Metabolic Health in Individuals With Spinal Cord Injury (SCI)

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.

Inclusion Criteria:

- between the ages of 18 and 60 years;

- diagnosis of traumatic SCI at the cervical or thoracic level (C5-T12) classified as
AIS A (motor and sensory complete);

- within 14 days of the SCI and the first week of initial inpatient rehabilitation;

- medically stable at the time of testing;

- no history of metabolic syndrome and/or type 1 or type 2 diabetes.

Exclusion Criteria:

- Pregnant women

- Orthopedic condition that limits lower extremity function

- Neurological (other than SCI), vascular, or cardiac problems that may limit function
and interfere with testing procedures

- Have 1 or more contraindications to NMES

- Have lidocaine or iodine allergy