# Influence of aromatase on neuromuscular plasticity resulting from testosterone plus locomotor training after spinal cord injury

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

The motor dysfunction resulting from spinal cord injury (SCI) is precipitated by the neural insult and is
exacerbated by other factors that hinder motoneuron survival and muscle recovery, including disuse and low
testosterone (T). The success of bodyweight-supported treadmill training (BWSTT) diminishes as the SCI
severity worsens. We have developed a novel strategy involving BWSTT with adjuvant T-enanthate (TE) drug
treatment that promotes use-dependent neuroplasticity, in-part, by preserving white matter at the spinal lesion
and by supporting motoneuron survival, which stimulates neuromuscular recovery. However, the
supraphysiologic TE dose we used produced prostate enlargement in our rodent severe contusion SCI model,
which limits translation. The purpose of this proposal is to improve the translational applicability of BWSTT+TE
by identifying the lowest TE dose that enhances BWSTT-mediated neuromotor improvement, in an effort to
limit prostate growth and other androgenic side-effects. Secondly, we will determine the influence of estradiol
(E2) on BWSTT-mediated locomotor recovery and neuromuscular plasticity. The latter remains important from
translational and mechanistic perspectives because (1) T is converted to E2, via aromatase, within the central
nervous system and (2) E2 treatment produces potent neuroprotection in rats after SCI. To provide
comprehensive evidence of neuroplasticity, we will evaluate functional adaptations in our rodent SCI model in
response to the proposed treatments and assess anatomical changes that occur at the spinal cord lesion and
distal to the lesion, and in spinal motoneurons and muscle. To support this proposal, we have established a
male rodent severe mid-thoracic contusion SCI model that exhibits persistent hindlimb paralysis and
progressive muscle decline and 50% lower circulating T than non-SCI animals, similar to the T deficiency
present in nearly all men after SCI. Our data indicate that BWSTT+TE restored hindlimb overground walking
after severe SCI more so than BWSTT (alone) or TE (alone). Moreover, BWSTT+TE improved recovery of
muscle fiber cross-sectional area (fCSA), muscle force output, and prevented the deleterious slow (oxidative)
to fast (glycolytic) fiber-type transition in muscle. In Aim 1, we will perform a dose-optimization experiment to
identify the lowest effective TE dose and we will build upon our original data by comprehensively evaluating
locomotor recovery and neuromuscular plasticity in response to BWSTT+TE. The primary outcomes are open-
field locomotor recovery, soleus muscle function, soleus fCSA and fiber type distribution. In Experiment 1a,
SCI animals will remain untreated (vehicle) or will receive BWSTT with low, moderate, or high-dose TE, with
the lowest effective dose advancing. In Experiment 1b, SCI animals will receive vehicle, BWSTT, TE, or
BWSTT+TE. Aim 2 will then determine the influence of estradiol (E2) on BWSTT-mediated locomotor recovery
and neuromuscular plasticity....

## Key facts

- **NIH application ID:** 10120524
- **Project number:** 5IK2RX003268-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Dana M Otzel
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120524

## Citation

> US National Institutes of Health, RePORTER application 10120524, Influence of aromatase on neuromuscular plasticity resulting from testosterone plus locomotor training after spinal cord injury (5IK2RX003268-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120524. Licensed CC0.

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