Musculoskeletal Plasticity After Spinal Cord Injury

Study Overview
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Brief Summary
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Patients with spinal cord injury (SCI) experience metabolic syndrome, diabetes, obesity, pressure ulcers, and cardiovascular disease at far greater rates than the general population. A rehabilitation method to prevent or reverse the systemic metabolic consequences of SCI is a pressing need. The purpose of this study is to determine the dose of muscle activity that can enhance an oxidative muscle phenotype and improve clinical markers of metabolic health and bone turnover in patients with SCI. The long-term goal of this research is to develop exercise-based interventions to prevent secondary health conditions such as diabetes and to ultimately protect health-related quality of life (QOL). Specific Aim 1: To compare changes in skeletal muscle gene regulation in individuals who receive high frequency (HF) active-resisted stance and low frequency (LF) active-resisted stance for 3 years. Hypothesis 1: The expression of genes regulating skeletal muscle metabolism will support that HF and LF both instigate a shift toward an oxidative muscle phenotype. A novel finding will be that LF is a powerful regulator of oxidative pathways in skeletal muscle. Specific Aim 2: To compare changes in systemic markers of metabolic health and bone turnover in individuals with SCI who receive HF or LF for 3 years. Hypothesis 2: HF and LF will both reduce glucose/insulin levels and HOMA (homeostasis model assessment) score. Secondary Aim: To measure subject-reported QOL using the EQ-5D survey metric. Hypothesis 3: HF and LF subjects will show a trend toward improved self-reported QOL after 3 years. There will be an association between metabolic improvement and improved perception of QOL. These observations will support that this intervention has strong feasibility for future clinical translation.

Official Title
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Musculoskeletal Plasticity After Spinal Cord Injury

Conditions
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Spinal Cord Injuries

Intervention / Treatment
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* Behavioral: Single-session electrically induced exercise
* Behavioral: Electrically-induced exercise training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Motor complete SCI (AIS A-B) Exclusion Criteria: Pressure ulcers Chronic infection Lower extremity muscle contractures Deep vein thrombosis Bleeding disorder Recent limb fractures Any comorbid disease known to affect bone metabolism (such as parathyroid dysfunction) Pregnancy Anti-osteoporosis medications Vitamin D supplements Metformin or other medications for diabetes.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acute gene regulation<br>Adaptations in gene regulation in response to single-session electrically induced exercise | Behavioral: Single-session electrically induced exercise<br>* A single session of electrically induced exercise to the quadriceps and hamstring muscle groups of people with paralysis.<br>|
| Experimental: Training Study<br>Adaptations in gene regulation, metabolic markers, and subject-report metrics in response to up to 3 years of electrically induced exercise | Behavioral: Electrically-induced exercise training<br>* Multiple sessions of electrically induced exercise to the quadriceps and hamstring muscle groups for up to 3 years in people with paralysis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Gene Regulation: MSTN | Acute post-stimulation effect upon skeletal muscle myostatin (MSTN) expression, measured via muscle biopsy and exon array analysis. Probe summarization and probe set normalization were performed using robust multichip average, which included background correction, quantile normalization, log2 transformation and median polish probe set summarization. 0 represents no mRNA expression and higher values represent greater expression compared to all genes in the microarray. | 3 hours after a single session of electrical stimulation | 
| Acute Gene Regulation: PGC1-alpha | Acute post-stimulation effect upon skeletal muscle peroxisome proliferator-activated receptor gamma coactivator alpha (PGC1-alpha) expression, measured via muscle biopsy and exon array analysis. Probe summarization and probe set normalization were performed using robust multichip average, which included background correction, quantile normalization, log2 transformation and median polish probe set summarization. 0 represents no mRNA expression and higher values represent greater expression compared to all genes in the microarray. | 3 hours after a single session of electrical stimulation | 
| Acute Gene Regulation: PDK4 | Acute post-stimulation effect upon skeletal muscle pyruvate dehydrogenase kinase, isozyme 4 (PDK4-alpha) expression, measured via muscle biopsy and exon array analysis. Probe summarization and probe set normalization were performed using robust multichip average, which included background correction, quantile normalization, log2 transformation and median polish probe set summarization. 0 represents no mRNA expression and higher values represent greater expression compared to all genes in the microarray. | 3 hours after a single session of electrical stimulation | 
| Acute Gene Regulation: SDHB | Acute post-stimulation effect upon skeletal muscle succinate dehydrogenase-B (SDHB) expression, measured via muscle biopsy and exon array analysis. Probe summarization and probe set normalization were performed using robust multichip average, which included background correction, quantile normalization, log2 transformation and median polish probe set summarization. 0 represents no mRNA expression and higher values represent greater expression compared to all genes in the microarray. | 3 hours after a single session of electrical stimulation | 
| Post-training Gene Regulation: MSTN | Pre- and post-training skeletal muscle myostatin (MSTN) expression, measured via muscle biopsy and exon array analysis. Probe summarization and probe set normalization were performed using robust multichip average, which included background correction, quantile normalization, log2 transformation and median polish probe set summarization. 0 represents no mRNA expression and higher values represent greater expression compared to all genes in the microarray. | up to 3 years | 
| Post-training Gene Regulation: PGC1-alpha | Pre- and post-training skeletal muscle peroxisome proliferator-activated receptor gamma coactivator alpha (PGC1-alpha) expression, measured via muscle biopsy and exon array analysis. Probe summarization and probe set normalization were performed using robust multichip average, which included background correction, quantile normalization, log2 transformation and median polish probe set summarization. 0 represents no mRNA expression and higher values represent greater expression compared to all genes in the microarray. | up to 3 years | 
| Post-training Gene Regulation: PDK4 | Pre- and post-training skeletal muscle pyruvate dehydrogenase kinase, isozyme 4 (PDK4-alpha) expression, measured via muscle biopsy and exon array analysis. Probe summarization and probe set normalization were performed using robust multichip average, which included background correction, quantile normalization, log2 transformation and median polish probe set summarization. 0 represents no mRNA expression and higher values represent greater expression compared to all genes in the microarray. | up to 3 years | 
| Post-training Gene Regulation: SDHB | Pre- and post-training skeletal muscle succinate dehydrogenase-B (SDHB) expression, measured via muscle biopsy and exon array analysis. Probe summarization and probe set normalization were performed using robust multichip average, which included background correction, quantile normalization, log2 transformation and median polish probe set summarization. 0 represents no mRNA expression and higher values represent greater expression compared to all genes in the microarray. | up to 3 years | 
| Post-training Metabolism: Fasting Glucose | Pre- and post-training fasting glucose, measured via venipuncture and standard laboratory assays | up to 3 years | 
| Post-training Metabolism: Fasting Insulin | Pre- and post-training fasting insulin, measured via venipuncture and standard laboratory assays | up to 3 years | 
| Post-training Metabolism: HOMA Score | Pre- and post-training HOMA score, calculated via the Homeostasis Model Assessment equation. Maximum/minimum values: not applicable. Scores >2 are indicative of insulin resistance. | up to 3 years | 
| Post-training Bone Turnover: Osteocalcin | Pre- and post-training serum osteocalcin, measured via venipuncture and enzyme-linked immunosorbent assay | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-training Subject-report Measures: EQ-5D | Pre- and post-training QALY (quality-adjusted life-years) via the EQ-5D subject-report survey instrument. Scale ranges from -0.287 to 0.992. Higher values indicated a higher self-perceived health state. | up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metabolism, glucose, osteoporosis, secondary health conditions, quality of life, standing, electrical stimulation, diabetes, insulin, skeletal muscle