Testosterone and Long Pulse Stimulation After SCI
Condition: Spinal Cord Injury
MeSH terms: Spinal Cord Injuries
Study type: Interventional
Phase: Phase 2

Summary: 
      Denervation following spinal cord injury (SCI) limits beneficial application of neuromuscular
      electrical stimulation (NMES). SCI with denervation results in extensive muscle atrophy that
      is accompanied with several cardio-metabolic health risks. The current proposal provides a
      novel intervention by examining the effects of long pulse width stimulation (LPWS) and
      testosterone replacement therapy (TRT) on restoring muscle size and leg lean mass after
      denervation in persons with SCI. This intervention will be rewarding for Veterans and
      Civilians with SCI who do not benefit from exercising their lower extremity muscles because
      denervation has limited the response to standard surface NMES. The investigators will study
      the biochemical mechanisms that contribute to changes in muscle size following this novel
      training. Combing both pharmaceutical and physical-therapeutic interventions will optimize
      restoration of muscle size after SCI.
    

Detailed description: 
      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.
    

Intervention name(s): Testosterone and LPWS; Testosterone and standard NMES
Intervention type(s): Device; Drug
Intervention description(s): Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and long pulse width stimulation (LPWS) in persons with denervated spinal cord injury.; Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury.
Other intervention name(s): Testosterone and long pulse width stimulation; Testosterone and neuromuscular electrical stimulation
Intervention MeSH terms: Methyltestosterone; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Electric Stimulation; Spinal Cord Injuries; Muscle Denervation; carbohydrate metabolism; Lipids metabolism; Basal Metabolic Rate; Muscle Proteins; Mitochondria, Muscle; RNA; Rehabilitation