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PubMed2000

Gene transfer of endothelial nitric oxide isoform decreases rat hindlimb vascular resistance in vivo.

The objective of this study was to design a methodology of gene transfer into a resistance vascular bed and to show if such a method can be used to examine the physiological function of a given gene product in vivo. We developed such a method and validated it by defining the role in vivo of endothelial nitric oxide synthase (eNOS). In a constant flow perfused rat hindlimb, gene transfer to the vascular endothelium was accomplished by incubating a "first-generation" serotype 5, replication-deficient, adenoviral vector (1.2 X 10(9) plaque-forming units/ml) containing cDNA encoding either the eNOS or the beta-galactosidase (beta-Gal) gene in the hindlimb vasculature for 30 min. Five days after infection, immunohistochemical staining for eNOS localized recombinant gene expression to vascular endothelial cells and eNOS protein levels were increased fourfold (11.9 +/- 6.6 vs. 2.9 +/- 1.3 intensity units/microg protein, n = 4, p < 0.05). Perfusion pressures were measured at different flow rates (10-50 ml/min). In addition, basal and acetylcholine (ACh)-stimulated vascular resistance (VR) in phenylephrine (PE)-precontracted (100 microM) hindlimb was measured at constant flow. There were flow-dependent increases (p < 0.05) in perfusion pressure. Overexpression of eNOS shifted the pressure-flow curve downward and administration of N(G)-nitro-L-arginine methyl ester (L-NAME) shifted the curve upward. Compared with beta-Gal-transfected rats, PE-induced VR decreased (p < 0.05) in eNOS-transfected rats (100 +/- 27 vs. 164 +/- 49 mmHg, n = 5). Addition of 100 microM L-NAME increased (p < 0.05) PE-induced VR in both eNOS-transfected and control rats (145 +/- 50 and 232 +/- 38 mmHg, n = 5, p < 0.05), respectively, which was partially abolished by L-arginine pretreatment. ACh-induced vasorelaxation was increased 45% (p < 0.05) in eNOS-transfected hindlimbs. L-NAME decreased (p < 0.05) ACh-induced vasorelaxation by 58% in eNOS-transfected hindlimbs versus 25% in beta-Gal-transfected hindlimbs (p < 0.05). We used this gene transfer method to examine the physiological function of a gene product in vivo and showed that (1) the flow-pressure relationship in the hindlimb vascular bed is NO dependent and (2) the eNOS enzyme modulates NO-mediated vasorelaxation in the rat hindlimb resistance arteries in vivo.

Adenoviridae↗
PubMed2006

Increased serotonergic innervation of lumbosacral motoneurons of rolling mouse Nagoya in correlation with abnormal hindlimb extension.

Rolling Mouse Nagoya (RMN) carries a mutation in a gene encoding for alpha(1A) subunit of P/Q-type Ca(2+) channel (Ca(v)2.1). In addition to ataxia, this mutant mouse exhibits abnormal hindlimb extension, which is characterized by a sustained excessive tone of hindlimb extensor muscles. This study aimed to clarify whether serotonergic (5-HTergic) innervation of the spinal motoneurons was altered in RMN in relation to the abnormal hindlimb extension. The density of 5-HT immunoreactive fibres in the ventral horn of lumbar and sacral regions of spinal cord was significantly greater in RMN than in controls. Retrograde wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) labelling combined with 5-HT immunostaining revealed that the number of 5-HT immunoreactive terminals adjoining femoris quadriceps motoneurons was about 2.5-fold greater in RMN than in controls. Furthermore, 5-HT immunostaining in the lumbar cord ventral horn was examined in three other Ca(v)2.1 mutant mice (tottering, leaner and pogo) as to whether or not they showed the abnormal hindlimb extension. Among these mutants, the increased density of 5-HT immunoreactive fibres was observed in correlation with the presence of the abnormal hindlimb extension. The results suggest an increased 5-HTergic innervation of the lumbosacral motoneurons in correlation with the abnormal hindlimb extension in RMN and other Ca(v)2.1 mutant mice. As 5-HT is known to induce the sustained membrane depolarizations without continuous excitatory synaptic inputs (plateau potentials) in spinal motoneurons, the increased 5-HTergic innervation may cause the sustained excitation of hindlimb extensor motoneurons, resulting in the abnormal hindlimb extension.

