# Testosterone and Long Pulse Width Stimulation for Denervated Muscles after Spinal Cord Injury

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2020 · —

## Abstract

Our long-term goal is to develop a rehabilitation strategy to mitigate the deleterious
changes in muscle size and lower leg lean mass in persons with denervation following spinal
cord injury (SCI). Currently, there is no available rehabilitation intervention following lower motor
neuron (LMN) denervation. More than 46,000 Veterans are affected with SCI and may
experience profound skeletal muscle atrophy and loss of lean mass and about 20-25%
experience LMN denervation. Skeletal muscle cross-sectional area is 6 times smaller following
LMN denervation compared to the innervated muscles. Denervation atrophy may be
accompanied by several SCI health-related consequences.
 Twelve weeks of twice weekly of surface neuromuscular electrical stimulation (NMES)
resistance training (RT) can elicit more than a 35% increase in skeletal muscle size, decreased
ectopic adipose tissue accumulation, increased insulin sensitivity after SCI. Moreover, the
applicant’s CDA-2 preliminary findings showed that 16 weeks of NMES-RT and testosterone
replacement therapy (TRT) increased leg lean mass by 1.5 kg with no changes in the TRT
group only. This was accompanied by an increase in the basal metabolic rate (BMR) of 218
kcal/day in the NMES-RT+TRT with no changes in the TRT group. During the course of
recruitment for the study, 20% of individuals with SCI were excluded and could not benefit from
exercising their lower extremity muscles, presumably because of LMN denervation.
 Long pulse width stimulation (LPWS; 120-150 ms) has the potential to stimulate
denervated muscles and to restore muscle size in people with SCI. The previous paradigm has
focused on daily activation of the denervated muscles without applying progressive loading
similar to RT. Daily training is not a clinically feasible approach in persons with SCI. Moreover,
previous trials did not focus on enhancing the neuromuscular homeostasis by promoting the
increase in lean mass independent of LMN denervation. Testosterone replacement therapy
(TRT) has been shown to increase lean mass and basal metabolic rate in hypogonadal men
with SCI. We will determine if TRT+LPWS would increase skeletal muscle size, leg lean mass
and improve overall metabolic health in SCI persons with LMN denervation. We hypothesize
that the one year TRT+LPWS protocol will upregulate protein synthesis pathways, down-
regulate protein degradation pathways and increase overall mitochondrial health. Three specific
aims will address these hypotheses. Aim 1 will assess the effects of TRT+LPWS compared to
TRT+ standard neuromuscular electrical stimulation (NMES; as a control group) on the size of
thigh skeletal muscle, intramuscular fat (IMF) and leg lean mass. Aim 2 will determine the
association between the changes in skeletal muscle size, leg lean mass and the metabolic
profile as determined by measuring BMR, serum lipids and carbohydrate profile. Aim 3 will
investigate the cellular mechanisms responsible for evoking skeletal muscle hypertrophy...

## Key facts

- **NIH application ID:** 9934879
- **Project number:** 5I01RX002649-03
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** Ashraf S Gorgey
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934879

## Citation

> US National Institutes of Health, RePORTER application 9934879, Testosterone and Long Pulse Width Stimulation for Denervated Muscles after Spinal Cord Injury (5I01RX002649-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934879. Licensed CC0.

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