Spinal Cord Injury
Conditions
Keywords
Electric Stimulation, Spinal Cord Injuries, Muscle Denervation, carbohydrate metabolism, Lipids metabolism, Basal Metabolic Rate, Muscle Proteins, Mitochondria, Muscle, RNA, Rehabilitation
Brief summary
Denervation following spinal cord injury (SCI) limits beneficial application of neuromuscular electrical stimulation (NMES). SCI with denervation results in extensive muscle atrophy that is accompanied with several cardio-metabolic health risks. The current proposal provides a novel intervention by examining the effects of long pulse width stimulation (LPWS) and testosterone replacement therapy (TRT) on restoring muscle size and leg lean mass after denervation in persons with SCI. This intervention will be rewarding for Veterans and Civilians with SCI who do not benefit from exercising their lower extremity muscles because denervation has limited the response to standard surface NMES. The investigators will study the biochemical mechanisms that contribute to changes in muscle size following this novel training. Combing both pharmaceutical and physical-therapeutic interventions will optimize restoration of muscle size after SCI.
Detailed description
The long-term goal is to develop a rehabilitation strategy to mitigate the deleterious changes in muscle size and lower leg lean mass in persons with denervation following spinal cord injury (SCI). Currently, there is no available rehabilitation intervention following lower motor neuron (LMN) denervation. More than 46,000 Veterans are affected with SCI and may experience profound skeletal muscle atrophy and loss of lean mass and about 20-25% experience LMN denervation. Skeletal muscle cross-sectional area is 6 times smaller following LMN denervation compared to the innervated muscles. Denervation atrophy may be accompanied by several SCI health-related consequences. Twelve weeks of twice weekly of surface neuromuscular electrical stimulation (NMES) resistance training (RT) can elicit more than a 35% increase in skeletal muscle size, decreased ectopic adipose tissue accumulation, increased insulin sensitivity after SCI. Moreover, the applicant's CDA-2 preliminary findings showed that 16 weeks of NMES-RT and testosterone replacement therapy (TRT) increased leg lean mass by 1.5 kg with no changes in the TRT group only. This was accompanied by an increase in the basal metabolic rate (BMR) of 218 kcal/day in the NMES-RT+TRT with no changes in the TRT group. During the course of recruitment for the study, 20% of individuals with SCI were excluded and could not benefit from exercising their lower extremity muscles, presumably because of LMN denervation. Long pulse width stimulation (LPWS; 120-150 ms) has the potential to stimulate denervated muscles and to restore muscle size in people with SCI. The previous paradigm has focused on daily activation of the denervated muscles without applying progressive loading similar to RT. Daily training is not a clinically feasible approach in persons with SCI. Moreover, previous trials did not focus on enhancing the neuromuscular homeostasis by promoting the increase in lean mass independent of LMN denervation. Testosterone replacement therapy (TRT) has been shown to increase lean mass and basal metabolic rate in hypogonadal men with SCI. The investigators will determine if TRT+LPWS would increase skeletal muscle size, leg lean mass and improve overall metabolic health in SCI persons with LMN denervation. The investigators hypothesize that the one year TRT+LPWS protocol will upregulate protein synthesis pathways, down-regulate protein degradation pathways and increase overall mitochondrial health. Three specific aims will address these hypotheses. Aim 1 will assess the effects of TRT+LPWS compared to TRT+ standard neuromuscular electrical stimulation (NMES; as a control group) on the size of thigh skeletal muscle, intramuscular fat (IMF) and leg lean mass. Aim 2 will determine the association between the changes in skeletal muscle size, leg lean mass and the metabolic profile as determined by measuring BMR, serum lipids and carbohydrate profile. Aim 3 will investigate the cellular mechanisms responsible for evoking skeletal muscle hypertrophy following TRT+LPWS. This study is novel because it provides a feasible rehabilitation intervention by combining two approaches; which are likely to improve the quality of life in SCI persons with LMN denervation. If proven successful, the intervention will be easily translated into clinical practice for persons with SCI.
Interventions
DEVICETestosterone and LPWS
Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and long pulse width stimulation (LPWS) in persons with denervated spinal cord injury.
