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The cetacean hindlimb skeleton massively decreased to only vestigial limb elements as cetaceans evolved from land to aquatic lifestyles; however, the molecular mechanism underlying this major morphological transition remains unclear. In this study, four deletions and specific substitutions were detected in cetacean hindlimb enhancer A (HLEA), an enhancer that can regulate Tbx4 expression in hindlimb tissues to control hindlimb development. Transcriptional activation of HLEA was significantly weaker in bottlenose dolphin than mice, and this was found to be closely associated with cetacean-specific deletions. Furthermore, deletions in cetacean HLEA might disrupt HOX and PITX1 binding sites, which are required for enhancer activation. The ancestral state of these deletions was investigated, and all four specific deletions were found to have occurred after the species diverged from their common ancestor, suggesting that the deletion occurred recently, during a secondary aquatic adaptation. Taking these findings together, we suggest that cetacean-specific sequence changes reduced the Tbx4 gene expression pattern, and consequently drove the gradual loss of hindlimb in cetaceans.
The hindlimb casting model was developed to study skeletal muscle reloading following a period of unloading. It is unknown if ventilation parameters of mice are affected by the casting model. We tested the hypothesis that hindlimb casted mice have similar ventilatory patterns compared to mice with the casts removed. Male CD-1 mice underwent 14 days of hindlimb immobilization via plaster casting. Breathing parameters were obtained utilizing unrestrained barometric plethysmography (UBP). Breathing traces were analyzed with Ponemah software for breathing frequency, tidal volume (TV), and minute ventilation (MV). Frequency, TV and MV did not show any differences in quiet breathing patterns during or post-casting in mice. Thus, the hindlimb casting model does not complicate breathing during and after casting and should not interfere with the unloading and reloading of skeletal muscle.
αB-crystallin is a small heat shock protein that acts as a molecular chaperone under various stress conditions. Microtubules, which consist of tubulin, are related to maintain the intracellular organelles and cellular morphology. These two proteins have been shown to be related to the properties of different types of myofibers based on their contractile properties. The response of these proteins during muscular atrophy, which induces a myofibril component change, is not clearly understood.
Bone loss induced by microgravity exposure seriously endangers the astronauts' health, but its countermeasures still have certain limitations. The study aims to find potential protective drugs for the prevention of the microgravity-induced bone loss. Here, we utilized the network pharmacology approach to discover a natural compound calycosin by constructing the compound-target interaction network and analyzing the topological characteristics of the network. Furthermore, the hind limb unloading (HLU) rats' model was conducted to investigate the potential effects of calycosin in the prevention of bone loss induced by microgravity. The results indicated that calycosin treatment group significantly increased the bone mineral density (BMD), ameliorated the microstructure of femoral trabecular bone, the thickness of cortical bone and the biomechanical properties of the bone in rats, compared that in the HLU group. The analysis of bone turnover markers in serum showed that both the bone formation markers and bone resorption markers decreased after calycosin treatment. Moreover, we found that bone remodeling-related cytokines in serum including IFN-γ, IL-6, IL-8, IL-12, IL-4, IL-10 and TNF-α were partly recovered after calycosin treatment compared with HLU group. In conclusion, calycosin partly recovered hind limb unloading-induced bone loss through the regulation of bone remodeling. These results provided the evidence that calycosin might play an important role in maintaining bone mass in HLU rats, indicating its promising application in the treatment of bone loss induced by microgravity.
Targeted disruption of the Hoxd-10 gene, a 5' member of the mouse HoxD linkage group, produces mice with hindlimb-specific defects in gait and adduction. To determine the underlying causes of this locomotor defect, mutant mice were examined for skeletal, muscular and neural abnormalities. Mutant mice exhibit alterations in the vertebral column and in the bones of the hindlimb. Sacral vertebrae beginning at the level of S2 exhibit homeotic transformations to adopt the morphology of the next most anterior vertebra. In the hindlimb, there is an anterior shift in the position of the patella, an occasional production of an anterior sesamoid bone, and an outward rotation of the lower part of the leg, all of which contribute to the defects in locomotion. No major alterations in hindlimb musculature were observed, but defects in the nervous system were evident. There was a decrease in the number of spinal segments projecting nerve fibers through the sacral plexus to innervate the musculature of the hindlimb. Deletion of a hindlimb nerve was seen in some animals, and a shift was evident in the position of the lumbar lateral motor column. These observations suggest a role for the Hoxd-10 gene in establishing regional identity within the spinal cord and imply that patterning of the spinal cord may have intrinsic components and is not completely imposed by the surrounding mesoderm.
