Targeting Skeletal Muscle to Improve Metabolic Health in Individuals With Spinal Cord Injury (SCI)
Targeting Skeletal Muscle to Improve Metabolic Health in Individuals With Spinal Cord Injury (SCI)
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.
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.
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