Musculoskeletal Plasticity After Spinal Cord Injury

NCT02622295 | Completed Results

• 2 other identifiers: 200412709R01HD084645
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 1

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.

Conditions

Spinal Cord Injuries

Keywords

metabolism; glucose; osteoporosis; secondary health conditions; quality of life; standing; electrical stimulation; diabetes; insulin; skeletal muscle

Outcome Measures

Primary Outcomes (12)

• 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.

  3 hours after a single session of electrical stimulation

• 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.

  3 hours after a single session of electrical stimulation

• 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.

  3 hours after a single session of electrical stimulation

• 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.

  3 hours after a single session of electrical stimulation

• 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.

  up to 3 years

• 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.

  up to 3 years

• 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.

  up to 3 years

• 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.

  up to 3 years

• Post-training Metabolism: Fasting Glucose

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

  up to 3 years

• Post-training Metabolism: Fasting Insulin

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

  up to 3 years

• 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.

  up to 3 years

• Post-training Bone Turnover: Osteocalcin

  Pre- and post-training serum osteocalcin, measured via venipuncture and enzyme-linked immunosorbent assay

  up to 3 years

Secondary Outcomes (1)

• Post-training Subject-report Measures: EQ-5D

  up to 3 years

Study Arms (2)

Acute gene regulation

EXPERIMENTAL

Adaptations in gene regulation in response to single-session electrically induced exercise

Behavioral: Single-session electrically induced exercise

Training Study

EXPERIMENTAL

Adaptations in gene regulation, metabolic markers, and subject-report metrics in response to up to 3 years of electrically induced exercise

Behavioral: Electrically-induced exercise training

Interventions

Single-session electrically induced exercise BEHAVIORAL

A single session of electrically induced exercise to the quadriceps and hamstring muscle groups of people with paralysis.

Acute gene regulation

Electrically-induced exercise training BEHAVIORAL

Multiple sessions of electrically induced exercise to the quadriceps and hamstring muscle groups for up to 3 years in people with paralysis.

Training Study

Eligibility Criteria

• Age: 21 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Motor complete SCI (AIS A-B)

You may not qualify if:

• Pressure ulcers
• Chronic infection
• Lower extremity muscle contractures
• Deep vein thrombosis
• Bleeding disorder
• Recent limb fractures
• Any comorbid disease known to affect bone metabolism (such as parathyroid dysfunction)
• Pregnancy
• Anti-osteoporosis medications
• Vitamin D supplements
• Metformin or other medications for diabetes.

Sponsors & Collaborators

• Richard K Shields: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Related Publications (28)

• Dudley-Javoroski S, Saha PK, Liang G, Li C, Gao Z, Shields RK. High dose compressive loads attenuate bone mineral loss in humans with spinal cord injury. Osteoporos Int. 2012 Sep;23(9):2335-46. doi: 10.1007/s00198-011-1879-4. Epub 2011 Dec 21.

  PMID: 22187008 BACKGROUND

• Dudley-Javoroski S, Shields RK. Dose estimation and surveillance of mechanical loading interventions for bone loss after spinal cord injury. Phys Ther. 2008 Mar;88(3):387-96. doi: 10.2522/ptj.20070224. Epub 2008 Jan 17.

  PMID: 18202080 BACKGROUND

• 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.

  PMID: 23809588 BACKGROUND

• 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.

  PMID: 18436697 BACKGROUND

• Dudley-Javoroski S, Shields RK. Assessment of physical function and secondary complications after complete spinal cord injury. Disabil Rehabil. 2006 Jan 30;28(2):103-10. doi: 10.1080/09638280500163828.

  PMID: 16393840 BACKGROUND

• Adams CM, Suneja M, Dudley-Javoroski S, Shields RK. Altered mRNA expression after long-term soleus electrical stimulation training in humans with paralysis. Muscle Nerve. 2011 Jan;43(1):65-75. doi: 10.1002/mus.21831.

  PMID: 21171097 BACKGROUND

• Frey Law LA, Shields RK. Femoral loads during passive, active, and active-resistive stance after spinal cord injury: a mathematical model. Clin Biomech (Bristol). 2004 Mar;19(3):313-21. doi: 10.1016/j.clinbiomech.2003.12.005.