The shapes of homologous skeletal elements in the vertebrate forelimb and hindlimb are distinct, with each element exquisitely adapted to their divergent functions. Many of the signals and signalling pathways responsible for patterning the developing limb bud are common to both forelimb and hindlimb. How disparate morphologies are generated from common signalling inputs during limb development remains poorly understood. We show that, similar to what has been shown in the chick, characteristic differences in mouse forelimb and hindlimb cartilage morphology are maintained when chondrogenesis proceeds in vitro away from the endogenous limb bud environment. Chondrogenic nodules that form in high-density micromass cultures derived from forelimb and hindlimb buds are consistently different in size and shape. We described analytical tools we have developed to quantify these differences in nodule morphology and demonstrate that characteristic hindlimb nodule morphology is lost in the absence of the hindlimb-restricted limb modifier gene Pitx1. Furthermore, we show that ectopic expression of Pitx1 in the forelimb is sufficient to generate nodule patterns characteristic of the hindlimb. We also demonstrate that hindlimb cells are less adhesive to the tissue culture substrate and, within the limb environment, to the extracellular matrix and to each other. These results reveal autonomously programmed differences in forelimb and hindlimb cartilage precursors of the limb skeleton are controlled, at least in part, by Pitx1 and suggest this has an important role in generating distinct limb-type morphologies. Our results demonstrate that the micromass culture system is ideally suited to study cues governing morphogenesis of limb skeletal elements in a simple and experimentally tractable in vitro system that reflects in vivo potential.
Skeletal muscle atrophy can occur under many different conditions, including prolonged disuse or immobilization, cachexia, cushingoid conditions, secondary to surgery, or with advanced age. The mechanisms by which unloading of muscle is sensed and translated into signals controlling tissue reduction remains a major question in the field of musculoskeletal research. While the fibroblast growth factors (FGFs) and their receptors are synthesized by, and intimately involved in, embryonic skeletal muscle growth and repair, their role maintaining adult muscle status has not been examined.
The gradual buildup of neural activity over experimentally imposed delay periods, termed climbing activity, is well documented and is a potential mechanism by which interval time is encoded by distributed cortico-thalamico-striatal networks in the brain. Additionally, when multiple delay periods are incorporated, this activity has been shown to scale its rate of climbing proportional to the delay period. However, it remains unclear whether these patterns of activity occur within areas of motor cortex dedicated to hindlimb movement. Moreover, the effects of behavioral training (e.g., motor tasks) under different reward conditions but with similar behavioral output are not well addressed. To address this, we recorded activity from the hindlimb sensorimotor cortex (HLSMC) of two groups of rats performing a skilled hindlimb press task. In one group, rats were trained only to a make a valid press within a finite window after cue presentation for reward (non-interval trained, nIT; n = 5), while rats in the second group were given duration-specific cues in which they had to make presses of either short or long duration to receive reward (interval trained, IT; n = 6). Using perievent time histogram (PETH) analyses, we show that cells recorded from both groups showed climbing activity during the task in similar proportions (35% IT and 47% nIT), however, only climbing activity from IT rats was temporally scaled to press duration. Furthermore, using single trial decoding techniques (Wiener filter), we show that press duration can be inferred using climbing activity from IT animals (R = 0.61) significantly better than nIT animals (R = 0.507, p < 0.01), suggesting IT animals encode press duration through temporally scaled climbing activity. Thus, if temporal intervals are behaviorally relevant then the activity of climbing neurons is temporally scaled to encode the passage of time.
Conditions of extended bed rest and limb immobilization can initiate rapid and significant loss of skeletal muscle mass and function. Physical rehabilitation is standard practice following a period of disuse, yet mobility may be severely compromised, and recovery is commonly delayed or incomplete in special populations. Thus, a novel approach toward recovery of muscle mass is highly desired. Pericytes [neuron-glial antigen 2 (NG2)+CD31-CD45- (Lineage- [Lin-]) and CD146+Lin-] demonstrate capacity to facilitate muscle repair, yet the ability to enhance myofiber growth following disuse is unknown. In the current study, 3-4-mo-old mice were unilaterally immobilized for 14 d (IM) or immobilized for 14 d followed by 14 d of remobilization (RE). Flow cytometry and targeted gene expression analyses were completed to assess pericyte quantity and function following IM and RE. In addition, a transplantation study was conducted to assess the impact of pericytes on recovery. Results from targeted analyses suggest minimal impact of disuse on pericyte gene expression, yet NG2+Lin- pericyte quantity is reduced following IM (P < 0.05). Remarkably, pericyte transplantation recovered losses in myofiber cross-sectional area and the capillary-to-fiber ratio following RE, whereas deficits remained with vehicle alone (P = 0.01). These findings provide the first evidence that pericytes effectively rehabilitate skeletal muscle mass following disuse atrophy.-Munroe, M., Dvoretskiy, S., Lopez, A., Leong, J., Dyle, M. C., Kong, H., Adams, C. M., Boppart, M. D. Pericyte transplantation improves skeletal muscle recovery following hindlimb immobilization.
