Characterization of the Changes in the Signalling Pathways During Spinal Cord Injury-induced Skeletal Muscle Atrophy

Study Overview
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Brief Summary
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Atrogin-1 and muscle RING finger-1 are skeletal muscle specific genes, with ubiquitin ligase activities, that are upregulated during muscle atrophy in mice. The Akt/GSK3 and Akt/mTOR pathways are involved in muscle hypertrophy in mice. Recent studies by the investigators team and others have demonstrated the implication of these signalling pathways in the control of muscle mass in humans. However no study has yet investigated the involvement of these systems in the early stages of spinal cord injury induced human skeletal muscle atrophy. The investigators propose to investigate the level of expression of the different components of the ubiquitin-proteasome system together with the level of expression and activity of the Akt/mTOR and Akt/GSK3 signalling pathways after SCI in humans during the first months following the injury. A second aim of this project is to assess if a novel apparatus of electrical stimulation which generate movements by closed-loop electrical muscle stimulation may improve strength and muscle mass in these patients. The patients will be recruited jointly at the Clinique Romande de Réadaptation (CRR) in Sion and the Swiss paraplegic centre in Nottwil. They will be randomly divided into two groups, a first group of patients will undergo a conventional treatment of rehabilitation while a second set of patients will be treated using a brand new system of electro-stimulation called MotionMaker TM. Biopsies will be obtained in the first weeks after admission; two other biopsies will be taken respectively 3 and 6 months post-lesion. Our results will provide an increased understanding of the molecular mechanisms contributing to skeletal muscle atrophy during the early stages following SCI and a characterization of the impact of endurance training in the no more voluntary innervated muscle. Moreover this study will also investigate the potential improvement in the rehabilitation process by using a new system of electro-stimulation.

Detailed Description
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Measures: For each group, the muscle biopsies will be divided into 3 samples which will be used for a) real-time PCR to quantify the gene expression of the different components of the ubiquitin-proteasome system (Atrogin-1, MuRF1, Nedd4, UBB and Psma) b) Western blotting, using anti-phospho-site specific antibodies to quantify the activities of the Akt/GSK3 and Akt/mTOR pathways and of their downstream regulators of protein synthesis, eIF2B, p70S6K and PHAS-1/4E-BP1and c) fiber type analysis to quantify the variation in MHC expression.

Official Title
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Characterization of the Changes in the Signalling Pathways During Spinal Cord Injury-induced Skeletal Muscle Atrophy

Conditions
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Spinal Cord Injuries, Muscle Atrophy

Intervention / Treatment
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* Procedure: Motionmaker


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: acute, motor complete SCI lesion level C5-T12 Exclusion Criteria: diabetes type I pregnancy oral anti-coagulation osteosyntheses of the femur hepatitis B,C or D HIV

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MotionMaker Training<br>Device description: MotionMaker™ is a stationary robotic system for the active mobilization of the lower limbs. With its proprietary 'Closed-Loop' technology, it is a novel and exciting development that offers a truly interactive patient training system Training 3 times a week with MotionMaker device together with conventional treatment | Procedure: Motionmaker<br>* 3 times per week, FES Training on the Motionmaker device, for 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Signaling pathways in human muscles after spinal cord injury | Molecular adaptations will be assessed from biopsies of the Vastus Lateralis muscle. Quantitative PCR method will allow to measure mRNA expression levels while proteins quantification will be performed by Western Blot analyses. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle strength | Improvement of muscle strenght | 6 months | 
| Spacity | Reduction of spasticity | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Functional Electrical Stimulation, Signalling Pathways