Voluntary Treadmill Research Articles

Breaking Mental Barriers Promotes Recovery After Spinal Cord Injury.

Functional recovery after spinal cord injury (SCI) often proves difficult as physical and mental barriers bar survivors from enacting their designated rehabilitation programs. We recently demonstrated that adult mice administered gabapentinoids, clinically approved drugs prescribed to mitigate chronic neuropathic pain, recovered upper extremity function following cervical SCI. Given that rehabilitative training enhances neuronal plasticity and promotes motor recovery, we hypothesized that the combination of an aerobic-based rehabilitation regimen like treadmill training with gabapentin (GBP) administration will maximize recovery in SCI mice by strengthening synaptic connections along the sensorimotor axis. Whereas mice administered GBP recovered forelimb functions over the course of weeks and months following SCI, no additive forelimb recovery as the result of voluntary treadmill training was noted in these mice. To our surprise, we also failed to find an additive effect in mice administered vehicle. As motivation is crucial in rehabilitation interventions, we scored active engagement toward the rehabilitation protocol and found that mice administered GBP were consistently participating in the rehabilitation program. In contrast, mice administered vehicle exhibited a steep decline in participation, especially at chronic time points. Whereas neuroinflammatory gene expression profiles were comparable between experimental conditions, we discovered that mice administered GBP had increased hippocampal neurogenesis and exhibited less anxiety-like behavior after SCI. We also found that an external, social motivator effectively rescues participation in mice administered vehicle and promotes forelimb recovery after chronic SCI. Thus, not only does a clinically relevant treatment strategy preclude the deterioration of mental health after chronic SCI, but group intervention strategies may prove to be physically and emotionally beneficial for SCI individuals.

A Formalized Method to Acclimate Dogs to Voluntary Treadmill Locomotion at Various Speeds and Inclines.

Simple SummaryThe land treadmill provides a range of behavioral and physical training benefits for dogs. Walking and trotting on the treadmill, however, is unfamiliar to many dogs and requires acclimation. This study developed and conducted a voluntary treadmill acclimation protocol on eight working dogs in training or working dogs performing detection research. The acclimation protocol was successfully completed for seven out of eight dogs. An acclimation assessment protocol was developed to measure a previously exposed dog’s degree of acclimation. This protocol was successfully used in two previously exposed dogs. A muscle soreness protocol was created to evaluate the soreness developed during the acclimation protocol. These protocols offer an option to acclimate dogs to the treadmill and determine the degree of acclimation for previously exposed dogs for research and training purposes.The land treadmill is a multipurpose tool with a unique set of behavioral and physical benefits for training and assessing active dogs. Habituation to voluntary treadmill locomotion is crucial for training a dog or accurately assessing a dog’s fitness on a treadmill. Therefore, a treadmill acclimation program was developed and evaluated with working dogs in training or working dogs performing detection research. Seven of eight naive dogs became acclimated to the treadmill using the protocol developed. Two previously experienced dogs successfully conducted an acclimation assessment to test for habituation to the treadmill. A muscle soreness protocol was created to evaluate the soreness developed during the acclimation program. This detailed protocol was successful in acclimating dogs to the treadmill at various safe speeds and inclines.

Distribution of Fos-immunoreactive cells in the ventral part of rat medulla following voluntary treadmill exercise.