In vertebrates, active movement is driven by muscle forces acting on bones, either directly or through tendinous insertions. There has been much debate over how muscle size and force are reflected by the muscular attachment areas (AAs). Here we investigate the relationship between the physiological cross-sectional area (PCSA), a proxy for the force production of the muscle, and the AA of hindlimb muscles in Nile crocodiles and five bird species. The limbs were held in a fixed position whilst blunt dissection was carried out to isolate the individual muscles. AAs were digitised using a point digitiser, before the muscle was removed from the bone. Muscles were then further dissected and fibre architecture was measured, and PCSA calculated. The raw measures, as well as the ratio of PCSA to AA, were studied and compared for intra-observer error as well as intra- and interspecies differences. We found large variations in the ratio between AAs and PCSA both within and across species, but muscle fascicle lengths are conserved within individual species, whether this was Nile crocodiles or tinamou. Whilst a discriminant analysis was able to separate crocodylian and avian muscle data, the ratios for AA to cross-sectional area for all species and most muscles can be represented by a single equation. The remaining muscles have specific equations to represent their scaling, but equations often have a relatively high success at predicting the ratio of muscle AA to PCSA. We then digitised the muscle AAs of Coelophysis bauri, a dinosaur, to estimate the PCSAs and therefore maximal isometric muscle forces. The results are somewhat consistent with other methods for estimating force production, and suggest that, at least for some archosaurian muscles, that it is possible to use muscle AA to estimate muscle sizes. This method is complementary to other methods such as digital volumetric modelling.
Angiogenesis is a complex process that depends on the delicate regulation of gene expression. Dysregulation of transcription during angiogenesis often leads to various human diseases. Emerging evidence has recently begun to show that long non-coding RNAs (lncRNAs) may mediate angiogenesis in both physiological and pathological conditions; concurrently, underlying molecular mechanisms are largely unexplored. Previously, our lab identified metastasis associates lung adenocarcinoma transcript 1 (Malat1) as an oxygen-glucose deprivation (OGD)-responsive endothelial lncRNA. Here we reported that genetic deficiency of Malat1 leads to reduced blood vessel formation and local blood flow perfusion in mouse hind limbs at one to four weeks after hindlimb ischemia. Malat1 and vascular endothelial growth factor receptor 2 (VEGFR2) levels were found to be increased in both cultured mouse primary skeletal muscle microvascular endothelial cells (SMMECs) after 16 h OGD followed by 24 h reperfusion and in mouse gastrocnemius muscle that underwent hindlimb ischemia followed by 28 days of reperfusion. Moreover, Malat1 silencing by locked nucleic acid (LNA)-GapmeRs significantly reduced tube formation, cell migration, and cell proliferation in SMMEC cultures. Mechanistically, RNA subcellular isolation and RNA-immunoprecipitation experiments demonstrate that Malat1 directly targets VEGFR2 to facilitate angiogenesis. The results suggest that Malat1 regulates cell-autonomous angiogenesis through direct regulation of VEGFR2.
Repeated stress is one of the major risk factors for cerebrovascular disease, including stroke, and vascular dementia. However, the functional alterations in the cerebral hemodynamic response induced by chronic stress have not been clarified. Here, we investigated the in vivo cerebral hemodynamic changes and accompanying cellular and molecular changes in chronically stressed rats. After 3 weeks of restraint stress, the elicitation of stress was verified by behavioral despair in the forced swimming test and by physical indicators of stress. The evoked changes in the cerebral blood volume and pial artery responses following hindpaw electrical stimulation were measured using optical intrinsic signal imaging. We observed that, compared to the control group, animals under chronic restraint stress exhibited a decreased hemodynamic response, with a smaller pial arterial dilation in the somatosensory cortex during hindpaw electrical stimulation. The effect of chronic restraint stress on vasomodulator enzymes, including neuronal nitric oxide synthase (nNOS) and heme oxygenase-2 (HO-2), was assessed in the somatosensory cortex. Chronic restraint stress downregulated nNOS and HO-2 compared to the control group. In addition, we examined the subtypes of cells that can explain the environmental changes due to the decreased vasomodulators. The expression of parvalbumin in GABAergic interneurons and glutamate receptor-1 in neurons were decreased, whereas the microglial activation was increased. Our results suggest that the chronic stress-induced alterations in cerebral vascular function and the modulations of the cellular expression in the neuro-vasomodulatory system may be crucial contributing factors in the development of various vascular-induced conditions in the brain.