Animals↗
PubMed2005

The versatility of the pump-perfused rat hindlimb preparation: examples relating to skeletal muscle function and energy metabolism.

The pump-perfused rat hindlimb model, in various forms, has been in use for several decades. There are many applications for this model, owing to the ability to control the content and rate of perfusion. In the context of exercise physiology this model has been put to particularly good use. In this report we summarize some of the central surgical differences between different versions of the pump-perfused rat hindlimb model, including the double hindlimb + trunk, double hindlimb alone, single hindlimb, and distal hindlimb-alone models. We also summarize specific elements of the perfusion medium and measurement of force used in our lab during assessment of muscle metabolic and contractile responses, and illustrate some of the differences from the in vivo condition that merit consideration. We then provide specific examples of how the single pump-perfused hindlimb and distal hindlimb-alone versions of this model have been used to study muscle function and energy metabolism. In this context we show how this model can be used to permit the experimenter to manipulate and control the rate of O(2)delivery and to add specific compounds that inhibit a particular aspect of muscle metabolism, such that in combination with measurements of the flux of specific substances across the muscle and/or fast-freezing of muscle after contractions, more can be understood about the metabolic state of the contracting muscles.

Animals↗
PubMed1987

Constant-flow perfusion of the hindlimb vascular bed in conscious dogs.

Hindlimb vascular bed pressure-flow relationships were evaluated in seven conscious dogs using a newly developed controlled-flow perfusion technique. For controlled-flow perfusion, blood was diverted from a common carotid artery to a roller pump for perfusion of the left hindlimb vascular bed via an artificial vascular graft anastomosed to the left external iliac artery. An occlusion cuff positioned around the external iliac artery proximal to the graft arrested normal hindlimb blood flow during perfusion. Collateral flow was minimized by ligating all other major arteries supplying the left hindlimb. Hindlimb perfusion pressure, measured via the left deep femoral artery, decreased to a plateau value of 19.7 +/- 3.4 mmHg when pump flow was zero. Pressure-flow relationships were evaluated while the dogs were at rest by changing flow in small "square-wave" steps for 3 min each and measuring the steady-state perfusion pressure at each step. The hindlimb was perfused over a wide range of flows (25-450 ml/min) that resulted in perfusion pressures ranging from 40 to 175 mmHg. The hindlimb pressure-flow relationship obtained was indicative of net passive vascular behavior. That is, resistance to flow decreased with increases in flow, such that a curvilinear pressure-flow relationship occurred that was convex to the pressure axis. We conclude that the hindlimb circulation of resting conscious dogs can be perfused using controlled-flow perfusion techniques. These techniques can also be applied to other vascular beds and should be useful for evaluating peripheral vascular responses to drugs and reflexogenic alterations.

Animals↗
PubMed1995

ATP-sensitive K+ channel blockade impairs O2 extraction during progressive ischemia in pig hindlimb.

Tissues maintain O2 consumption (VO2) when blood flow and O2 delivery (DO2) are decreased by better matching of blood flow to meet local cellular O2 demand, a process that increases extraction of available O2. This study tested the hypothesis that ATP-sensitive K+ channels play a significant role in the response of pig hindlimb to ischemia. We pump perfused the vascularly isolated but innervated right hindlimb of 14 anesthetized pigs with normoxic blood while measuring hindlimb DO2, VO2, perfusion pressure, and cytochrome aa3 redox state. In one-half of the pigs, the pump-perfused hindlimb was also infused with 10 micrograms.min-1.kg-1 of glibenclamide, a potent blocker of ATP-sensitive K+ channels. Control animals were infused with 5% glucose solution alone. Blood flow was then progressively reduced in both groups in 10 steps at 10-min intervals. Glibenclamide had no effect on any preischemic hindlimb or systemic measurements. Hindlimb VO2 and cytochrome aa3 redox state began to decrease at a significantly higher DO2 in glibenclamide-treated compared with control pigs. At this critical DO2, the O2 extraction ratio (VO2/DO2) was 53 +/- 4% in the glibenclamide group and 73 +/- 5% in the control group (P < 0.05). Hindlimb vascular resistance increased significantly with ischemia in the glibenclamide group but did not change in the control group. We conclude that ATP-sensitive K+ channels may be importantly involved in the vascular recruitment response that tried to meet tissue O2 needs as blood flow was progressively reduced in the pig hindlimb.