The ventral part of the medulla, which contains important cardiovascular regions, is reportedly activated during exercise. Nevertheless, it was uncertain which region(s) in the ventral medulla are specifically activated by exercise. The present study aimed to demonstrate a general pattern of exercise-specific distribution of excited neuronal cells in the rat ventral medulla. Via immunohistochemical experiments, we mapped tyrosine hydroxylase- and Fos-immunoreactive cells (TH-IR and Fos-IR cells, respectively) on rat medullary coronal sections following a bout of voluntary treadmill exercise, a comparative control period, or after pharmacologically induced-hypotension under anesthesia. In the ventral medulla at the rostrocaudal level adjacent, but not rostral or caudal, to the caudal edge of the facial nucleus, voluntary treadmill exercise induced significant (P<0.05) increases in Fos expression, similar to hypotension. The rostral ventrolateral medulla (RVLM), as compared with the rostral ventromedial medulla (RVMM), displayed a greater number of Fos-IR cells due to either exercise or hypotension. In the RVLM, either exercise or hypotension induced significant expression of Fos in both TH-IR and TH non-immunoreactive cells. In the caudal ventrolateral medulla (CVLM), hypotension, but not exercise, increased the ratio of Fos-IR cells in the TH-IR population. These findings demonstrate that RVLM adrenergic and non-adrenergic neurons are specifically excited by voluntary exercise in rats, while RVMM or CVLM neurons are not. We suggest that RVLM C1/non-C1 neurons are a major part of central circuitries underlying sympathetic adjustments to exercise.

Differential effects of voluntary treadmill exercise and caloric restriction on tau pathogenesis in a mouse model of Alzheimer's disease-like tau pathology fed with Western diet

BackgroundTau is a microtubule-associated protein that becomes pathological when it undergoes hyperphosphorylation and aggregation as seen in Alzheimer's disease (AD). AD is mostly sporadic, with environmental, biological and/or genetic risks factors, interacting together to promote the disease. In the past decade, reports have suggested that obesity in midlife could be one of these risk factors. On the other hand, caloric restriction and physical exercise have been reported to reduce the incidence and outcome of obesity as well as AD. MethodsWe evaluated the impact of voluntary physical exercise and caloric restriction on tau pathology during 2months in hTau mice under high caloric diet in order to evaluate if these strategies could prevent AD-like pathology in obese conditions. ResultsWe found no effects of obesity induced by Western diet on both Tau phosphorylation and aggregation compared to controls. However, exercise reduced tau phosphorylation while caloric restriction exacerbated its aggregation in the brains of obese hTau mice. We then examined the mechanisms underlying changes in tau phosphorylation and aggregation by exploring major tau kinases and phosphatases and key proteins involved in autophagy. However, there were no significant effects of voluntary exercise and caloric restriction on these proteins in hTau mice that could explain our results. ConclusionIn this study, we report differential effects of voluntary treadmill exercise and caloric restriction on tau pathogenesis in our obese mice, namely beneficial effect of exercise on tau phosphorylation and deleterious effect of caloric restriction on tau aggregation. Our results suggest that lifestyle strategies used to reduce metabolic disorders and AD must be selected and studied carefully to avoid exacerbation of pathologies.

Sprint Interval Training Induces A Sexual Dimorphism but does not Improve Peak Bone Mass in Young and Healthy Mice

Elevated peak bone mass in early adulthood reduces the risk for osteoporotic fractures at old age. As sports participation has been correlated with elevated peak bone masses, we aimed to establish a training program that would efficiently stimulate bone accrual in healthy young mice. We combined voluntary treadmill running with sprint interval training modalities that were tailored to the individual performance limits and were of either high or intermediate intensity. Adolescent male and female STR/ort mice underwent 8 weeks of training before the hind legs were analyzed for cortical and trabecular bone parameters and biomechanical strength. Sprint interval training led to increased running speeds, confirming an efficient training. However, males and females responded differently. The males improved their running speeds in response to intermediate intensities only and accrued cortical bone at the expense of mechanical strength. High training intensities induced a significant loss of trabecular bone. The female bones showed neither adverse nor beneficial effects in response to either training intensities. Speculations about the failure to improve geometric alongside mechanical bone properties include the possibility that our training lacked sufficient axial loading, that high cardio-vascular strains adversely affect bone growth and that there are physiological limits to bone accrual.

Augmentation of Voluntary Locomotor Activity by Transcutaneous Spinal Cord Stimulation in Motor-Incomplete Spinal Cord-Injured Individuals.

