause of non-dystrophic myopathy. The most
severe cases of RYR1-related myopathy (RYR1-RM) exhibit a recessive pattern of inheritance and present in
infancy with muscle hypotrophy, weakness, respiratory insufficiency, short stature, and a marked reduction in
RYR1 protein expression in muscle. Despite their severity, high prevalence and association with significant
disability and early mortality, there are no treatments or disease-modifying therapies for RYR1-RM. A major
barrier to therapy development has been the lack of an animal model that mirrors the early onset and clinical
severity of recessive RYR1-RM. To overcome this barrier, we developed two mouse models of recessive
RYR1-RM that pheno-copy key characteristics of the human disorder including myofiber hypotrophy, reduced
muscle/body mass, muscle weakness, markedly reduced RYR1 expression, and premature death.
The scientific premise of this proposal is that these new mouse models of RYR1-RM provide a unique
opportunity to explore the underlying patho-mechanisms of RYR1-RM and test the therapeutic efficacy of
mechanism-based interventions. The overall goal of the project is to elucidate the patho-mechanisms
responsible for muscle dysfunction in recessive RYR1-RM and to develop and validate effective treatments.
We hypothesize that reduced folding/stability of mutated RYR1 homotetramers results in increased RYR1
protein degradation that markedly reduces RYR1 expression, and that even a modest increase in either RYR1
expression or function will ameliorate the myopathy and prolong survival. Furthermore, we also hypothesize
that reduced myofiber size in RYR1-RM is a key aspect of disease pathogenesis, that hypotrophy is due to
epigenetic abnormalities, and that drugs that target the epigenome or promote muscle growth can ameliorate
the disease phenotype. The validity of these hypotheses will rigorously evaluated in three specific aims.
Aim 1 will characterize RYR1 expression, function and myopathy in two mouse models of severe, recessive
RYR1-RM and assess the therapeutic potential of systemic treatment with ebselen, an FDA-approved drug
and known RYR1 activator. Aim 2 will elucidate the mechanism(s) for reduced RYR1 expression in our mouse
models of RYR1-RM mice and evaluate the therapeutic efficacy of systemic treatment with a chemical
chaperone and ER stress inhibitor (4PBA). Aim 3 will determine the mechanisms leading to muscle hypotrophy
in RYR1-RM mice and test the potential of treatment with either HDAC inhibitors or modulators of myofiber
size. The results of these studies will provide novel insights into the patho-mechanisms responsible for
reduced RYR1 expression and muscle fiber hypotrophy in recessive RYR1-RM and determine the therapeutic
potential of several mechanism-based interventions designed to enhance RYR...

## Key facts

- **NIH application ID:** 10071615
- **Project number:** 1R01AR078000-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** JAMES J DOWLING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $416,980
- **Award type:** 1
- **Project period:** 2020-07-29 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071615

## Citation

> US National Institutes of Health, RePORTER application 10071615, Pathophysiology and Treatment of Recessive RYR1 Related Myopathy (1R01AR078000-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071615. Licensed CC0.

---

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