Spinal Cord Injuries
Conditions
Keywords
metabolism, glucose, osteoporosis, secondary health conditions, quality of life, standing, electrical stimulation, diabetes, insulin, skeletal muscle
Brief summary
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.
Interventions
BEHAVIORALSingle-session electrically induced exercise
A single session of electrically induced exercise to the quadriceps and hamstring muscle groups of people with paralysis.
BEHAVIORALElectrically-induced exercise training
Multiple sessions of electrically induced exercise to the quadriceps and hamstring muscle groups for up to 3 years in people with paralysis.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Richard K Shields
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Motor complete SCI (AIS A-B)
Exclusion criteria
1. Pressure ulcers 2. Chronic infection 3. Lower extremity muscle contractures 4. Deep vein thrombosis 5. Bleeding disorder 6. Recent limb fractures 7. Any comorbid disease known to affect bone metabolism (such as parathyroid dysfunction) 8. Pregnancy 9. Anti-osteoporosis medications 10. Vitamin D supplements 11. Metformin or other medications for diabetes.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Post-training Bone Turnover: Osteocalcin | up to 3 years | Pre- and post-training serum osteocalcin, measured via venipuncture and enzyme-linked immunosorbent assay |
| Acute Gene Regulation: MSTN | 3 hours after a single session of electrical stimulation | 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. |
| Acute Gene Regulation: PGC1-alpha | 3 hours after a single session of electrical stimulation | 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. |
| Acute Gene Regulation: PDK4 | 3 hours after a single session of electrical stimulation | 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. |
| Acute Gene Regulation: SDHB | 3 hours after a single session of electrical stimulation | 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. |
| Post-training Gene Regulation: MSTN | up to 3 years | 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. |
| Post-training Gene Regulation: PGC1-alpha | up to 3 years | 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. |
| Post-training Gene Regulation: PDK4 | up to 3 years | 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. |
| Post-training Gene Regulation: SDHB | up to 3 years | 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. |
| Post-training Metabolism: Fasting Glucose | up to 3 years | Pre- and post-training fasting glucose, measured via venipuncture and standard laboratory assays |
| Post-training Metabolism: Fasting Insulin | up to 3 years | Pre- and post-training fasting insulin, measured via venipuncture and standard laboratory assays |
| Post-training Metabolism: HOMA Score | up to 3 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-training Subject-report Measures: EQ-5D | up to 3 years | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Acute Gene Regulation Adaptations in gene regulation in response to single-session electrically induced exercise
Single-session electrically induced exercise: A single session of electrically induced exercise to the quadriceps and hamstring muscle groups of people with paralysis. | 40 |
| Training Study Adaptations in gene regulation, metabolic markers, and subject-report metrics in response to up to 3 years of electrically induced exercise
Electrically-induced exercise training: Multiple sessions of electrically induced exercise to the quadriceps and hamstring muscle groups for up to 3 years in people with paralysis. | 31 |
| Total | 71 |
Baseline characteristics
| Characteristic | Acute Gene Regulation | Training Study | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 40 Participants | 31 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 31 Participants | 70 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Quadriplegia versus Paraplegia Paraplegia | 26 Participants | 20 Participants | 46 Participants |
| Quadriplegia versus Paraplegia Quadriplegia | 14 Participants | 11 Participants | 25 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 34 Participants | 28 Participants | 62 Participants |
| Region of Enrollment United States | 40 participants | 31 participants | 71 participants |
| Sex: Female, Male Female | 13 Participants | 10 Participants | 23 Participants |
| Sex: Female, Male Male | 27 Participants | 21 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 31 |
| other Total, other adverse events | 0 / 40 | 0 / 31 |
| serious Total, serious adverse events | 0 / 40 | 0 / 31 |
Outcome results
Primary
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.
Time frame: 3 hours after a single session of electrical stimulation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Gene Regulation | Acute Gene Regulation: MSTN | Pre-Stimulation | 5.49 arbitrary units | Standard Deviation 0.633 |
| Acute Gene Regulation | Acute Gene Regulation: MSTN | Post-Stimulation | 4.76 arbitrary units | Standard Deviation 0.748 |
p-value: <0.001ANOVA
Primary
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.
Time frame: 3 hours after a single session of electrical stimulation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Gene Regulation | Acute Gene Regulation: PDK4 | Pre-Stimulation | 6.59 arbitrary units | Standard Deviation 0.413 |
| Acute Gene Regulation | Acute Gene Regulation: PDK4 | Post-Stimulation | 7.29 arbitrary units | Standard Deviation 0.416 |
p-value: <0.001ANOVA
Primary
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.
