Molecular responses in skeletal muscles following spinal cord injury and the effect of locomotor training
ABSTRACT: Spinal cord injury (SCI) is one of the most disabling health problems facing adults today. Locomotor training has been shown to induce substantial recovery in muscle size and muscle function in both transected and contusion injury animal models of SCI. The overall objective of this study is to implement genome wide expression profiling of skeletal muscle to define the molecular pathways associated with muscle remodeling after SCI and during locomotor training (TM). We profiled rat soleus of total 36 samples including controls; 3, 8 and 14 days after SCI; 8 and 14 days after SCI with locomotor treadmill training (TM).
Project description:Loading and testosterone may influence musculoskeletal recovery after spinal cord injury (SCI). Our objectives were to determine (a) the acute effects of bodyweight-supported treadmill training (TM) on hindlimb cancellous bone microstructure and muscle mass in adult rats after severe contusion SCI and (b) whether longer-term TM with adjuvant testosterone enanthate (TE) delivers musculoskeletal benefit. In Study 1, TM (40 min/day, 5 days/week, beginning 1 week postsurgery) did not prevent SCI-induced hindlimb cancellous bone loss after 3 weeks. In Study 2, TM did not attenuate SCI-induced plantar flexor muscles atrophy nor improve locomotor recovery after 4 weeks. In our main study, SCI produced extensive distal femur and proximal tibia cancellous bone deficits, a deleterious slow-to-fast fiber-type transition in soleus, lower muscle fiber cross-sectional area (fCSA), impaired muscle force production, and levator ani/bulbocavernosus (LABC) muscle atrophy after 8 weeks. TE alone (7.0 mg/week) suppressed bone resorption, attenuated cancellous bone loss, constrained the soleus fiber-type transition, and prevented LABC atrophy. In comparison, TE+TM concomitantly suppressed bone resorption and stimulated bone formation after SCI, produced near-complete cancellous bone preservation, prevented the soleus fiber-type transition, attenuated soleus fCSA atrophy, maintained soleus force production, and increased LABC mass. 75% of SCI+TE+TM animals recovered voluntary over-ground hindlimb stepping, while no SCI and only 20% of SCI+TE animals regained stepping ability. Positive associations between testosterone and locomotor function suggest that TE influenced locomotor recovery. In conclusion, short-term TM alone did not improve bone, muscle, or locomotor recovery in adult rats after severe SCI, while longer-term TE+TM provided more comprehensive musculoskeletal benefit than TE alone.
Project description:Traumatic spinal cord injury (SCI) often leads to loss of locomotor function. Neuroplasticity of spinal circuitry underlies some functional recovery and therefore represents a therapeutic target to improve locomotor function following SCI. However, the cellular and molecular mechanisms mediating neuroplasticity below the lesion level are not fully understood. The present study performed a gene expression profiling in the rat lumbar spinal cord at 1 and 3 weeks after contusive SCI at T9 compared to control rat that received sham injury (laminectomy). The below-level gene expression profiles were compared with those of animals that were subjected to treadmill locomotor training. Rat lumbar spinal cords were taken for the microarray analysis at 1 and 3 weeks after contusive spinal cord injury at the T9 level. Another group of rats received treadmill locomotor training for 3 weeks, and theirs spinal cords were harvested for the microarray. The changes in gene expression after spinal cord injury were analyzed at the two time points. The influence of treadmill locomotor training was evaluated by comparing gene expression profiles between animals with or without treadmill training.
Project description:Outcomes of training are thought to be related to the amount of training (training dose). Although various approaches to locomotor training have been used to improve walking function in persons with spinal cord injury (SCI), little is known about the relationship between dose of locomotor training and walking outcomes. This secondary analysis aimed to identify the relationship between training dose and improvement in walking distance and speed associated with locomotor training in participants with chronic motor-incomplete spinal cord injury (MISCI). We compared the dose-response relationships associated with each of four different locomotor training approaches. Participants were randomized to either: treadmill-based training with manual assistance (TM?=?17), treadmill-based training with stimulation (TS?=?18), overground training with stimulation (OG?=?15), and treadmill-based training with locomotor robotic device assistance (LR?=?14). Subjects trained 5 days/week for 12 weeks, with a target of 60 training sessions. The distance-dose and time-dose were calculated based on the total distance and total time, respectively, participants engaged in walking over all sessions combined. Primary outcome measures included walking distance (traversed in 2?min) and walking speed (over 10?m). Only OG training showed a good correlation between distance-dose and change in walking distance and speed walked over ground (r?=?0.61, p?=?0.02; r?=?0.62, p?=?0.01). None of the treadmill-based training approaches were associated with significant correlations between training dose and improvement of functional walking outcome. The findings suggest that greater distance achieved over the course of OG training is associated with better walking outcomes in the studied population. Further investigation to identify the essential elements that determine outcomes would be valuable for guiding rehabilitation.
