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Completed

NCT Number: NCT03139344

Long Duration Activity and Metabolic Control After Spinal Cord Injury

Skeletal muscle is the largest endocrine organ in the body, playing an indispensable role in glucose homeostasis. Spinal cord injury (SCI) prevents skeletal muscle from carrying out this important function. Dysregulation of glucose metabolism precipitates high rates of metabolic syndrome, diabetes, and other secondary health conditions (SHCs) of SCI. These SHCs exert a negative influence on health-related quality of life (HRQOL). New discoveries support that a low level of activity throughout the day offers a more effective metabolic stimulus than brief, episodic exercise bouts. The proposed study will translate this emerging concept to the population of individuals with SCI by using low-force, long-duration electrical muscle stimulation to subsidize daily activity levels. Recently, we demonstrated that this type of stimulation up-regulates key genes that foster an oxidative, insulin-sensitive phenotype in paralyzed muscle. We will now test whether this type of activity can improve glucose homeostasis and metabolic function in patients with chronic paralysis. We hypothesize that improvements in metabolic function will be accompanied by a reduction in SHCs and a concomitant improvement in self-reported HRQOL. The long-term goal of this research is to develop a rehabilitation strategy to protect the musculoskeletal health, metabolic function, and health-related quality of life of people living with complete SCI.

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Key information

Conditions

Spinal Cord Injuries Behavior Central Nervous System Diseases Motor Activity Nervous System Diseases Spinal Cord Diseases Trauma, Nervous System Wounds and Injuries

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

University of Iowa

Iowa City, Iowa, 52242, United States

About this study

Skeletal muscle is a critical organ for regulating glucose and insulin in the body as a whole, and post-spinal cord injury (SCI) adaptations in muscle severely undermine this capacity. Contemporary SCI rehabilitation for people with complete SCI does not intervene to protect the function of paralyzed skeletal muscle as a key regulator of metabolic homeostasis. Through its deleterious effects on multiple systems, metabolic disease is one of the leading sources of morbidity, mortality, and health care cost for this population.

In the non-SCI population, pervasive, frequent, low-magnitude muscle contractions can increase energy expenditure by 50.3% above sitting levels. The loss of this component of muscle activity contributes to the energy imbalance and metabolic dysregulation observed in SCI. Subsidizing low-magnitude muscle contractions may offer an important metabolic stimulus for people with SCI. The significance of this study is that it builds on previous work demonstrating healthful transcriptional and translational gene adaptations in response to electrical stimulation training in SCI. These adaptations may initiate improvements in systemic biomarkers of metabolic health and improvements in secondary health conditions and health-related quality of life.

In our previous work, we demonstrated that regular electrical stimulation of paralyzed muscle up-regulates PGC-1α, a key transcriptional co-activator for skeletal muscle and metabolic adaptation. Our previous work also indicates that electrical stimulation alters the expression of genes controlling mitochondrial biogenesis. However, we understand very little about the optimal amount of electrically-evoked muscle activity to deliver in order to promote positive metabolic adaptations. Long duration, low force contractions are likely to be most advantageous for promoting metabolic stability in people with chronic SCI, who also have osteoporosis and are unable to receive high force muscle contractions induced by conventional rehabilitation protocols. This study will intervene with a protocol of low-force, long-duration muscle stimulation designed to instigate systemic metabolic adaptations. In the proposed study we hypothesize that gene-level adaptations will yield tissue-level improvements in glucose utilization that facilitate systemic improvements in clinical markers of metabolic control, culminating in fewer secondary health conditions and enhanced health-related quality of life.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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, pregnancy, metformin or other medications for diabetes

Treatment and study plan

Low-frequency Exercise

Other

The quadriceps/hamstrings will perform exercise via the application of low-frequency electrical stimulation.

High-frequency Exercise

Other

The quadriceps/hamstrings will perform exercise via the application of high-frequency electrical stimulation.

Primary outcomes

  1. Acute Gene Regulation: NR4A3 mRNA Expression Pre and Post-Stimulation

    Time frame: 3 hours after a single session of electrical stimulation

    Acute post-stimulation effect upon skeletal muscle nuclear receptor subfamily 4 group A member 3 (NR4A3) 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.

