# Role of ryanodine receptor dysfunction after spinal cord injury

> **NIH VA I01** · JAMES J PETERS VA  MEDICAL CENTER · 2022 · —

## Abstract

Muscles paralyzed by spinal cord injury (SCI) atrophy extensively, are weaker, fatigue more quickly and
generate lower specific tension (force produced per unit of cross-sectional area), such that they generate
less force in response to maximal motor neuron activation. For individuals with motor-incomplete lesions,
interventions that improve specific force and/or fatigue resistance would be obvious opportunities to improve
function. A newly recognized cause of impaired specific force production is oxidation/nitrosylation of
ryanodine receptors (RyR) which results in dissociation of calstabin and spontaneous opening of RyR
thereby impairing RyR gating; the ultimate physiological effect of RyR dysfunction is diminished force of
muscle contraction and lower muscle endurance. Small molecules such as S107 bind oxidized/nitrosylated
RyR and improve specific force by as much as 50%. Our preliminary data demonstrates extensive
oxidation/nitrosylation of RyR in muscle after SCI thus implicating RyR dysfunction in reduced specific force
production and endurance of paralyzed muscle after SCI. These changes in RyR are associated with
increased expression of NADH oxidase 4 (Nox4) which is a potent source of reactive oxygen species
(ROS) that has been linked to RyR. A direct link between Nox4 and oxidation/nitrosylation of RyR is
supported by findings that binding of Nox4 to RyR is also increased in muscle after SCI. The overarching
objectives of this application are to test the possibility that administration of S107 or a Nox4 inhibitor after
SCI will improve skeletal muscle specific tension and endurance, and hence function, and to investigate the
role of Nox4 in oxidation/nitrosylation of RyR in skeletal muscle after SCI.
 Aim 1. To determine the role of elevated Nox4 expression in the oxidation/nitrosylation of RyR in
muscle after spinal cord transection. Hypothesis: oxidation/nitrosylation of RyR after SCI results from
increased expression and activity of Nox4. Approach. Aim 1A. We will compare SCI and sham-operated
groups over time after a spinal cord transection at various times between 1 and 56 days after SCI. We will
examine the temporal relationships between oxidation/nitrosylation of RyR and dissociation of calstabin
from RyR with changes in Nox4 expression. Aim 1B: Effects of a conditional knockout of Nox4 in skeletal
muscle on muscle strength, specific force, fatigue, RyR oxidation after SCI will be determined. Aim 1C: We
will compare muscle force production, specific force, fatigue, RyR oxidation/nitrosylation and binding of RyR
to calstabin between spinal cord transected mice treated with a Nox4 inhibitor or vehicle.
 Aim 2) To test the effects of S107 on muscle force production and RyR-calstabin binding
interactions after spinal cord transection. Hypothesis: administration of S107 will improve muscle
specific force and endurance and increase calstabin binding to RyR but will not alter RyR
oxidation/nitrosylation. Approach: We will compare muscl...

## Key facts

- **NIH application ID:** 10515284
- **Project number:** 5I01RX002313-05
- **Recipient organization:** JAMES J PETERS VA  MEDICAL CENTER
- **Principal Investigator:** Helen M Bramlett
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10515284

## Citation

> US National Institutes of Health, RePORTER application 10515284, Role of ryanodine receptor dysfunction after spinal cord injury (5I01RX002313-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10515284. Licensed CC0.

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