Project description:For rehabilitation strategies to be effective, training should be based on principles of motor learning, such as feedback-error learning, that facilitate adaptive processes in the nervous system by inducing errors and recalibration of sensory and motor systems. This case report suggests that locomotor resistance training can enhance somatosensory and corticospinal excitability and modulate resting-state brain functional connectivity in a patient with motor-incomplete spinal cord injury (SCI).The short-term cortical plasticity of a 31-year-old man who had sustained an incomplete SCI 9.5 years previously was explored in response to body-weight-supported treadmill training with velocity-dependent resistance applied with a robotic gait orthosis. The following neurophysiological and neuroimaging measures were recorded before and after training. Sensory evoked potentials were elicited by electrical stimulation of the tibial nerve and recorded from the somatosensory cortex. Motor evoked potentials were generated with transcranial magnetic stimulation applied over the tibialis anterior muscle representation in the primary motor cortex. Resting-state functional magnetic resonance imaging was performed to evaluate short-term changes in patterns of brain activity associated with locomotor training.Somatosensory excitability and corticospinal excitability were observed to increase after locomotor resistance training. Motor evoked potentials increased (particularly at higher stimulation intensities), and seed-based resting-state functional magnetic resonance imaging analyses revealed increased functional connectivity strength in the motor cortex associated with the less affected side after training.The observations suggest evidence of short-term cortical plasticity in 3 complementary neurophysiological measures after one session of locomotor resistance training. Future investigation in a sample of people with incomplete SCI will enhance the understanding of potential neural mechanisms underlying the behavioral response to locomotor resistance training.
Project description:BACKGROUND:We know little about the budget impact of integrating robotic exoskeleton over-ground training into therapy services for locomotor training. The purpose of this study was to estimate the budget impact of adding robotic exoskeleton over-ground training to existing locomotor training strategies in the rehabilitation of people with spinal cord injury. METHODS:A Budget Impact Analysis (BIA) was conducted using data provided by four Spinal Cord Injury (SCI) Model Systems rehabilitation hospitals. Hospitals provided estimates of therapy utilization and costs about people with spinal cord injury who participated in locomotor training in the calendar year 2017. Interventions were standard of care walking training including body-weight supported treadmill training, overground training, stationary robotic systems (i.e., treadmill-based robotic gait orthoses), and overground robotic exoskeleton training. The main outcome measures included device costs, training costs for personnel to use the device, human capital costs of locomotor training, device demand, and the number of training sessions per person with SCI. RESULTS:Robotic exoskeletons for over-ground training decreased hospital costs associated with delivering locomotor training in the base case analysis. This analysis assumed no difference in intervention effectiveness across locomotor training strategies. Providing robotic exoskeleton overground training for 10% of locomotor training sessions over the course of the year (range 226-397 sessions) results in decreased annual locomotor training costs (i.e., net savings) between $1114 to $4784 per annum. The base case shows small savings that are sensitive to parameters of the BIA model which were tested in one-way sensitivity analyses, scenarios analyses, and probability sensitivity analyses. The base case scenario was more sensitive to clinical utilization parameters (e.g., how often devices sit idle and the substitution of high cost training) than device-specific parameters (e.g., robotic exoskeleton device cost or device life). Probabilistic sensitivity analysis simultaneously considered human capital cost, device cost, and locomotor device substitution. With probabilistic sensitivity analysis, the introduction of a robotic exoskeleton only remained cost saving for one facility. CONCLUSIONS:Providing robotic exoskeleton for over-ground training was associated with lower costs for the locomotor training of people with SCI in the base case analyses. The analysis was sensitive to parameter assumptions.
Project description:The genetic and molecular events associated with changes in muscle mass and function after SCI and after the implementation of candidate therapeutic approaches are still not completely known. The overall objective of this study was to identify key molecular pathways activated with muscle remodeling after SCI and locomotor training. We implemented treadmill training in a well-characterized rat model of moderate SCI and performed genome wide expression profiling on soleus muscles at multiple time points: 3, 8, and 14 days after SCI. We found that the activity of the protein ubiquitination and mitochondrial function related pathways was altered with SCI and corrected with treadmill training. The BMP pathway was differentially activated with early treadmill training as shown by Ingenuity Pathway Analysis. The expression of several muscle mass regulators was modulated by treadmill training, including Fst, Jun, Bmpr2, Actr2b, and Smad3. In addition, key players in fatty acids metabolism (Lpl and Fabp3) responded to both SCI induced inactivity and reloading with training. The decrease in Smad3 and Fst early after the initiation of treadmill training was confirmed by RT-PCR. Our data suggest that TGF?/Smad3 signaling may be mainly involved in the decrease in muscle mass observed with SCI, while the BMP pathway was activated with treadmill training.