  2. Acute Gene Regulation: PGC1-alpha mRNA Expression Pre and Post-Stimulation

    Time frame: 3 hours after a single session of electrical stimulation

    Acute post-stimulation effect upon skeletal muscle peroxisome proliferator-activated gamma coactivator (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. Acute Gene Regulation: ABRA mRNA Expression Pre and Post-Stimulation

    Time frame: 3 hours after a single session of electrical stimulation

    Acute post-stimulation effect upon skeletal muscle actin binding Rho activating protein (ABRA) 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.

  4. Acute Gene Regulation: PDK4 mRNA Expression Pre and Post-Stimulation

    Time frame: 3 hours after a single session of electrical stimulation

    Acute post-stimulation effect upon skeletal muscle pyruvate dehydrogenase kinase 4 (PDK4) 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.

  5. Post-training Gene Regulation: MYH6 mRNA Expression Baseline and Post-Training

    Time frame: 6 months

    Pre- and post-training skeletal muscle myosin heavy chain 6 (MYH6) 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.

  6. Post-training Gene Regulation: MYL3 mRNA Expression Baseline and Post-Training

    Time frame: 6 months

    Pre- and post-training skeletal muscle myosin light chain 3 (MYL3) 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.

  7. Post-training Gene Regulation: MYH7 mRNA Expression Baseline and Post-Training

    Time frame: 6 months

    Pre- and post-training skeletal muscle myosin heavy chain 7 (MYH7) 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.

  8. Post-training Gene Regulation: ACTN3 mRNA Expression Baseline and Post-Training

    Time frame: 6 months

    Pre- and post-training skeletal muscle actin 3 (ACTN3) 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.

  9. Post-training Metabolism: Fasting Insulin

    Time frame: 6 months

    Pre- and post-training fasting insulin, measured via venipuncture and standard laboratory assays

  10. Post-training Metabolism: Fasting Glucose

    Time frame: 6 months

    Pre- and post-training fasting glucose, measured via venipuncture and standard laboratory assays

  11. Post-training Metabolism: Fasting Glucose-insulin Ratio

    Time frame: 6 months

    Pre- and post-training ratio of fasting glucose to fasting insulin, measured via venipuncture and standard laboratory assays

  12. Post-training Metabolism: Fasting Hemoglobin A1c (HBA1c)

    Time frame: 6 months

    Pre- and post-training fasting Hemoglobin A1C (HbA1c), measured via venipuncture and standard laboratory assays

  13. Post-training Metabolism: C-reactive Protein (CRP)

    Time frame: 6 months

    Pre- and post-training C-reactive protein (CRP), measured via venipuncture and standard laboratory assays

  14. Pre-training Subject-report Measures: PROMIS Physical Health

    Time frame: Baseline

    Pre-training Patient Reported Outcomes Measurement Information Systems (PROMIS) Global Health - Physical health T-score

    Theoretical minimum = 16.2, Theoretical maximum = 67.7, higher scores signify more of the construct being measured (eg. physical health). US population mean = 50, SD = 10.

  15. Pre-training Subject Report Measures: PROMIS Mental Health

    Time frame: Baseline

    Pre-training Patient Reported Outcomes Measurement Information Systems (PROMIS) Global Health - Mental health T-score

    Theoretical minimum = 21.2, Theoretical maximum = 67.6, higher scores signify more of the construct being measured (eg. mental health). US population mean = 50, SD = 10.

  16. Post-training Subject-report Measures: PROMIS Physical Health

    Time frame: 6 months

    Pre- and post-training Patient Reported Outcomes Measurement Information Systems (PROMIS) Global Health - Physical health T-score

    Theoretical minimum = 16.2, Theoretical maximum = 67.7, higher scores signify more of the construct being measured (eg. physical health). US population mean = 50, SD = 10.

  17. Post-training Subject-report Measures: PROMIS Mental Health

    Time frame: 6 months

    Pre- and post-training Patient Reported Outcomes Measurement Information Systems (PROMIS) Global Health - Mental health T-score

    Theoretical minimum = 21.2, Theoretical maximum = 67.6, higher scores signify more of the construct being measured (eg. mental health). US population mean = 50, SD = 10.

Sponsors and collaborators

Lead sponsor

Richard K Shields

Other

Collaborators

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Registry information

Important dates

Study start
2015
Primary completion
2022
Study completion
2022
First posted
May 3, 2017
Registry last updated
Feb 16, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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