Spinal Cord Injuries
Conditions
Keywords
Quadriceps Muscle, RNA, Messenger, Hypertrophy, Electric Stimulation Therapy
Brief summary
The loss of muscle contraction (paralysis) removes an important stimulus for maintenance of overall health for individuals with complete spinal cord injury (SCI). Increased protein catabolism (atrophy) limits important stresses to the skeletal system. Bone loss doubles the risk of fracture and contributes to increased mortality in Veterans with SCI. Metabolic syndrome and diabetes lead to heart disease in Veterans with SCI at higher rates than the general population. Exercise methods to sustain muscle tissue, bone density, and metabolic stability after SCI are lacking scientific justification. If left unchecked, the secondary complications of SCI can be health limiting or even life threatening to Veterans with paralysis. The importance of maintaining the health of the musculoskeletal system after SCI has never been greater as a cure for paralysis may become a reality. Contemporary rehabilitation interventions lack the ability to functionally load muscle tissue, quantify the dose of load, stress the cardiovascular system, monitor the overall stresses during daily exercise training, or offer portability to improve compliance with the exercise. The long-term goal of this project is to establish the optimal dose of muscle and bone stress during functional exercise in order to improve the health of Veterans with complete paralysis. The practical outcome of this research is to offer a form of activity that is feasible, portable, and grounded in sound scientific principles. The scientific goal is to understand whether the dose of force generated in paralyzed muscle via evoked contractions is critical to muscle atrophy/hypertrophy molecular pathways, physiologic performance, and insulin sensitivity. The investigators will administer various doses of muscle force by manipulating the frequency of electrical stimulation while keeping stimulation current (i.e. muscle fiber recruitment) constant. Interestingly, no previous study has examined the dose of muscle force necessary to trigger adaptations in protein synthesis/degradation pathways. The investigators wish to discover the most effective method to maintain the molecular and physiologic properties of paralyzed muscle. The investigators believe such a method will be in urgent demand as a co-intervention with pharmaceutical strategies in post-SCI rehabilitation.
Detailed description
Central Hypothesis: The investigators hypothesize that high muscle force induced via a novel, portable, active standing intervention will increase muscle force properties, alter gene expression for atrophy and fiber type pathways, and improve systemic insulin sensitivity in Veterans with complete paralysis. Aim 1: To determine the training effects of 3 tiers of quadriceps muscle force on muscle physiological properties in Veterans with chronic paralysis from SCI. Aim 2: To determine the training effects of 3 tiers of quadriceps muscle forces on muscle mRNA for genes associated with atrophy and muscle fiber type in Veterans with complete paralysis. Aim 3: To determine the training effects of 2 tiers of compressive load induced by quadriceps muscle forces on insulin sensitivity and markers of inflammation in Veterans with SCI.
Interventions
BEHAVIORALLow-force muscle stimulation
Electrical stimulation of paralyzed muscle in seated or standing to evoke non-summated, low-force contractions, using either a lab-based system or a portable system for up to 1 year.
BEHAVIORALHigh-force muscle stimulation
Electrical stimulation of paralyzed muscle in seated or standing to evoke summated, high-force contractions, using either a lab-based system or a portable system for up to 1 year.
BEHAVIORALSequential low-force and high-force muscle stimulation
Electrical stimulation of paralyzed muscle in seated or standing to evoke non-summated, low-force contractions, followed by: 1) a 1-month washout period, then; 2) electrical stimulation to evoke summated, high-force contractions.
Sponsors
University of Iowa
VA Office of Research and Development
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Inclusion criteria for all subjects will be upper motor neuron lesions between the 10th thoracic and the 7th cervical spinal levels. The completeness of the injury will be verified by somatosensory evoked potentials.