Time frame: 3 hours after a single session of electrical stimulation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Gene Regulation | Acute Gene Regulation: PGC1-alpha | Pre-Stimulation | 5.23 arbitrary units | Standard Deviation 0.486 |
| Acute Gene Regulation | Acute Gene Regulation: PGC1-alpha | Post-Stimulation | 6.63 arbitrary units | Standard Deviation 0.395 |
p-value: <0.001ANOVA
Primary
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.
Time frame: 3 hours after a single session of electrical stimulation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Gene Regulation | Acute Gene Regulation: SDHB | Pre-Stimulation | 7.15 arbitrary units | Standard Deviation 0.478 |
| Acute Gene Regulation | Acute Gene Regulation: SDHB | Post-Stimulation | 7.20 arbitrary units | Standard Deviation 0.49 |
p-value: 0.467ANOVA
Primary
Post-training Bone Turnover: Osteocalcin
Pre- and post-training serum osteocalcin, measured via venipuncture and enzyme-linked immunosorbent assay
Time frame: up to 3 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Gene Regulation | Post-training Bone Turnover: Osteocalcin | Baseline | 6638.5 pg/mL | Standard Deviation 2711.9 |
| Acute Gene Regulation | Post-training Bone Turnover: Osteocalcin | Post-Training (up to 3 years) | 6874.1 pg/mL | Standard Deviation 3197.5 |
p-value: 0.493ANOVA
Primary
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.
Time frame: up to 3 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Gene Regulation | Post-training Gene Regulation: MSTN | Baseline | 5.34 arbitrary units | Standard Deviation 0.51 |
| Acute Gene Regulation | Post-training Gene Regulation: MSTN | Post-Training (up to 3 years) | 4.78 arbitrary units | Standard Deviation 0.668 |
p-value: <0.001ANOVA
Primary
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.
Time frame: up to 3 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Gene Regulation | Post-training Gene Regulation: PDK4 | Baseline | 7.01 arbitrary units | Standard Deviation 0.377 |
| Acute Gene Regulation | Post-training Gene Regulation: PDK4 | Post-Training (up to 3 years) | 6.87 arbitrary units | Standard Deviation 0.372 |
p-value: 0.326ANOVA
Primary
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.
Time frame: up to 3 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Gene Regulation | Post-training Gene Regulation: PGC1-alpha | Baseline | 5.89 arbitrary units | Standard Deviation 0.372 |
| Acute Gene Regulation | Post-training Gene Regulation: PGC1-alpha | Post-Training (up to 3 years) | 5.90 arbitrary units | Standard Deviation 0.337 |
p-value: 0.932ANOVA
Primary
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.
Time frame: up to 3 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Gene Regulation | Post-training Gene Regulation: SDHB | Baseline | 7.22 arbitrary units | Standard Deviation 0.456 |
| Acute Gene Regulation | Post-training Gene Regulation: SDHB | Post-Training (up to 3 years) | 7.26 arbitrary units | Standard Deviation 0.556 |
p-value: 0.673ANOVA
Primary
Post-training Metabolism: Fasting Glucose
Pre- and post-training fasting glucose, measured via venipuncture and standard laboratory assays
Time frame: up to 3 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Gene Regulation | Post-training Metabolism: Fasting Glucose | Baseline | 95.5 mg/dL | Standard Deviation 10.5 |
| Acute Gene Regulation | Post-training Metabolism: Fasting Glucose | Post-Training (up to 3 years) | 97.8 mg/dL | Standard Deviation 7.7 |
p-value: 0.539ANOVA
Primary
Post-training Metabolism: Fasting Insulin
Pre- and post-training fasting insulin, measured via venipuncture and standard laboratory assays
Time frame: up to 3 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Gene Regulation | Post-training Metabolism: Fasting Insulin | Baseline | 20.6 microU/mL | Standard Deviation 16.7 |
| Acute Gene Regulation | Post-training Metabolism: Fasting Insulin | Post-Training (up to 3 years) | 11.8 microU/mL | Standard Deviation 8.37 |
p-value: 0.155ANOVA
Primary
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.
Time frame: up to 3 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Gene Regulation | Post-training Metabolism: HOMA Score | Baseline | 2.3 score on a scale | Standard Deviation 1.8 |
| Acute Gene Regulation | Post-training Metabolism: HOMA Score | Post-Training (up to 3 years) | 1.3 score on a scale | Standard Deviation 0.9 |
p-value: 0.164ANOVA
Secondary
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.
Time frame: up to 3 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Gene Regulation | Post-training Subject-report Measures: EQ-5D | Baseline | 0.296 score on a scale | Standard Deviation 0.111 |
| Acute Gene Regulation | Post-training Subject-report Measures: EQ-5D | Post-Training (up to 3 years) | 0.265 score on a scale | Standard Deviation 0.093 |
p-value: 0.458ANOVA