This work demonstrates a neuromechanical model of rat hindlimb locomotion undergoing nominal walking with perturbations. In the animal, two types of responses to perturbations are observed: resetting and non-resetting deletions. This suggests that the animal locomotor system contains a memory-like organization. To model this phenomenon, we built a synthetic nervous system that uses separate rhythm generator and pattern formation layers to activate antagonistic muscle pairs about each joint in the sagittal plane. Our model replicates the resetting and non-resetting deletions observed in the animal. In addition, in the intact (i.e., fully afferented) rat walking simulation, we observe slower recovery after perturbation, which is different from the deafferented animal experiment. These results demonstrate that our model is a biologically feasible description of some of the neural circuits in the mammalian spinal cord that control locomotion, and the difference between our simulation and fictive motion shows the importance of sensory feedback on motor output. This model also demonstrates how the pattern formation network can activate muscle synergies in a coordinated way to produce stable walking, which motivates the use of more complex synergies activating more muscles in the legs for three-dimensional limb motion.
Previous studies examining whether autophagy has a protective or deleterious role during ischemia/reperfusion (I/R) injury have reported a varying role in different organs and remains a matter of debate. The aim of the current study was to explore the role of autophagy in hindlimb I/R injury in a murine model. An increase in apoptosis was observed in vitro, in C2C12 myoblast cells, following hypoxia/reoxygenation (H/R), while downregulation of autophagic flux was induced by chloroquine as compared with the vehicle group under hypoxia and H/R conditions. In vivo, an increase in severe damage of gastrocnemius muscles was observed in the I/R and ischemia groups compared with the control group, was more severe in the I/R group compared with the ischemia group. Electron microscopy revealed an increased number of autophagosomes in the ischemia group, whereas a reduced number was detected in the I/R group. Following administration of rapamycin, the infarct size ratio and cell apoptosis was significantly reduced, while the amount of autophagosomes significantly increased in the ischemic phase. In conclusion, autophagy is upregulated in the ischemia phase and downregulated in the reperfusion phase. Notably, upregulation of autophagy via rapamycin intervention during ischemia alleviated skeletal muscle damage, suggesting a potential protective role during hindlimb I/R injury.
Ischaemia caused by lower extremity artery stenosis is the main cause of peripheral artery disease (PAD) in patients with diabetes. Trimetazidine (TMZ) has traditionally been used as an anti-ischaemic drug for coronary artery disease. The effect of TMZ on PAD in a diabetic animal model and the underlying molecular mechanisms remain unclear.
The impairment in microvascular network formation could delay the restoration of blood flow after acute limb ischemia. A high-content screen of a GSK-published kinase inhibitor library identified a set of ROCK inhibitor hits enhancing endothelial network formation. Subsequent kinase activity profiling against a panel of 224 protein kinases showed that two indazole-based ROCK inhibitor hits exhibited high selectivity for ROCK1 and ROCK2 isoforms compared to other ROCK inhibitors. One of the chemical entities, GSK429286, was selected for follow-up studies. We found that GSK429286 was ten times more potent in enhancing endothelial tube formation than Fasudil, a classic ROCK inhibitor. ROCK1 inhibition by RNAi phenocopied the angiogenic phenotype of the GSK429286 compound. Using an organotypic angiogenesis co-culture assay, we showed that GSK429286 formed a dense vascular network with thicker endothelial tubes. Next, mice received either vehicle or GSK429286 (10 mg/kg i.p.) for seven days after hindlimb ischemia induction. As assessed by laser speckle contrast imaging, GSK429286 potentiated blood flow recovery after ischemia induction. At the histological level, we found that GSK429286 significantly increased the size of new microvessels in the regenerating areas of ischemic muscles compared with vehicle-treated ones. Our findings reveal that selective ROCK inhibitors have in vitro pro-angiogenic properties and therapeutic potential to restore blood flow in limb ischemia.