  PMID: 15003348 BACKGROUND

• Kunkel SD, Suneja M, Ebert SM, Bongers KS, Fox DK, Malmberg SE, Alipour F, Shields RK, Adams CM. mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Cell Metab. 2011 Jun 8;13(6):627-38. doi: 10.1016/j.cmet.2011.03.020.

  PMID: 21641545 BACKGROUND

• McHenry CL, Wu J, Shields RK. Potential regenerative rehabilitation technology: implications of mechanical stimuli to tissue health. BMC Res Notes. 2014 Jun 3;7:334. doi: 10.1186/1756-0500-7-334.

  PMID: 24894666 BACKGROUND

• McHenry CL, Shields RK. A biomechanical analysis of exercise in standing, supine, and seated positions: Implications for individuals with spinal cord injury. J Spinal Cord Med. 2012 May;35(3):140-7. doi: 10.1179/2045772312Y.0000000011.

  PMID: 22507023 BACKGROUND

• 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.

  PMID: 25531450 BACKGROUND

• 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.

  PMID: 24744911 BACKGROUND

• Shields RK, Dudley-Javoroski S. Monitoring standing wheelchair use after spinal cord injury: a case report. Disabil Rehabil. 2005 Feb 4;27(3):142-6. doi: 10.1080/09638280400009337.

  PMID: 15823996 BACKGROUND

• 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.

  PMID: 25635001 BACKGROUND

• Zhorne R, Dudley-Javoroski S, Shields RK. Skeletal muscle activity and CNS neuro-plasticity. Neural Regen Res. 2016 Jan;11(1):69-70. doi: 10.4103/1673-5374.169623. No abstract available.

  PMID: 26981083 BACKGROUND

• 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.

  PMID: 27486743 BACKGROUND

• Shields RK. Turning Over the Hourglass. Phys Ther. 2017 Oct 1;97(10):949-963. doi: 10.1093/ptj/pzx072.

  PMID: 29029555 BACKGROUND

• Woelfel JR, Kimball AL, Yen CL, Shields RK. Low-Force Muscle Activity Regulates Energy Expenditure after Spinal Cord Injury. Med Sci Sports Exerc. 2017 May;49(5):870-878. doi: 10.1249/MSS.0000000000001187.

  PMID: 28009786 BACKGROUND

• Yen CL, McHenry CL, Petrie MA, Dudley-Javoroski S, Shields RK. Vibration training after chronic spinal cord injury: Evidence for persistent segmental plasticity. Neurosci Lett. 2017 Apr 24;647:129-132. doi: 10.1016/j.neulet.2017.03.019. Epub 2017 Mar 16.

  PMID: 28315725 BACKGROUND

• 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.

  PMID: 29225972 BACKGROUND

• 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.

  PMID: 30388254 BACKGROUND

• 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.

  PMID: 29923814 BACKGROUND

• 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.

  PMID: 31914347 BACKGROUND

• 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.

  PMID: 31869286 BACKGROUND

• 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.

  PMID: 30943119 BACKGROUND

• Shields RK. Precision Rehabilitation: How Lifelong Healthy Behaviors Modulate Biology, Determine Health, and Affect Populations. Phys Ther. 2022 Jan 1;102(1):pzab248. doi: 10.1093/ptj/pzab248. No abstract available.

  PMID: 34718793 BACKGROUND

• 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.

  PMID: 34718813 BACKGROUND

• 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.

  PMID: 34718779 BACKGROUND

MeSH Terms

Conditions

Spinal Cord Injuries; Osteoporosis; Diabetes Mellitus; Insulin Resistance

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Trauma, Nervous System; Wounds and Injuries; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Glucose Metabolism Disorders; Endocrine System Diseases; Hyperinsulinism

Results Point of Contact

• Title: Dr. Richard K. Shields
• Organization: University of Iowa Department of Physical Therapy and Rehabilitation Science

richard-shields@uiowa.edu

319-335-9791

Study Officials

• Richard K Shields, PhD, PT

  University of Iowa

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: December 2, 2015
• First Posted: December 4, 2015
• Study Start: May 1, 2015
• Primary Completion: November 18, 2021
• Study Completion: November 18, 2021
• Last Updated: November 4, 2022
• Results First Posted: November 4, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)