Testosterone and Long Pulse Stimulation After SCI

The 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.
The investigators will determine if TRT+LPWS would increase skeletal muscle size, leg lean
mass and improve overall metabolic health in SCI persons with LMN denervation. The
investigators 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 following TRT+LPWS. This study is novel because it provides a
feasible rehabilitation intervention by combining two approaches; which are likely to improve
the quality of life in SCI persons with LMN denervation. If proven successful, the
intervention will be easily translated into clinical practice for persons with SCI.

Inclusion Criteria:

- Traumatic motor complete SCI and level of injury of T10 and below

- Only participants with lower motor neuron (LMN) denervation as determined by EMG
testing

- Participants must also have an absence of reflexes, denervation of both knee extensor
muscles

- Tolerance to LPWS paradigm

- Both knee extensors will also have to be unresponsive (i.e., no observed tetanic
contraction or twitches) to standard electrical stimulation procedures (stimulation
frequency: 30 Hz; pulse duration:450 s and amplitude of the current:200 mA)

- All participants will undergo International Standards for Neurological Classification
of SCI (ISNCSCI) examination for neurological level and function and only those with
American Spinal Injury Classification (AIS A and B; i.e. motor deficit below the level
of injury)

Exclusion Criteria:

- Diagnosis of neurological injury other than SCI

- Pre-existing medical conditions will be excluded (cardiovascular disease, uncontrolled
type II DM and those on insulin requirements) or other concurrent medical conditions
judged to be contraindicated by the site physician.

- Hematocrit above 50% and severe urinary tract infection or symptoms

- Those with hyper-physiological testosterone level above 800 ng/dl

- Those who will fail to tolerate the LPWS paradigm

- Progressive condition that would be expected to result in changing neurological status

- Lower extremity fracture around the knee joint (distal femur or proximal tibia) within
the last 2 years from enrollment in the study

- Knee BMD < 0.60 gm/cm2

- Total hip BMD T-scores < -3.5

- Untreatable severe spasticity judged to be contraindicated by the site Physician

- Untreated or uncontrolled hypertension (systolic blood pressure >140 mmHg; diastolic
blood pressure >90 mmHg)

- Pressure ulcer of the trunk, pelvic area, or lower extremities of grade 3 or more

- Psychopathology documentation in the medical record or history that may conflict with
study objectives