Adenosine Triphosphate↗
PubMed2001

Muscle regeneration during hindlimb unloading results in a reduction in muscle size after reloading.

The hindlimb-unloading model was used to study the ability of muscle injured in a weightless environment to recover after reloading. Satellite cell mitotic activity and DNA unit size were determined in injured and intact soleus muscles from hindlimb-unloaded and age-matched weight-bearing rats at the conclusion of 28 days of hindlimb unloading, 2 wk after reloading, and 9 wk after reloading. The body weights of hindlimb-unloaded rats were significantly (P < 0.05) less than those of weight-bearing rats at the conclusion of hindlimb unloading, but they were the same (P > 0.05) as those of weight-bearing rats 2 and 9 wk after reloading. The soleus muscle weight, soleus muscle weight-to-body weight ratio, myofiber diameter, number of nuclei per millimeter, and DNA unit size were significantly (P < 0.05) smaller for the injured soleus muscles from hindlimb-unloaded rats than for the soleus muscles from weight-bearing rats at each recovery time. Satellite cell mitotic activity was significantly (P < 0.05) higher in the injured soleus muscles from hindlimb-unloaded rats than from weight-bearing rats 2 wk after reloading, but it was the same (P > 0.05) as in the injured soleus muscles from weight-bearing rats 9 wk after reloading. The injured soleus muscles from hindlimb-unloaded rats failed to achieve weight-bearing muscle size 9 wk after reloading, because incomplete compensation for the decrease in myonuclear accretion and DNA unit size expansion occurred during the unloading period.

Animals↗
PubMed2005

Effects of space flight conditions on the function of the immune system and catecholamine production simulated in a rodent model of hindlimb unloading.

UNLABELLED: The rodent model of hindlimb unloading has been successfully used to simulate some of the effects of space flight conditions. Previous studies have indicated that mice exposed to hindlimb-unloading conditions have decreased resistance to infections compared to restrained and normally housed control mice. OBJECTIVE: The purpose of this study was to clarify the mechanisms involved in resistance to infection in this model by examining the effects of hindlimb unloading on the function of the immune system and its impact on the production of catecholamines. METHODS: Female Swiss Webster mice were hindlimb-unloaded during 48 h and the function of the immune system was assessed in spleen and peritoneal cells immediately after this period. In addition, the kinetics of catecholamine production was measured throughout the hindlimb-unloading period. RESULTS: The function of the immune system was significantly suppressed in the hindlimb-unloaded group compared to restrained and normally housed control mice. Levels of catecholamines were increased in the hindlimb-unloaded group and peaked at 12 h following the commencement of unloading. CONCLUSION: These results suggest that physiological responses of mice are altered early after hindlimb unloading and that catecholamines may play a critical role in the modulation of the immune system. These changes may affect the ability of mice to resist infections.

Animals↗
PubMed1999

Hindlimb patterning and mandible development require the Ptx1 gene.

The restricted expression of the Ptx1 (Pitx1) gene in the posterior half of the lateral plate mesoderm has suggested that it may play a role in specification of posterior structures, in particular, specification of hindlimb identity. Ptx1 is also expressed in the most anterior ectoderm, the stomodeum, and in the first branchial arch. Ptx1 expression overlaps with that of Ptx2 in stomodeum and in posterior left lateral plate mesoderm. We now show that targeted inactivation of the mouse Ptx1 gene severely impairs hindlimb development: the ilium and knee cartilage are absent and the long bones are underdeveloped. Greater reduction of the right femur size in Ptx1 null mice suggests partial compensation by Ptx2 on the left side. The similarly sized tibia and fibula of mutant hindlimbs may be taken to resemble forelimb bones: however, the mutant limb buds appear to have retained their molecular identity as assessed by forelimb expression of Tbx5 and by hindlimb expression of Tbx4, even though Tbx4 expression is decreased in Ptx1 null mice. The hindlimb defects appear to be, at least partly, due to abnormal chondrogenesis. Since the most affected structures derive from the dorsal side of hindlimb buds, the data suggest that Ptx1 is responsible for patterning of these dorsal structures and that as such it may control development of hindlimb-specific features. Ptx1 inactivation also leads to loss of bones derived from the proximal part of the mandibular mesenchyme. The dual role of Ptx1 revealed by the gene knockout may reflect features of the mammalian jaw and hindlimbs that were acquired at a similar time during tetrapod evolution.