The level of sustainable excitability within lumbar spinal cord circuitries is one of the factors determining the functional outcome of locomotor therapy after motor-incomplete spinal cord injury. Here, we present initial data using noninvasive transcutaneous lumbar spinal cord stimulation (tSCS) to modulate this central state of excitability during voluntary treadmill stepping in three motor-incomplete spinal cord-injured individuals. Stimulation was applied at 30 Hz with an intensity that generated tingling sensations in the lower limb dermatomes, yet without producing muscle reflex activity. This stimulation changed muscle activation, gait kinematics, and the amount of manual assistance required from the therapists to maintain stepping with some interindividual differences. The effect on motor outputs during treadmill-stepping was essentially augmentative and step-phase dependent despite the invariant tonic stimulation. The most consistent modification was found in the gait kinematics, with the hip flexion during swing increased by 11.3° ± 5.6° across all subjects. This preliminary work suggests that tSCS provides for a background increase in activation of the lumbar spinal locomotor circuitry that has partially lost its descending drive. Voluntary inputs and step-related feedback build upon the stimulation-induced increased state of excitability in the generation of locomotor activity. Thus, tSCS essentially works as an electrical neuroprosthesis augmenting remaining motor control.

Exercise promotes collateral artery growth mediated by monocytic nitric oxide.

Collateral artery growth (arteriogenesis) is an important adaptive response to hampered arterial perfusion. It is unknown whether preventive physical exercise before limb ischemia can improve arteriogenesis and modulate mononuclear cell function. This study aimed at investigating the effects of endurance exercise before arterial occlusion on MNC function and collateral artery growth. After 3 weeks of voluntary treadmill exercise, ligation of the right femoral artery was performed in mice. Hindlimb perfusion immediately after surgery did not differ from sedentary mice. However, previous exercise improved perfusion restoration ≤7 days after femoral artery ligation, also when exercise was stopped at ligation. This was accompanied by an accumulation of peri-collateral macrophages and increased expression of endothelial nitric oxide synthase and inducible nitric oxide synthase (iNOS) in hindlimb collateral and in MNC of blood and spleen. Systemic monocyte and macrophage depletion by liposomal clodronate but not splenectomy attenuated exercise-induced perfusion restoration, collateral artery growth, peri-collateral macrophage accumulation, and upregulation of iNOS. iNOS-deficient mice did not show exercise-induced perfusion restoration. Transplantation of bone marrow-derived MNC from iNOS-deficient mice into wild-type animals inhibited exercise-induced collateral artery growth. In contrast to sedentary controls, thrice weekly aerobic exercise training for 6 months in humans increased peripheral blood MNC iNOS expression. Circulating mononuclear cell-derived inducible nitric oxide is an important mediator of exercise-induced collateral artery growth.

Reduced Muscle Glycogen Differentially Affects Exercise Performance and Muscle Fatigue

This investigation examined the effects of reduced muscle glycogen on exercise performance and muscle fatigue. Male rats were assigned to a low glycogen group (LG) that participated in a protocol of exercise and fasting, a high glycogen group (HG) that exercised but were allowed free access to food, or control group (CON) that did not exercise but were allowed free access to food. Following the protocol, muscle glycogen content of the LG animals was reduced by 45%. The LG animals also performed 79 and 81% less voluntary treadmill exercise than the HG and CON groups. At exhaustion, the LG group had lower blood glucose than HG and CON but exhibited no reduction in sarcoplasmic reticulum (SR) function. During 30 min of in situ stimulation, the rates and magnitudes of muscle fatigue were not significantly different between groups, and fatigue-induced reductions in SR function were similar between groups. The results indicate that reduced muscle glycogen markedly impairs voluntary exercise performance but does not appreciably affect isolated muscle function. It is likely that exercise exhaustion due to reduced muscle glycogen is due, in large part, to hypoglycemia and central fatigue as opposed to peripheral mechanisms.