Project description:Locomotor training (LT) as a therapeutic intervention following spinal cord injury (SCI) is an effective rehabilitation strategy for improving motor outcomes, but its impact on non-locomotor functions is unknown. Given recent results of our labs' pre-clinical animal SCI LT studies and existing overlap of lumbosacral spinal circuitries controlling pelvic-visceral and locomotor functions, we addressed whether LT can improve bladder, bowel and sexual function in humans at chronic SCI time-points (> two years post-injury).Prospective cohort study; pilot trial with small sample size.Eight SCI research participants who were undergoing 80 daily one-hour sessions of LT on a treadmill using body-weight support, or one-hour of LT and stand training on alternate days, as part of another research study conducted at the Kentucky Spinal Cord Injury Research Center, University of Louisville, were enrolled in this pilot trial. Urodynamic assessments were performed and International Data Set questionnaire forms completed for bladder, bowel and sexual functions at pre-and post-training time points. Four usual care (non-trained; regular at-home routine) research participants were also enrolled in this study and had the same assessments collected twice, at least 3 months apart.Filling cystometry documented significant increases in bladder capacity, voiding efficiency and detrusor contraction time as well as significant decreases in voiding pressure post-training relative to baseline. Questionnaires revealed a decrease in the frequency of nocturia and urinary incontinence for several research participants as well as a significant decrease in time required for defecation and a significant increase in sexual desire post-training. No significant differences were found for usual care research participants.These results suggest that an appropriate level of sensory information provided to the spinal cord, generated through task-specific stepping and/or loading, can positively benefit the neural circuitries controlling urogenital and bowel functions.ClinicalTrials.gov NCT03036527.
Project description:Traumatic spinal cord injury (SCI) often leads to debilitating loss of locomotor function. Neuroplasticity of spinal circuitry underlies some functional recovery and therefore represents a therapeutic target to improve locomotor function following SCI. However, the cellular and molecular mechanisms mediating neuroplasticity below the lesion level are not fully understood. The present study performed a gene expression profiling in the rat lumbar spinal cord at 1 and 3 weeks after contusive SCI at T9. Another group of rats received treadmill locomotor training (TMT) until 3 weeks, and gene expression profiles were compared between animals with and without TMT. Microarray analysis showed that many inflammation-related genes were robustly upregulated in the lumbar spinal cord at both 1 and 3 weeks after thoracic injury. Notably, several components involved in an early complement activation pathway were concurrently upregulated. In line with the microarray finding, the number of microglia substantially increased not only in the white matter but also in the gray matter. C3 and complement receptor 3 were intensely expressed in the ventral horn after injury. Furthermore, synaptic puncta near ventral motor neurons were frequently colocalized with microglia after injury, implicating complement activation and microglial cells in synaptic remodeling in the lumbar locomotor circuitry after SCI. Interestingly, TMT did not influence the injury-induced upregulation of inflammation-related genes. Instead, TMT restored pre-injury expression patterns of several genes that were downregulated by injury. Notably, TMT increased the expression of genes involved in neuroplasticity (Arc, Nrcam) and angiogenesis (Adam8, Tie1), suggesting that TMT may improve locomotor function in part by promoting neurovascular remodeling in the lumbar motor circuitry.
Project description:Neuromuscular impairment and reduced musculoskeletal integrity are hallmarks of spinal cord injury (SCI) that hinder locomotor recovery. These impairments are precipitated by the neurological insult and resulting disuse, which has stimulated interest in activity-based physical rehabilitation therapies (ABTs) that promote neuromuscular plasticity after SCI. However, ABT efficacy declines as SCI severity increases. Additionally, many men with SCI exhibit low testosterone, which may exacerbate neuromusculoskeletal impairment. Incorporating testosterone adjuvant to ABTs may improve musculoskeletal recovery and neuroplasticity because androgens attenuate muscle loss and the slow-to-fast muscle fiber-type transition after SCI, in a manner independent from mechanical strain, and promote motoneuron survival. These neuromusculoskeletal benefits are promising, although testosterone alone produces only limited functional improvement in rodent SCI models. In this review, we discuss the (1) molecular deficits underlying muscle loss after SCI; (2) independent influences of testosterone and locomotor training on neuromuscular function and musculoskeletal integrity post-SCI; (3) hormonal and molecular mechanisms underlying the therapeutic efficacy of these strategies; and (4) evidence supporting a multimodal strategy involving ABT with adjuvant testosterone, as a potential means to promote more comprehensive neuromusculoskeletal recovery than either strategy alone.
Project description:Approximately one-third of people with a spinal cord injury (SCI) will experience persistent neuropathic pain following injury. This pain negatively affects quality of life and is difficult to treat. Opioids are among the most effective drug treatments, and are commonly prescribed, but experimental evidence suggests that opioid treatment in the acute phase of injury can attenuate recovery of locomotor function. In fact, spinal cord injury and opioid administration share several common features (e.g. central sensitization, excitotoxicity, aberrant glial activation) that have been linked to impaired recovery of function, as well as the development of pain. Despite these effects, the interactions between opioid use and spinal cord injury have not been fully explored. A review of the literature, described here, suggests that caution is warranted when administering opioids after SCI. Opioid administration may synergistically contribute to the pathology of SCI to increase the development of pain, decrease locomotor recovery, and leave individuals at risk for infection. Considering these negative implications, it is important that guidelines are established for the use of opioids following spinal cord and other central nervous system injuries.