Animals↗
PubMed2004

Hindlimb unloading in adult rats using an alternative tail harness design.

INTRODUCTION: Hindlimb unloading has proven to be an effective model for studying the physiological effects of spaceflight. However, using current methodologies, maintenance of adult rats in hindlimb unloading for long periods is challenging. Therefore, our goal was to develop a technique allowing long-term hindlimb unloading in adult rats. METHODS: Adult male Sprague Dawley rats were assigned to control (C), control pinned (CP), and hindlimb unloaded (HU) groups. All rats were anesthetized and a stainless steel needle was inserted through the skin in the ventral side of the tail of CP and HU groups. A cable was inserted through the needle, wrapped around to the dorsal side, secured, and stabilized with casting tape. HU rats were hindlimb suspended for 28 d by attaching the cable to an adjustable bar, resulting in a 30 degrees head-down tilt, and were monitored for health status and bodyweight. Fecal corticosterone levels were used as a stress index. Hindlimb muscles and adrenals were weighed. RESULTS: Attrition due to animals slipping from their tail harness was eliminated. HU animals lost 9.9% bodyweight within the first 6 d of hindlimb unloading, but maintained that bodyweight the remaining 22 d. Stress levels, as measured by fecal corticosterone and adrenal weights, were not elevated significantly during suspension and muscle weights were decreased significantly. DISCUSSION: Results indicate that this method is suitable for long-term hindlimb unloading of adult rats, providing an alternative approach to study loss of musculoskeletal mass in simulated microgravity.

Adrenal Glands↗
PubMed2006

Motor enrichment sustains hindlimb movement recovered after spinal cord injury and glial transplantation.

PURPOSE: This study investigated whether enrichment improves hindlimb movement following complete spinal cord transection and transplantation of olfactory ensheathing glia (OEG), with or without a Schwann cell (SC) bridge. METHODS: Motor activity was encouraged through provision of motor enrichment housing (MEH); a multi-level cage containing ramps, textured surfaces and rewards. Hindlimb joint movement was assessed weekly for 22 weeks starting one week post-surgery, comparing rats housed in MEH to those in basic housing (BH). Transganglionic tracer was injected into the crushed right sciatic nerve three days prior to sacrifice, allowing sensory axons in the dorsal columns to be visualized by immunolabeling. Serotonergic axons and glial cells expressing low affinity nerve growth factor receptor were identified by immunolabeling. RESULTS: All rats, having received transplants, recovered some hindlimb movement. Rats housed in BH progressively lost recovered hindlimb function whereas recovered hindlimb movements were sustained in most rats in MEH. In rats transplanted with SCs and OEG, effects of MEH were first significant 14 weeks after injury. In rats transplanted with OEG, a trend was seen from 14 weeks after injury, but this did not reach significance. In all rats, traced sensory axons died back from sites of transplantation and did not regenerate rostrally. Further, in no rat were serotonergic axons observed regenerating into, around or beyond transplants. CONCLUSIONS: Transection and transplantation of SC/OEG or OEG induced recovery of hindlimb function. This recovered hindlimb movement was sustained in rats housed in MEH but was progressively lost in rats housed in BH. Because benefits of MEH were not observed until 14 weeks after injury, long-term assessment of behavior is recommended. BH conditions are not conducive to maintenance of recovered hindlimb function, and MEH should be used in studies of recovery of function following spinal cord injury.

Analysis of Variance↗
PubMed1986

Evaluation of the role of alpha-1 and alpha-2 adrenoceptors in the maintenance of neurogenic tone to the hindlimb vasculature.