Assessing recruitment of lung diffusing capacity in exercising guinea pigs with a rebreathing technique

Noninvasive techniques for assessing cardiopulmonary function in small animals are limited. We previously developed a rebreathing technique for measuring lung volume, pulmonary blood flow, diffusing capacity for carbon monoxide (Dl(CO)) and its components, membrane diffusing capacity (Dm(CO)) and pulmonary capillary blood volume (Vc), and septal volume, in conscious nonsedated guinea pigs at rest. Now we have extended this technique to study guinea pigs during voluntary treadmill exercise with a sealed respiratory mask attached to a body vest and a test gas mixture containing 0.5% SF(6) or Ne, 0.3% CO, and 0.8% C(2)H(2) in 40% or 98% O(2). From rest to exercise, O(2) uptake increased from 12.7 to 25.5 ml x min(-1) x kg(-1) while pulmonary blood flow increased from 123 to 239 ml/kg. The measured Dl(CO), Dm(CO), and Vc increased linearly with respect to pulmonary blood flow as expected from alveolar microvascular recruitment; body mass-specific relationships were consistent with those in healthy human subjects and dogs studied with a similar technique. The results show that 1) cardiopulmonary interactions from rest to exercise can be measured noninvasively in guinea pigs, 2) guinea pigs exhibit patterns of exercise response and alveolar microvascular recruitment similar to those of larger species, and 3) the rebreathing technique is widely applicable to human ( approximately 70 kg), dog (20-30 kg), and guinea pig (1-1.5 kg). In theory, this technique can be extended to even smaller animals provided that species-specific technical hurdles can be overcome.

Reply from G. D. Wadley, J. Choate and G. K. McConell

We would firstly like to confirm that our eNOS−/− mice (Wadley et al. 2007) were indeed from a background generated by Shesely et al. (1996) and we apologise for any confusion this may have caused. We agree there seems to be distinct differences in strain between eNOS−/− mice generated from Huang et al. (1995) and Shesely et al. (1996) backgrounds. Nisoli et al. have shown quite comprehensively that mitochondrial biogenesis is reduced under basal conditions in a number of tissues in eNOS−/− mice generated from the Huang et al. (1995) background (Nisoli et al. 2003, 2004). We also feel that accurate consideration of methodological aspects between studies will contribute to a better understanding and discussion of the relevance of eNOS on basal (and exercise-induced) mitochondrial biogenesis. Indeed, the work by Ojaimi et al. (2005), showing decreased PGC-1α in the heart of very old (21 months) eNOS−/− mice from the Shesely et al. (1996) background, also showed a greater decline in exercise capacity with ageing compared with wildtype mice. So it is possible that mitochondrial biogenesis is impaired with ageing in eNOS−/− mice more than wildtype mice. Thus, caution should be taken when making comparisons between our findings in 16-week-old eNOS−/− mice and the 21-month-old mice used by Ojaimi et al. (2005). Very recently, Le Gouill et al. (2007) observed reduced mitochondrial protein and DNA content and lower beta oxidation in skeletal muscle of eNOS−/− mice generated from the Shesely et al. (1996) background, which would also suggest reduced basal skeletal muscle mitochondrial biogenesis, although unfortunately we do not know the age of these mice, so again direct comparison between our findings and those of Le Gouill et al. is difficult. However, it is highly unlikely that our observation of no impairments in basal mitochondrial biogenesis in the skeletal muscle of our eNOS−/− mice could be due to measurement error. This is because we analysed all strains of mice (contol (CON), eNOS−/− and nNOS−/−) together and we were able to detect altered basal mitochondrial biogenesis in the nNOS−/− mice and exercise-induced mitochondrial biogenesis in all strains of mice (Wadley et al. 2007). We do not agree that it has previously been demonstrated that mitochondrial biogenesis is markedly reduced in eNOS−/− mice under exercise conditions. Previous research is this area is quite limited and unclear. Prior to our study no previous study had examined the effect of an acute bout of exercise on mitochondrial biogenesis markers. In addition, the only study to examine the effect of exercise training on skeletal muscle of eNOS−/− was difficult to interpret (Momken et al. 2004). For instance, Momken et al. found that not only did citrate synthase (CS) activity not increase with exercise training (voluntary treadmill running) in either the eNOS−/− or the wildtype mice, but cytochrome c oxidase (COX) activity actually decreased with voluntary wheel running (Momken et al. 2004). Furthermore, basal COX protein expression and CS activity were not impaired in the eNOS−/− mice. They did not measure markers of mitochondrial biogenesis (i.e. PGC-1α, NRF1, NRF2, mtTFA). Also, voluntary wheel running may not be the ideal exercise protocol for these experiments, since eNOS−/− mice ran significantly less (about half) than their wildtype controls and thus the exercise was not matched between groups. To our knowledge, ours is the first study to measure markers of mitochondrial biogenesis in skeletal muscle of eNOS−/− (and nNOS−/−) mice following exercise and we clearly observe normal increases in skeletal muscle PGC-1α mRNA following acute exercise in mice that have no detectable eNOS protein (Wadley et al. 2007). Furthermore, we have previously shown that pharmacologically blocking all NOS isoforms with the non-specific NOS inhibitor, l-NAME, does not prevent increased skeletal muscle PGC-1α mRNA following acute exercise in rats (Wadley & McConell, 2007). Thus, we feel it is unlikely that NO is involved in exercise-induced mitochondrial biogenesis in skeletal muscle. In conclusion, we agree further work is required to investigate the differences in strain between eNOS−/− mice generated from the Huang et al. (1995) and Shesely et al. (1996) backgrounds on basal mitochondrial biogenesis. Careful consideration needs to be taken regarding methodological differences (i.e. age, body fatness, etc.), since this could impact on the interpretation of results. However, given our recent findings of normal exercise-induced mitochondrial biogenesis in both eNOS−/− mice (Wadley et al. 2007) and in rats treated with l-NAME (Wadley & McConell, 2007) we feel it is unlikely that eNOS has a direct role in exercise-induced mitochondrial biogenesis.