Contrary to cats and primates, cortical contribution to hindlimb locomotor movements is not critical in rats. However, the importance of the motor cortex to regain locomotion after neurological disorders in rats suggests that cortical engagement in hindlimb motor control may depend on the behavioral context. To investigate this possibility, we recorded whole-body kinematics, muscle synergies, and hindlimb motor cortex modulation in freely moving rats performing a range of natural locomotor procedures. We found that the activation of hindlimb motor cortex preceded gait initiation. During overground locomotion, the motor cortex exhibited consistent neuronal population responses that were synchronized with the spatiotemporal activation of hindlimb motoneurons. Behaviors requiring enhanced muscle activity or skilled paw placement correlated with substantial adjustment in neuronal population responses. In contrast, all rats exhibited a reduction of cortical activity during more automated behavior, such as stepping on a treadmill. Despite the facultative role of the motor cortex in the production of locomotion in rats, these results show that the encoding of hindlimb features in motor cortex dynamics is comparable in rats and cats. However, the extent of motor cortex modulations appears linked to the degree of volitional engagement and complexity of the task, reemphasizing the importance of goal-directed behaviors for motor control studies, rehabilitation, and neuroprosthetics.
Early at the onset of exercise, breathing rate accelerates in order to anticipate the increasing metabolic demand resulting from the extra effort produced. Accordingly, the respiratory neural networks are the target of various input signals originating either centrally or peripherally. For example, during locomotion, the activation of muscle sensory afferents is able to entrain and thereby increase the frequency of spontaneous respiratory rhythmogenesis. Moreover, the lumbar spinal networks engaged in generating hindlimb locomotor rhythms are also capable of activating the medullary respiratory generators through an ascending excitatory command. However, in the context of quadrupedal locomotion, the influence of other spinal cord regions, such as cervical and thoracic segments, remains unknown. Using isolated brainstem-spinal cord preparations from neonatal rats and mice, we show that cervicothoracic circuitry may also contribute to locomotion-induced acceleration of respiratory cycle frequency. As previously observed for the hindlimb CPGs, the pharmacological activation of forelimb locomotor networks produces episodes of fictive locomotion that in turn increase the ongoing respiratory rhythm. Thoracic neuronal circuitry may also participate indirectly in this modulation via the activation of both cervical and lumbar CPG neurons. Furthermore, using light stimulation of CHR2-expressing glutamatergic neurons, we found that the modulation of the respiratory rate during locomotion involves lumbar glutamatergic circuitry. Our results demonstrate that during locomotion, the respiratory rhythm-generating networks receive excitatory ascending inputs from the spinal circuits responsible for generating and coordinating fore- and hindlimb movements. This constitutes a distributed central mechanism that contributes to matching breathing rate to the speed of locomotion.
Sepsis induces a myopathy characterized by loss of muscle mass and weakness. Septic patients undergo prolonged periods of limb muscle disuse due to bed rest. The contribution of limb muscle disuse to the myopathy phenotype remains poorly described. To characterize sepsis-induced myopathy with hindlimb disuse, we combined the classic sepsis model via cecal ligation and puncture (CLP) with the disuse model of hindlimb suspension (HLS) in mice. Male C57bl/6j mice underwent CLP or SHAM surgeries. Four days after surgeries, mice underwent HLS or normal ambulation (NA) for 7 days. Soleus (SOL) and extensor digitorum longus (EDL) were dissected for in vitro muscle mechanics, morphological, and histological assessments. In SOL muscles, both CLP+NA and SHAM+HLS conditions elicited ~20% reduction in specific force (p < 0.05). When combined, CLP+HLS elicited ~35% decrease in specific force (p < 0.05). Loss of maximal specific force (~8%) was evident in EDL muscles only in CLP+HLS mice (p < 0.05). CLP+HLS reduced muscle fiber cross-sectional area (CSA) and mass in SOL (p < 0.05). In EDL muscles, CLP+HLS decreased absolute mass to a smaller extent (p < 0.05) with no changes in CSA. Immunohistochemistry revealed substantial myeloid cell infiltration (CD68+) in SOL, but not in EDL muscles, of CLP+HLS mice (p < 0.05). Combining CLP with HLS is a feasible model to study sepsis-induced myopathy in mice. Hindlimb disuse combined with sepsis induced muscle dysfunction and immune cell infiltration in a muscle dependent manner. These findings highlight the importance of rehabilitative interventions in septic hosts to prevent muscle disuse and help attenuate the myopathy.
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