The location of two distinct subtypes of alpha adrenoceptors on blood vessels is now well established. The present study was designed to assess the relative contribution of alpha-1 and alpha-2 adrenoceptors to the maintenance of sympathetic vasoconstrictor tone to the canine hindlimb. Bilateral hindlimb perfusion was carried out at controlled flow rates where one of the hindlimbs was neurally intact and the other limb was denervated surgically. Vascular resistances in the hindlimbs were evaluated by pressure-flow curves which were constructed by recording perfusion pressures at various flow levels. Administration of alpha-1 adrenoceptor antagonist, prazosin (50 micrograms/kg), which selectively inhibited the hindlimb vasoconstrictor effect of phenylephrine but not of B-HT 933, produced a significant decrease in the hindlimb vascular resistance in the innervated limb. This was reflected in a decrease in perfusion pressure and a downward shift of the pressure-flow curve of 30% from control. No changes in resistance occurred in the denervated limb. The alpha-2 adrenoceptor antagonist, yohimbine (100 micrograms/kg), which selectively antagonized vasoconstriction to B-HT 933 but not to phenylephrine, further decreased by 27% hindlimb vascular resistance in the innervated limb when given to the same group of prazosin-treated animals. The magnitude of the decrease in vascular resistance produced by yohimbine (27%) was similar to that caused by prazosin (30%). The vascular resistance in the innervated limb was now similar to that in the denervated limb after prazosin and yohimbine. Phentolamine, when administered after prazosin and yohimbine, did not produce any changes in the hindlimb vascular resistance in these dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Bilateral control of hindlimb scratching in the spinal turtle: contralateral spinal circuitry contributes to the normal ipsilateral motor pattern of fictive rostral scratching.

In a spinal turtle, unilateral stimulation in the rostral scratch receptive field elicited rhythmic fictive rostral scratching in ipsilateral hindlimb motor neurons; contralateral hip motor activity was also rhythmic and out-of-phase with ipsilateral hip motor activity. When left and right rostral scratch receptive fields were stimulated simultaneously, bilateral rhythmic fictive rostral scratching was produced; left hindlimb scratching was out-of-phase with right hindlimb scratching. Thus, spinal circuits coordinate interlimb phase during bilateral fictive scratching. We examined the contributions of contralateral spinal circuitry to the normal pattern of right hindlimb fictive rostral scratching by removing the left halves of the D7 segment and the hindlimb enlargement (D8-S2 segments). After left-hemicord removal, stimulation in the right rostral scratch receptive field usually elicited a variation of rostral scratching with rhythmic right hip flexor activity and no right hip extensor activity; thus, right hip flexor rhythm generation does not require left hindlimb enlargement circuitry. Normal right hindlimb rostral scratching with rhythmic alternation between hip flexor and extensor activities was rarely observed; thus, contralateral spinal circuitry contributes to the production of normal ipsilateral fictive rostral scratching. After left-hemicord removal, stimulation in the left rostral scratch receptive field elicited rhythmic right hip extensor activity; thus, contralateral spinal circuitry can generate a hip extensor rhythm during ipsilateral rostral scratch receptive field stimulation. Our observations and those of Berkowitz and Stein (1994a,b) support the concept that an ipsilateral hindlimb's normal rostral scratch motor pattern is generated by a modular central pattern generator that is bilaterally distributed in the spinal cord.

Animals↗
PubMedDate not supplied

Effect of indomethacin and N omega-nitro-L-arginine methyl ester on the pressure/flow relation in isolated perfused hindlimbs from pregnant and nonpregnant rats.

OBJECTIVE: To compare the pressure/flow relationship and to assess the roles of prostaglandins and nitric oxide in flow-induced vasodilation in the nonpregnant and late-pregnant rat hindlimb vasculature. METHODS: Pressure/flow and conductance/flow relationships were determined in isolated, Krebs buffer-perfused, norepinephrine (0.5 mumol/L) preconstricted hindlimbs from nonpregnant and late-pregnant Wistar-Kyoto rats before and after inhibition of cyclo-oxygenase with indomethacin (20 mumol/L), or nitric oxide synthase with N omega-nitro-L-arginine methyl ester (300 mumol/L). RESULTS: There were no significant differences in baseline perfusion pressure between nonpregnant and pregnant rat hindlimbs perfused at 2 mL/min (20.6 +/- 0.8 and 19.7 +/- 1.1 mmHg, respectively) and norepinephrine increased perfusion pressure about twofold (40.8 +/- 2.0 and 34.8 +/- 1.8 mmHg, respectively). After constriction, perfusion pressure increased linearly as flow was increased in a stepwise manner to a maximum of 4 mL/min. The slope of the pressure/flow regression line for the pregnant rat hindlimbs (6.00) was significantly lower (P < or = .001) than that for the nonpregnant rat hindlimbs (8.44). Vascular conductance also increased as flow was increased, and was significantly greater at all flow rates in the pregnant compared to the nonpregnant rat hindlimbs. Indomethacin slightly decreased the constrictor response to norepinephrine and increased the pressure/flow regression line slope in nonpregnant, but not in pregnant rat hindlimbs. N omega-nitro-L-arginine methyl ester abolished flow-mediated vasodilation in nonpregnant and pregnant rat hindlimbs, and there was no longer any significant difference between the pressure/flow regression line slopes. CONCLUSION: These results suggest that flow-induced vasodilation, mediated by endothelium-derived nitric oxide, is enhanced during pregnancy allowing the maternal vasculature to accommodate increased blood flow without increased blood pressure.

