Clinical trial NCT03139344: Long Duration Activity and Metabolic Control After Spinal Cord Injury
Official title: Long Duration Activity and Metabolic Control After Spinal Cord Injury
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Spinal Cord Injuries
Keywords: metabolism
exercise
glucose
secondary health conditions
quality of life
Lead sponsor: University of Iowa
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2017-05-03
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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

Primary outcomes:
measure: Acute Gene Regulation: NR4A3 mRNA Expression Pre and Post-Stimulation
timeFrame: 3 hours after a single session of electrical stimulation
measure: Acute Gene Regulation: PGC1-alpha mRNA Expression Pre and Post-Stimulation
timeFrame: 3 hours after a single session of electrical stimulation
measure: Acute Gene Regulation: ABRA mRNA Expression Pre and Post-Stimulation
timeFrame: 3 hours after a single session of electrical stimulation
measure: Acute Gene Regulation: PDK4 mRNA Expression Pre and Post-Stimulation
timeFrame: 3 hours after a single session of electrical stimulation
measure: Post-training Gene Regulation: MYH6 mRNA Expression Baseline and Post-Training
timeFrame: 6 months
measure: Post-training Gene Regulation: MYL3 mRNA Expression Baseline and Post-Training
timeFrame: 6 months
measure: Post-training Gene Regulation: MYH7 mRNA Expression Baseline and Post-Training
timeFrame: 6 months
measure: Post-training Gene Regulation: ACTN3 mRNA Expression Baseline and Post-Training
timeFrame: 6 months
measure: Post-training Metabolism: Fasting Insulin
timeFrame: 6 months
measure: Post-training Metabolism: Fasting Glucose
timeFrame: 6 months
measure: Post-training Metabolism: Fasting Glucose-insulin Ratio
timeFrame: 6 months
measure: Post-training Metabolism: Fasting Hemoglobin A1c (HBA1c)
timeFrame: 6 months
measure: Post-training Metabolism: C-reactive Protein (CRP)
timeFrame: 6 months
measure: Pre-training Subject-report Measures: PROMIS Physical Health
timeFrame: Baseline
measure: Pre-training Subject Report Measures: PROMIS Mental Health
timeFrame: Baseline
measure: Post-training Subject-report Measures: PROMIS Physical Health
timeFrame: 6 months
measure: Post-training Subject-report Measures: PROMIS Mental Health
timeFrame: 6 months
Secondary outcomes:
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
Study officials:
affiliation: University of Iowa
name: Richard K Shields, PhD, PT
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Dudley-Javoroski S, Shields RK. Active-resisted stance modulates regional bone mineral density in humans with spinal cord injury. J Spinal Cord Med. 2013 May;36(3):191-9. doi: 10.1179/2045772313Y.0000000092.
citation: Dudley-Javoroski S, Littmann AE, Iguchi M, Shields RK. Doublet stimulation protocol to minimize musculoskeletal stress during paralyzed quadriceps muscle testing. J Appl Physiol (1985). 2008 Jun;104(6):1574-82. doi: 10.1152/japplphysiol.00892.2007. Epub 2008 Apr 24.
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citation: Oza PD, Dudley-Javoroski S, Shields RK. Modulation of H-Reflex Depression with Paired-Pulse Stimulation in Healthy Active Humans. Rehabil Res Pract. 2017;2017:5107097. doi: 10.1155/2017/5107097. Epub 2017 Oct 31.
citation: Woelfel JR, Dudley-Javoroski S, Shields RK. Precision Physical Therapy: Exercise, the Epigenome, and the Heritability of Environmentally Modified Traits. Phys Ther. 2018 Nov 1;98(11):946-952. doi: 10.1093/ptj/pzy092.
citation: Cole KR, Dudley-Javoroski S, Shields RK. Hybrid stimulation enhances torque as a function of muscle fusion in human paralyzed and non-paralyzed skeletal muscle. J Spinal Cord Med. 2019 Sep;42(5):562-570. doi: 10.1080/10790268.2018.1485312. Epub 2018 Jun 20.
citation: Dudley-Javoroski S, Lee J, Shields RK. Cognitive function, quality of life, and aging: relationships in individuals with and without spinal cord injury. Physiother Theory Pract. 2022 Jan;38(1):36-45. doi: 10.1080/09593985.2020.1712755. Epub 2020 Jan 8.
citation: Petrie MA, Sharma A, Taylor EB, Suneja M, Shields RK. Impact of short- and long-term electrically induced muscle exercise on gene signaling pathways, gene expression, and PGC1a methylation in men with spinal cord injury. Physiol Genomics. 2020 Feb 1;52(2):71-80. doi: 10.1152/physiolgenomics.00064.2019. Epub 2019 Dec 23.
citation: Lee J, Dudley-Javoroski S, Shields RK. Motor demands of cognitive testing may artificially reduce executive function scores in individuals with spinal cord injury. J Spinal Cord Med. 2021 Mar;44(2):253-261. doi: 10.1080/10790268.2019.1597482. Epub 2019 Apr 3.
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citation: Shields RK, Dudley-Javoroski S. Epigenetics and the International Classification of Functioning, Disability and Health Model: Bridging Nature, Nurture, and Patient-Centered Population Health. Phys Ther. 2022 Jan 1;102(1):pzab247. doi: 10.1093/ptj/pzab247.
citation: Petrie MA, Taylor EB, Suneja M, Shields RK. Genomic and Epigenomic Evaluation of Electrically Induced Exercise in People With Spinal Cord Injury: Application to Precision Rehabilitation. Phys Ther. 2022 Jan 1;102(1):pzab243. doi: 10.1093/ptj/pzab243.