DRUGTestosterone and standard NMES
Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury.
Sponsors
Hunter Holmes McGuire VA Medical Center
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Participant will be masked to the type of electrical stimulation (LPWS vs. standard NMES)
Eligibility
Sex/Gender
MALE
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Traumatic motor complete SCI and level of injury of T10 and below * Only participants with lower motor neuron (LMN) denervation as determined by EMG testing * Participants must also have an absence of reflexes, denervation of both knee extensor muscles * Tolerance to LPWS paradigm * Both knee extensors will also have to be unresponsive (i.e., no observed tetanic contraction or twitches) to standard electrical stimulation procedures (stimulation frequency: 30 Hz; pulse duration:450 s and amplitude of the current:200 mA) * All participants will undergo International Standards for Neurological Classification of SCI (ISNCSCI) examination for neurological level and function and only those with American Spinal Injury Classification (AIS A and B; i.e. motor deficit below the level of injury)
Exclusion criteria
* Diagnosis of neurological injury other than SCI * Pre-existing medical conditions will be excluded (cardiovascular disease, uncontrolled type II DM and those on insulin requirements) or other concurrent medical conditions judged to be contraindicated by the site physician. * Hematocrit above 50% and severe urinary tract infection or symptoms * Those with hyper-physiological testosterone level above 800 ng/dl * Those who will fail to tolerate the LPWS paradigm * Progressive condition that would be expected to result in changing neurological status * Lower extremity fracture around the knee joint (distal femur or proximal tibia) within the last 2 years from enrollment in the study * Knee BMD \< 0.60 gm/cm2 * Total hip BMD T-scores \< -3.5 * Untreatable severe spasticity judged to be contraindicated by the site Physician * Untreated or uncontrolled hypertension (systolic blood pressure \>140 mmHg; diastolic blood pressure \>90 mmHg) * Pressure ulcer of the trunk, pelvic area, or lower extremities of grade 3 or more * Psychopathology documentation in the medical record or history that may conflict with study objectives
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Muscle Size Change | Baseline, 6 months and 12 months | Magnetic resonance imaging (MRI): The skeletal muscle area will be measured at baseline 6 months and 12 months after training (post-intervention). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Basal Metabolic Rate | Baseline, 6 months and 12 months | Using indirect canopy after overnight 10-12 hours fast. |
| Mitochondrial Complex Activities | Mitochondrial measurements were conducted over 1 year period at baseline [BL, before starting any intervention], Post-intervention 1 [ P1; 6 months after starting interventions] and Post-intervention 2 [P2-12 months after starting interventions] | Performing a simple muscle biopsy and them muscle samples will be assayed to measure mitochondrial citrate synthase and other complexes. |
Countries
United States
Participant flow
Pre-assignment details
Each participant underwent a detailed history and physical exam by a certified study medical provider to ensure eligibility. This was followed by electrodiagnosis to ensure denervation of the knee extensor muscle groups.
Participants by arm
| Arm | Count |
|---|---|
| Testosterone and LPWS Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and long pulse width stimulation (LPWS) in persons with denervated spinal cord injury.
Testosterone and LPWS: Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and long pulse width stimulation (LPWS) in persons with denervated spinal cord injury. | 6 |
| Testosterone and Standard NMES Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury.
Testosterone and standard NMES: Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury. | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Total | Testosterone and LPWS | Testosterone and Standard NMES |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 6 Participants | 6 Participants |
| Age, Continuous | 45 years STANDARD_DEVIATION 10 | 43 years STANDARD_DEVIATION 12 | 47 years STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 6 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 12 participants | 6 participants | 6 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 12 Participants | 6 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 1 / 6 | 0 / 6 |
| serious Total, serious adverse events | 2 / 6 | 0 / 6 |
Outcome results
Primary
Muscle Size Change
Magnetic resonance imaging (MRI): The skeletal muscle area will be measured at baseline 6 months and 12 months after training (post-intervention).