Exclusion criteria
* Subjects will be excluded if they have pressure ulcers * chronic infection * lower extremity muscle contractures * deep vein thrombosis * recent limb fractures * muscle metabolic disorders * any comorbid disease known to affect bone metabolism (such as parathyroid dysfunction) * or if they are pregnant or plan to become pregnant. * Subjects with distal femur trabecular bone mineral density less than 50 mg/cm3 will be excluded from participation in quadriceps electrical stimulation training
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HF Muscle Force | up to 1 year | Muscle force evoked during high-force muscle stimulation |
| LF Muscle Force | up to 1 year | Muscle force evoked during low-force muscle stimulation |
| Skeletal Muscle Gene Regulation: MSTN | up to 1 year | Messenger ribonucleic acid (mRNA) expression fold-change for myostatin (MSTN). Fold change: post-intervention expression / pre-intervention expression. Values greater than 1.0 indicate up-regulation. Values less than 1.0 indicate down-regulation. |
| Skeletal Muscle Gene Expression: PPARGC1A | up to 1 year | Messenger ribonucleic acid (mRNA) expression fold-change for peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PPARGC1A). Fold change: post-intervention expression / pre-intervention expression. Values greater than 1.0 indicate up-regulation. Values less than 1.0 indicate down-regulation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: High-force Muscle Stimulation High-force muscle stimulation | 12 |
| Arm 2: Low-force Muscle Stimulation Low-force muscle stimulation | 9 |
| Arm 3: Sequential Low-force and High-force Muscle Stimulation Sequential low-force and high-force muscle stimulation | 12 |
| Total | 33 |
Baseline characteristics
| Characteristic | Arm 1: High-force Muscle Stimulation | Arm 2: Low-force Muscle Stimulation | Arm 3: Sequential Low-force and High-force Muscle Stimulation | Total |
|---|---|---|---|---|
| Age, Continuous | 29.33 years STANDARD_DEVIATION 7.45 | 36.0 years STANDARD_DEVIATION 32.3 | 32.3 years STANDARD_DEVIATION 9.1 | 32.2 years STANDARD_DEVIATION 10.3 |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Male | 9 Participants | 6 Participants | 10 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 0 / 9 | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 9 | 0 / 12 |
Outcome results
Primary
HF Muscle Force
Muscle force evoked during high-force muscle stimulation
Time frame: up to 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: High-force Muscle Stimulation | HF Muscle Force | 23.9 Newtons (N) | Standard Deviation 5.9 |
| Arm 3: Sequential Low-force and High-force Muscle Stimulation | HF Muscle Force | 30.9 Newtons (N) | Standard Deviation 5.5 |
Primary
LF Muscle Force
Muscle force evoked during low-force muscle stimulation
Time frame: up to 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 2: Low-force Muscle Stimulation | LF Muscle Force | 26.72 N (newtons) | Standard Deviation 19.03 |
| Arm 3: Sequential Low-force and High-force Muscle Stimulation | LF Muscle Force | 27.58 N (newtons) | Standard Deviation 4.41 |
Primary
Skeletal Muscle Gene Expression: PPARGC1A
Messenger ribonucleic acid (mRNA) expression fold-change for peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PPARGC1A). Fold change: post-intervention expression / pre-intervention expression. Values greater than 1.0 indicate up-regulation. Values less than 1.0 indicate down-regulation.
Time frame: up to 1 year
Population: Only a subset of Arm 1 and Arm 3 participants underwent biopsy: we achieved statistical power with these subsets and further biopsies were not warranted.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: High-force Muscle Stimulation | Skeletal Muscle Gene Expression: PPARGC1A | 5.46 fold-change | Standard Deviation 0.64 |
| Arm 3: Sequential Low-force and High-force Muscle Stimulation | Skeletal Muscle Gene Expression: PPARGC1A | 4.97 fold-change | Standard Deviation 3.5 |
Primary
Skeletal Muscle Gene Regulation: MSTN
Messenger ribonucleic acid (mRNA) expression fold-change for myostatin (MSTN). Fold change: post-intervention expression / pre-intervention expression. Values greater than 1.0 indicate up-regulation. Values less than 1.0 indicate down-regulation.
Time frame: up to 1 year
Population: Only a subset of Arm 1 and Arm 3 participants underwent biopsy: we achieved statistical power with these subsets and further biopsies were not warranted.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: High-force Muscle Stimulation | Skeletal Muscle Gene Regulation: MSTN | .56 fold-change | Standard Deviation 0.06 |
| Arm 3: Sequential Low-force and High-force Muscle Stimulation | Skeletal Muscle Gene Regulation: MSTN | .67 fold-change | Standard Deviation 0.4 |