Animals↗
PubMed2000

Heat stress attenuates skeletal muscle atrophy in hindlimb-unweighted rats.

This study tested the hypothesis that elevation of heat stress proteins by whole body hyperthermia is associated with a decrease in skeletal muscle atrophy induced by reduced contractile activity (i.e. , hindlimb unweighting). Female adult rats (6 mo old) were assigned to one of four experimental groups (n = 10/group): 1) sedentary control (Con), 2) heat stress (Heat), 3) hindlimb unweighting (HLU), or 4) heat stress before hindlimb unweighting (Heat+HLU). Animals in the Heat and Heat+HLU groups were exposed to 60 min of hyperthermia (colonic temperature approximately 41.6 degrees C). Six hours after heat stress, both the HLU and Heat+HLU groups were subjected to hindlimb unweighting for 8 days. After hindlimb unweighting, the animals were anesthetized, and the soleus muscles were removed, weighed, and analyzed for protein content and the relative levels of heat shock protein 72 (HSP72). Compared with control and HLU animals, the relative content of HSP72 in the soleus muscle was significantly elevated (P < 0.05) in both the Heat and Heat+HLU animals. Although hindlimb unweighting resulted in muscle atrophy in both the HLU and Heat+HLU animals, the loss of muscle weight and protein content was significantly less (P < 0.05) in the Heat+HLU animals. These data demonstrate that heat stress before hindlimb unweighting can reduce the rate of disuse muscle atrophy. We postulate that HSP70 and/or other stress proteins play a role in the control of muscle atrophy induced by reduced contractile activity.

Animals↗
PubMed2005

Heterotopic hindlimb allotransplantation in rats: an alternative model for immunological research in composite-tissue allotransplantation.

A nonfunctional heterotopic hindlimb allotransplantation model is presented, and a study was performed between this model and standard orthotopic hindlimb transplantation to compare operation and ischemia time, overall morbidity, and mortality rates. In this model, the skin component of the hindlimb was stripped away to the ankle level, and the remaining part along with the vascularized epigastric skin was transplanted heterotopically to the inguinal space of the recipient. No osteotomy and intramedullary fixation were performed. Thirty heterotopic and orthotopic hindlimb transplantations were performed in two groups. Each group involved 15 transplantations from inbred, male Brown Norway (BN; RT1n) weighing 150-200 g to Lewis rats (LEW; RT1(1)) weighing 250-300 g. The animals were followed up for 2 weeks under immunosuppression with cyclosporine A (16 mg/kg/day). Mean operation times for heterotopic and orthotopic hindlimb transplantations were 60 and 105 min, with ischemia times of 35 and 85 min, respectively. No animal deaths or major complications were encountered in heterotopic hindlimb transplantation during the follow-up period. Seroma formation was observed in one animal as the only minor complication. The mortality rate for orthotopic hindlimb transplantation was 26.7%, and there were minor complications in 35%, including infection, ulceration, and loss of rigid fixation. This model circumvents the disadvantages of osteotomy and intramedullary fixation, which may increase the risk of blood loss, embolus, and infection in immunosuppressed animals. It also helps avoid tension or kinking on the anastomosis due to inadequate judgment of the osteotomy level, distortion associated with loss of rigid fixation, and weight mismatch between donor and recipient. From the immunological point of view, insult to bone marrow is avoided, and a relatively constant amount of bone marrow is introduced to be used in chimerism-based tolerance studies. We recommend this model for composite-tissue allotransplantation studies when functional recovery is not of primary importance.