Alteration of gene expression in rat colon mucosa after exercise

The development of colon cancer is highly influenced by lifestyle factors such as nutrition and physical inactivity. Detailed biological mechanisms are thus far unclear. The purpose of this study was to investigate the effects of regular treadmill exercise on gene expression in rat colon mucosa. For this purpose, 6-week-old male Wistar rats completed a stress-free voluntary treadmill exercise period of 12 weeks. Sedentary rats served as a control group. In the colon mucosa, steady-state mRNA expression levels of approximately 10,000 genes were compared between both groups by micro-array analysis (MWG rat 10K array). A total of 8846 mRNAs were detected above background level. Regular exercise led to a decreased expression of 47 genes at a threshold-factor of 2.0. Three genes were found to be up-regulated in the exercise group. The identified genes encode proteins involved in signal transduction (n=11), transport (n=8), immune system (n=7), cytoskeleton (n=6), protein targeting (n=6), metabolism (n=5), transcription (n=3) and vascularization (n=2). Among the genes regulated by regular exercise, the betaine-homocysteine methyltransferase 2 (BHMT2) seems to be of particular interest. Physical activity may protect against aberrant methylation by repressing the BHMT2 gene and thus contribute to a decreased risk of developing colon cancer. We have also identified vascular endothelial growth factor (VEGF), angiopoietin-2 (ANG-2) and calcium-independent phospholipase a2 (iPL-A2), all of them with markedly reduced transcript levels in the mucosa of active rats. In summary, our experiment presents the first gene expression pattern in rat colon mucosa following regular treadmill activity and represents an important step in understanding the molecular mechanisms responsible for the preventive effect of physical activity on the development of colon cancer.

Effort as a dimension of spontaneous activity in rats.

The relationship between effort and voluntary activity was studied in a braked running wheel and a voluntary treadmill. Effort was manipulated by varying the torque required to turn the wheel and by changing the angle of inclination of the treadmill. In both situations distance run was a linear decreasing function of effort, and work accomplished was a nonmonotonic increasing function of effort. These findings are discussed in relation to responsivity and regulatory views of the genesis of spontaneous activity.