Time frame: Baseline, 6 months and 12 months
Population: We are reporting the results of magnetic resonance imaging analysis of the right whole thigh muscle cross-sectional area (CSA, cm\^2) and knee extensor CSA (CSA, cm\^2) at baseline, 6 months and 12 months of completion of Testosterone and LPWS or Testosterone and standard NMES.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Testosterone and LPWS | Muscle Size Change | Thigh Muscle CSA-BL (cm^2) | 47.76 Muscle CSA (cm^2) | Standard Deviation 12.76 |
| Testosterone and LPWS | Muscle Size Change | Whole Thigh Muscle CSA (cm^2) 6 months | 52.4 Muscle CSA (cm^2) | Standard Deviation 16.7 |
| Testosterone and LPWS | Muscle Size Change | Whole Thigh Muscle CSA (cm^2) 12 months | 42.87 Muscle CSA (cm^2) | Standard Deviation 22.4 |
| Testosterone and Standard NMES | Muscle Size Change | Thigh Muscle CSA-BL (cm^2) | 31.1 Muscle CSA (cm^2) | Standard Deviation 12.65 |
| Testosterone and Standard NMES | Muscle Size Change | Whole Thigh Muscle CSA (cm^2) 6 months | 36.0 Muscle CSA (cm^2) | Standard Deviation 9.96 |
| Testosterone and Standard NMES | Muscle Size Change | Whole Thigh Muscle CSA (cm^2) 12 months | 41.1 Muscle CSA (cm^2) | Standard Deviation 12.6 |
Secondary
Basal Metabolic Rate
Using indirect canopy after overnight 10-12 hours fast.
Time frame: Baseline, 6 months and 12 months
Population: The numbers in P2 or at 12 months were different because of earlier withdrawal of participants from the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Testosterone and LPWS | Basal Metabolic Rate | BMR-BL | 1634 Basal Metabolic Rate (BMR; Kcal/day) | Standard Deviation 416 |
| Testosterone and LPWS | Basal Metabolic Rate | BMR- 6 Months | 1564 Basal Metabolic Rate (BMR; Kcal/day) | Standard Deviation 428 |
| Testosterone and LPWS | Basal Metabolic Rate | BMR- 12 Months | 1385 Basal Metabolic Rate (BMR; Kcal/day) | Standard Deviation 182 |
| Testosterone and Standard NMES | Basal Metabolic Rate | BMR-BL | 1580 Basal Metabolic Rate (BMR; Kcal/day) | Standard Deviation 383 |
| Testosterone and Standard NMES | Basal Metabolic Rate | BMR- 6 Months | 1424 Basal Metabolic Rate (BMR; Kcal/day) | Standard Deviation 250 |
| Testosterone and Standard NMES | Basal Metabolic Rate | BMR- 12 Months | 1671 Basal Metabolic Rate (BMR; Kcal/day) | Standard Deviation 194 |
Secondary
Mitochondrial Complex Activities
Performing a simple muscle biopsy and them muscle samples will be assayed to measure mitochondrial citrate synthase and other complexes.
Time frame: Mitochondrial measurements were conducted over 1 year period at baseline [BL, before starting any intervention], Post-intervention 1 [ P1; 6 months after starting interventions] and Post-intervention 2 [P2-12 months after starting interventions]
Population: Three participants withdrew from Testosterone and LPWS before P2 as well as two participants withdrew from testosterone and standard NMES group before conducting P2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Testosterone and LPWS | Mitochondrial Complex Activities | Complex II-Baseline | 43 nmol/min/mg | Standard Deviation 63 |
| Testosterone and LPWS | Mitochondrial Complex Activities | Complex II-Post-intervention 1 | 47 nmol/min/mg | Standard Deviation 39 |
| Testosterone and LPWS | Mitochondrial Complex Activities | Complex II-Post-intervention 2 | 14 nmol/min/mg | Standard Deviation 0.9 |
| Testosterone and Standard NMES | Mitochondrial Complex Activities | Complex II-Baseline | 46 nmol/min/mg | Standard Deviation 45 |
| Testosterone and Standard NMES | Mitochondrial Complex Activities | Complex II-Post-intervention 1 | 36 nmol/min/mg | Standard Deviation 31 |
| Testosterone and Standard NMES | Mitochondrial Complex Activities | Complex II-Post-intervention 2 | 13 nmol/min/mg | Standard Deviation 10 |