Animals↗
PubMed2001

The paralogous Hox genes Hoxa10 and Hoxd10 interact to pattern the mouse hindlimb peripheral nervous system and skeleton.

The most 5' mouse Hoxa and Hoxd genes, which occupy positions 9-13 and which are related to the Drosophila AbdB gene, are all active in patterning developing limbs. Inactivation of individual genes produces alterations in skeletal elements of both forelimb and hindlimb; inactivation of some of these genes also alters hindlimb innervation. Simultaneous inactivation of paralogous or nonparalogous Hoxa and Hoxd genes produces more widespread alterations, suggesting that combinatorial interactions between these genes are required for proper limb patterning. We have examined the effects of simultaneous inactivation of Hoxa10 and Hoxd10 on mouse hindlimb skeletal and nervous system development. These paralogous genes are expressed at lumbar and sacral levels of the developing neural tube and surrounding axial mesoderm as well as in developing forelimb and hindlimb buds. Double-mutant animals demonstrated impaired locomotor behavior and altered development of posterior vertebrae and hindlimb skeletal elements. Alterations in hindlimb innervation were also observed, including truncations and deletions of the tibial and peroneal nerves. Animals carrying fewer mutant alleles show similar, but less extreme phenotypes. These observations suggest that Hoxa10 and Hoxd10 coordinately regulate skeletal development and innervation of the hindlimb.

Animals↗
PubMed1996

Recovery of locomotion after spinal cord hemisection: an X-ray study of the cat hindlimb.

Hemisection of the spinal cord in adult cats is a suitable model to st udy the mechanisms underlying recovery of motor functions. The initial paresis of the hindlimb is followed by a considerable improvement of locomotor functions of the affected hindlimb. Kinematic analyses of treadmill locomotion were performed from 10 days to 8 months after complete hemisections (right side) of the spinal cord at the thoracolumbar level, using X-ray cinematography for precise measurements of the hindlimb joint angles. The footfall pattern and the electromyogram were recorded. Motor control of both proximal and distal hindlimb joints improved substantially during the 1st postoperative month. However, persistent locomotor deficits were still present several months after hemisection. They could be divided into three groups of symptoms: (1) The gait pattern was disturbed with regard to interlimb coordination. The stance-phase duration of the right hindlimb was shortened. (2) The flexor capacity of the affected hindlimb was reduced, resulting in a slow insufficient flexion of the hip, knee, and ankle during the swing phase. (3) The timing of the flexion-extension events was impaired. The onset of the E1-extension was delayed and the amplitude was reduced. Electromyographic patterns of muscle activity during locomotion of the lesioned side limb differed from the contralateral hindlimb, which served as a contro. The results indicate that in spite of a good short-term functional improvement there are long-term locomotor deficits present after spinal cord hemisection.

Animals↗
PubMed1987

Automatic postural responses in the cat: responses of proximal and distal hindlimb muscles to drop of support from a single hind- or forelimb.

Cats respond to drop of the support from beneath a single limb with the "diagonal stance response" (Coulmance et al. 1979). They load the limbs on the diagonal opposite to the one containing the dropped limb and unload the third supporting limb in the diagonal containing the dropped limb. Characteristic biomechanical delays in limb motion and in vertical force changes imposed upon the limbs are observed. These delays range from 30 to 45 ms, depending upon the location of the dropped limb. This study describes the kinematics of the "diagonal stance response" and the activation of selected agonist-antagonist muscle pairs acting on the joints of the hindlimb during the response. Proximal and distal hindlimb muscles respond to perturbations in groups that are appropriate to the vertical forces imposed upon the limb. When the hindlimb containing the recording electrodes is loaded by drop of the contralateral hindlimb or the ipsilateral forelimb medium latency (25-45 ms) EMG responses occur in the extensors. This response serves to stiffen the limb against the increased vertical force of loading. A similar response is observed when the hindlimb is reloaded after being dropped. In this case, however, short latency responses precede the medium latency responses in muscles that are passively stretched by the limb drop. When drop of the diagonal forelimb unloads the hindlimb containing the electrodes, medium latency responses are observed in the distal hindlimb flexors, which indicates that the unloading is evoked in part by active lifting of the limb. In most cases, the medium latency responses precede or are coincident with the changes in force imposed on the limb, suggesting that the observed responses are centrally programmed.

Animals↗