Long Duration Activity and Metabolic Control After Spinal Cord Injury
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Acute gene regulation Adaptations in gene regulation in response to single-session low-frequency exercise or high-frequency exercise. |
Other: Low-frequency Exercise
The quadriceps/hamstrings will perform exercise via the application of 1 Hz electrical stimulation.
Other: High-frequency Exercise
The quadriceps/hamstrings will perform exercise via the application of 3 Hz electrical stimulation.
|
| Experimental: Training study Adaptations in gene regulation, systemic metabolic markers, and patient-report metrics in response to training with high-frequency exercise. |
Other: High-frequency Exercise
The quadriceps/hamstrings will perform exercise via the application of 3 Hz electrical stimulation.
|
Outcome Measures
Primary Outcome Measures
- Acute gene regulation: NR4A3 [3 hours]
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
- Acute gene regulation: PGC1-alpha [3 hours]
Acute post-stimulation effect upon skeletal muscle peroxisome proliferator-activated gamma coactivator (PGC1-alpha) expression, measured via muscle biopsy and exon array analysis
- Acute gene regulation: ABRA [3 hours]
Acute post-stimulation effect upon skeletal muscle actin binding Rho activating protein (ABRA) expression, measured via muscle biopsy and exon array analysis
- Acute gene regulation: PDK4 [3 hours]
Acute post-stimulation effect upon skeletal muscle pyruvate dehydrogenase kinase 4 (PDK4) expression, measured via muscle biopsy and exon array analysis
- Post-training gene regulation: MYH6 [6 months]
Change from baseline in skeletal muscle myosin heavy chain 6 (MYH6) expression, measured via muscle biopsy and exon array analysis
- Post-training gene regulation: MYL3 [6 months]
Change from baseline in skeletal muscle myosin light chain 3 (MYL3) expression, measured via muscle biopsy and exon array analysis
- Post-training gene regulation: MYH7 [6 months]
Change from baseline in skeletal muscle myosin heavy chain 7 (MYH7) expression, measured via muscle biopsy and exon array analysis
- Post-training gene regulation: ACTN3 [6 months]
Change from baseline in skeletal muscle actin 3 (ACTN3) expression, measured via muscle biopsy and exon array analysis
- Post-training metabolism: fasting insulin [6 months]
Change from baseline in fasting insulin, measured via venipuncture and standard laboratory assays
- Post-training metabolism: fasting glucose [6 months]
Change from baseline in fasting glucose, measured via venipuncture and standard laboratory assays
- Post-training subject-report measures: PROMIS Physical health [6 months]
Change from baseline in Patient Reported Outcomes Measurement Information Systems (PROMIS) Global Health - Physical health T-score
- Post-training subject-report measures: PROMIS Mental health [6 months]
Change from baseline in Patient Reported Outcomes Measurement Information Systems (PROMIS) Global Health - Mental health T-score
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Iowa | Iowa City | Iowa | United States | 52242 |
Sponsors and Collaborators
- Richard K Shields
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
- Principal Investigator: Richard K Shields, PhD, PT, University of Iowa
Study Documents (Full-Text)
None provided.More Information
Publications
- Petrie M, Suneja M, Shields RK. Low-frequency stimulation regulates metabolic gene expression in paralyzed muscle. J Appl Physiol (1985). 2015 Mar 15;118(6):723-31. doi: 10.1152/japplphysiol.00628.2014. Epub 2015 Jan 29.
- Petrie MA, Kimball AL, McHenry CL, Suneja M, Yen CL, Sharma A, Shields RK. Distinct Skeletal Muscle Gene Regulation from Active Contraction, Passive Vibration, and Whole Body Heat Stress in Humans. PLoS One. 2016 Aug 3;11(8):e0160594. doi: 10.1371/journal.pone.0160594. eCollection 2016.
- Petrie MA, Suneja M, Faidley E, Shields RK. A minimal dose of electrically induced muscle activity regulates distinct gene signaling pathways in humans with spinal cord injury. PLoS One. 2014 Dec 22;9(12):e115791. doi: 10.1371/journal.pone.0115791. eCollection 2014.
- Petrie MA, Suneja M, Faidley E, Shields RK. Low force contractions induce fatigue consistent with muscle mRNA expression in people with spinal cord injury. Physiol Rep. 2014 Feb 25;2(2):e00248. doi: 10.1002/phy2.248. eCollection 2014 Feb 1.
- 201503732
- R01HD082109