Metabolic Health in Individuals With Spinal Cord Injury (SCI)
Condition: Spinal Cord Injuries; Skeletal Muscle Atrophy; Metabolic Disease
MeSH terms: Spinal Cord Injuries; Muscular Atrophy; Metabolic Diseases; Wounds and Injuries
Study type: Interventional

Summary: 
      Individuals with spinal cord injury (SCI) live longer than before and live to an age where
      metabolic disorders become highly prevalent. Due to loss of mobility and severe skeletal
      muscle atrophy, obesity, glucose intolerance, and peripheral insulin resistance develop soon
      after the onset of SCI. These abnormalities are thought to contribute to the increased
      diabetes disease risk and accelerated aging process in the SCI population. As a result of
      these trends, overall burden of complications, economic impact and reduced quality of life
      are increasing. Until there are effective treatments for SCI, it is imperative to develop
      effective interventions to mitigate metabolic disorders that develop in individuals with SCI.
      The proposed research project examines the impact of early utilization of a novel
      neuromuscular electrical stimulation (NMES) program on skeletal muscle metabolism and overall
      metabolic health in individuals with sub-acute, complete SCI.
    

Detailed description: 
      The escalating prevalence of metabolic disorders in individuals with long-standing spinal
      cord injury (SCI) highlights the urgent need for early interventions for prevention and
      improving quality of life. Individuals with SCI, while often relatively young, are at high
      risk for developing insulin resistance and type 2 diabetes soon after the onset of injury.
      Skeletal muscle is the major site of dietary glucose disposal, yet the relationship between
      adaptations in skeletal muscle after SCI and the development of metabolic disturbances
      remains poorly understood. Within 6 months after SCI, lower limb muscles atrophy by up to 45%
      and individuals show a 3-fold increase in intramuscular fat levels compared to able-bodied
      (AB) controls. Moreover, within 6 months after SCI, fatigue-resistant and oxidative Type I
      and Type IIa muscle fibers transform into highly fatigable, glycolytic Type IIax and IIx
      muscle fibers with impaired oxidative metabolism. The maintenance of adequate muscle mass and
      metabolic function has never been targeted as a potential strategy to prevent chronic
      metabolic disorders in individuals with SCI. Early prevention of these deleterious
      adaptations is expected to be more effective than attempting to reverse changes several
      months or years after SCI.

      Among the available experimental strategies to reverse atrophy and improve skeletal muscle
      metabolism in individuals with SCI, there seems to be consensus that muscle contraction via
      neuromuscular electrical stimulation (NMES) is the most potent approach. The investigators
      recently showed that 8 weeks of NMES-resistance exercise in people with long-standing SCI
      effectively increased myofiber size and distribution of Type IIa myofibers; however, this
      intervention did not increase the distribution of Type I fibers. There is a need for novel
      NMES programs that induce key molecular adaptations to both resistance and aerobic exercise
      to maintain an oxidative, fatigue-resistant, and insulin-sensitive phenotype following SCI.

      Here, the investigators propose an early intervention of combined NMES (Comb-NMES). This
      program couples electrically induced resistance and aerobic exercise on the knee extensor
      muscle group (quadriceps) with the goal of maintaining or even improving muscle mass and
      metabolic function. The proposed Comb-NMES program repetitively stresses the paralyzed knee
      extensor muscles with both low frequency electrical stimulation (aerobic training) to improve
      oxidative metabolism and retain Type I fibers and high frequency (resistance training)
      electrical stimulation with dynamic contractions to prevent atrophy and retain Type IIa
      fibers.

      The investigators will test the following central hypothesis that, compared to a control
      group, those treated with Comb-NMES for 6 weeks early after SCI will maintain a better
      whole-body metabolic profile, largely driven by maintenance of paralyzed muscle mass, fiber
      phenotype (maintenance of Type I and IIa fibers), and muscle oxidative metabolic function.
      The investigators will test this hypothesis in a controlled clinical trial of patients with
      SCI with the following specific aims:

      Aim 1: Quantify the effects of Comb-NMES on clinically important measures of metabolic
      function.

      Hypothesis 1. Compared to a control group, 6 weeks of Comb-NMES (3 days/week) will maintain
      higher glucose tolerance and whole-body insulin sensitivity.

      Aim 2: Quantify cellular, molecular and functional adaptations in the quadriceps muscle that
      are responsible for improvements in muscle metabolism and overall metabolic profile.

      Hypothesis 2.1. Compared to a control group, 6 weeks of Comb-NMES (3 days/week) will maintain
      better muscle glucose utilization, oxidative metabolism, muscle size, strength, and fatigue
      resistance, as well as a healthy muscle fiber phenotype (homogeneous distribution of Type I,
      IIa, and IIx fibers).

      Hypothesis 2.2. Comb-NMES-induced improvements in overall metabolic profile will be reflected
      in changes in metabolite signatures related to muscle mitochondrial function and intermediary
      metabolism.
    

Intervention name(s): Neuromuscular electrical stimulation
Intervention type(s): Other
Intervention description(s): NMES-RE will involve concentric/eccentric contractions of the quadriceps from a seated position. Briefly, each session will include four sets of 10 actions evoked using 50 Hz trains of 450 µs biphasic pulses. The protocol will be implemented using surface NMES. Upon completion of the NMES-RE session, participants will be given a short break (10-15 minutes) for recovery before starting aerobic training. NMES aerobic exercise will involve twitch electrical stimulation (pulse duration/interval=200/50 µs) applied to the quadriceps muscle via surface NMES. The current amplitude will set to 175 mA. The training will start with 10 minutes of twitch stimulation at 2 Hz. After the first weeks, the duration of the session will progressively increase up to 60 minutes at 10 Hz.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Other
Keywords: Spinal Cord Injury; Skeletal Muscle; Functional Electrical Stimulation; Diabetes