# The Role of Epigenetics in Mitochondrial Biogenesis-Mediated Recovery after Spinal Cord Injury

> **NIH VA IK2** · SOUTHERN ARIZONA VA HEALTH CARE SYSTEM · 2022 · —

## Abstract

The goal of this project is to determine the role of epigenetic modifications of mitochondrial genes in
the induction of the plateau phase after spinal cord injury (SCI), and to exploit these modifications to
promote recovery. SCI is a devastating disorder often resulting in loss of function below the injury site. In recent
years, service members have been threatened by more advanced warfare, such as improvised explosive
devices, ultimately inducing more severe and complex injuries, including SCI. The devastating and debilitating
nature of these injuries has not been lessened. The Department of Veterans Affairs (VA) is the largest healthcare
network for individuals suffering from SCI, providing care for 25% of total victims in the United States. Improved
therapeutics for the treatment of SCI would greatly benefit not only sufferers, but also the VA healthcare system.
SCI is defined by direct trauma to the spinal cord, which disrupts the vasculature, leading to decreased oxygen
delivery within the area and reducing the ability of mitochondria to maintain cellular energetics. Thus far, the
majority of studies targeting mitochondrial dysfunction following SCI have focused on downstream aspects of
mitochondrial function (e.g. antioxidant defenses). Reestablishment of mitochondrial function through
pharmacological induction of mitochondrial biogenesis (MB) remains an underexplored but novel strategy.
I previously reported that treatment with the mitochondrially biogenic FDA-approved β2-adrenergic receptor
agonist formoterol beginning up to 8h after SCI improves spinal cord mitochondrial function, decreases lesion
volume and enhances locomotor recovery by 7 days post-injury (DPI). Consistent with other published data, the
majority of the improvements observed with formoterol occurred within the first 2 weeks, after which recovery
plateaued. A similar effect is observed in humans, with the majority of recovery taking place within the first year
then reaching a plateau. The mechanism behind the development of this plateau phase, however, is not fully
understood. By determining the mechanism of its formation, the plateau phase could be prevented and/or
reversed, potentially allowing for continued recovery following injury. My preliminary studies revealed genetic
differences within the injured spinal cord of formoterol-treated mice between the recovery phase (7 DPI) and the
plateau phase (15 DPI), namely a decrease in genes associated with mitochondrial function, and a concurrent
increase in genes associated with epigenetic modifications. Therefore, I hypothesize that epigenetic
alterations contribute to decreased transcription of mitochondrial genes within the spinal cord during
the plateau phase, preventing continued recovery of mitochondrial function and limiting the efficacy of
formoterol treatment in mice. To address this hypothesis, I propose the following Specific Aims: 1) Further
elucidate the genetic profile within the spinal cord during the post-...

## Key facts

- **NIH application ID:** 10477196
- **Project number:** 5IK2BX005218-03
- **Recipient organization:** SOUTHERN ARIZONA VA HEALTH CARE SYSTEM
- **Principal Investigator:** Natalie E Scholpa
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477196

## Citation

> US National Institutes of Health, RePORTER application 10477196, The Role of Epigenetics in Mitochondrial Biogenesis-Mediated Recovery after Spinal Cord Injury (5IK2BX005218-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10477196. Licensed CC0.

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