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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
89
The quadriceps/hamstrings will perform exercise via the application of low-frequency electrical stimulation.
The quadriceps/hamstrings will perform exercise via the application of high-frequency electrical stimulation.
University of Iowa
Iowa City, Iowa, United States
Acute Gene Regulation: NR4A3 mRNA Expression Pre and Post-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.
Time frame: 3 hours after a single session of electrical stimulation
Acute Gene Regulation: PGC1-alpha mRNA Expression Pre and Post-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.
Time frame: 3 hours after a single session of electrical stimulation
Acute Gene Regulation: ABRA mRNA Expression Pre and Post-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.
Time frame: 3 hours after a single session of electrical stimulation
Acute Gene Regulation: PDK4 mRNA Expression Pre and Post-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.
Time frame: 3 hours after a single session of electrical stimulation
Post-training Gene Regulation: MYH6 mRNA Expression Baseline and Post-Training
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.
Time frame: 6 months
Post-training Gene Regulation: MYL3 mRNA Expression Baseline and Post-Training
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.
Time frame: 6 months
Post-training Gene Regulation: MYH7 mRNA Expression Baseline and Post-Training
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.
Time frame: 6 months
Post-training Gene Regulation: ACTN3 mRNA Expression Baseline and Post-Training
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.
Time frame: 6 months
Post-training Metabolism: Fasting Insulin
Pre- and post-training fasting insulin, measured via venipuncture and standard laboratory assays
Time frame: 6 months
Post-training Metabolism: Fasting Glucose
Pre- and post-training fasting glucose, measured via venipuncture and standard laboratory assays
Time frame: 6 months
Post-training Metabolism: Fasting Glucose-insulin Ratio
Pre- and post-training ratio of fasting glucose to fasting insulin, measured via venipuncture and standard laboratory assays
Time frame: 6 months
Post-training Metabolism: Fasting Hemoglobin A1c (HBA1c)
Pre- and post-training fasting Hemoglobin A1C (HbA1c), measured via venipuncture and standard laboratory assays
Time frame: 6 months
Post-training Metabolism: C-reactive Protein (CRP)
Pre- and post-training C-reactive protein (CRP), measured via venipuncture and standard laboratory assays
Time frame: 6 months
Pre-training Subject-report Measures: PROMIS Physical Health
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.
Time frame: Baseline
Pre-training Subject Report Measures: PROMIS Mental Health
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.
Time frame: Baseline
Post-training Subject-report Measures: PROMIS Physical Health
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.
Time frame: 6 months
Post-training Subject-report Measures: PROMIS Mental Health
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.
Time frame: 6 months
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