# Mechanisms and treatments of mitochondrial dysfunction in paralyzed skeletal muscle after spinal cord injury

> **NIH VA IK2** · BIRMINGHAM VA MEDICAL CENTER · 2021 · —

## Abstract

Unloading and paralysis of skeletal muscle after spinal cord injury (SCI) results in severe loss of muscle
contractile function and deleterious alterations in mitochondrial morphology and performance. One potential
mechanism is the de novo appearance of connexin hemichannels (Cx) in paralyzed muscle. We hypothesize
Cx destabilize mitochondrial function in paralyzed muscle. Cx43 and 45 appear in the sarcolemma de novo
after paralysis and are believed to contribute to muscle atrophy by permitting entry of extracellular calcium
(Ca2+) into the muscle fiber. We posit that the systematic study of the role of Cx43 and 45 after SCI using
transgenic mouse models will evaluate the potential of blockers of Cx for future drug development.
 We also propose that protecting mitochondrial function and morphology by a pharmaceutical
intervention may be beneficial for muscle health after SCI. SS-31 is a mitochondrial-targeted antioxidant that
has reduced muscle loss and protected mitochondrial function in mouse models of muscle wasting. No study
has tested whether SS-31 improves muscle health after paralysis.
 Our overall objective is to find interventions and treatments to increase the well-being of individuals with
SCI. We hypothesize that muscle-specific knockout of Cx43 and 45 will protect muscle health after SCI.
Additional studies will describe the role of drug or diet interventions in protecting muscle function after
paralysis. We believe data from this line of studies will provide insight into multiple novel treatments that
protect muscle health after SCI and provide a path to translatable medicine and future clinical investigations.
1. Specific Aim 1 (Year 1-[3]): Determine whether a muscle-specific knockout of Cx43 and 45 protects
mitochondrial morphology and metabolic function in mice paralyzed by SCI
Hypothesis: Muscle-specific knockout of Cx43 and 45 will slow the loss of muscle mass and function and
protect against the degradation of mitochondrial morphology after contusion SCI.
Approach: 4-month old transgenic mice carrying a muscle-specific MyoD-driven Cre-recombinase and floxed
Cx43 and 45 will be given a sham or contusion SCI and be compared to a MyoD-Cre-recombinase-only
genotype control. Behavioral tests, muscles function tests and biochemical outcomes will be analyzed.
2. Specific Aim 2 (Year [4-5]): Investigate the efficacy of an SS-31 drug intervention for preserving
muscle function and mitochondrial morphology and limiting ROS production after SCI.
Hypothesis: Daily injections of SS-31 will protect muscle and mitochondrial morphology after contusion SCI.
Approach: 4-month old wild type C57BL/6 female mice will be given a sham or SCI as well as daily injections of
SS-31 or vehicle across time. Muscle function will be measured ex vivo; ROS production rate will be measured
from isolated muscle mitochondria and whole muscle lysates.

## Key facts

- **NIH application ID:** 10241972
- **Project number:** 5IK2RX002781-05
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** Zachary Aaron Graham
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241972

## Citation

> US National Institutes of Health, RePORTER application 10241972, Mechanisms and treatments of mitochondrial dysfunction in paralyzed skeletal muscle after spinal cord injury (5IK2RX002781-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241972. Licensed CC0.

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