Aim: Activation of the sympathetic nervous system is common in resistant hypertension (RHT) and also in chronic kidney disease (CKD), a prevalent condition among resistant hypertensives. However, renal nerve ablation lowers blood pressure (BP) only in some patients with RHT. The influence of loss of nephrons per se on the antihypertensive response to renal denervation (RDNx) is unclear and was the focus of this study. Methods: Systemic hemodynamics and sympathetically mediated low frequency oscillations of systolic BP were determined continuously from telemetrically acquired BP recordings in rats before and after surgical excision of ∼80% of renal mass and subsequent RDNx. Results: After reduction of renal mass, rats fed a high salt (HS) diet showed sustained increases in mean arterial pressure (108 ± 3 mmHg to 128 ± 2 mmHg) and suppression of estimated sympathetic activity (∼15%), responses that did not occur with HS before renal ablation. After denervation of the remnant kidney, arterial pressure fell (to 104 ± 4 mmHg), estimated sympathetic activity and heart rate (HR) increased concomitantly, but these changes gradually returned to pre-denervation levels over 2 weeks of follow up. Subsequently, sympathoinhibition with clonidine did not alter arterial pressure while significantly suppressing estimated sympathetic activity and HR. Conclusion: These results indicate that RDNx does not chronically lower arterial pressure in this model of salt-sensitive hypertension associated with substantial nephron loss, but without ischemia and increased sympathetic activity, thus providing further insight into conditions likely to impact the antihypertensive response to renal-specific sympathoinhibition in subjects with CKD.

Uninephrectomy (UniNX) in rats on a fixed food intake leads to increased lipolysis and a low-grade inflammation with an increased subset of circulating cytokines. Because UniNX ablates renal nerves on the side of the removed kidney, we tested the contribution of unilateral renal denervation in the phenotype of UniNX. We compared Sham-operated controls, left nephrectomy (UniNX) and unilateral left kidney denervation (uDNX) in rats 4 weeks after surgery. uDNX did not affect kidney weight and function. In general, the uDNX phenotype was similar to the UniNX phenotype especially for lipolysis in fat pads and increased low-grade inflammation. uDNX led to decreased fat pad weight and increased hormone sensitive lipase and adipocyte triglyceride lipase mRNA levels in epididymal and inguinal adipose tissue, as well as increased circulating lipolysis markers β-hydroxybutyrate and glycerol. Measured circulating hormones such as leptin, T3 and insulin were similar amongst the three groups. The lipolytic cytokines interferon-gamma and granulocyte macrophage colony stimulating factor were increased in the circulation of both uDNX and UniNX groups. These two cytokines were also elevated in the spleen of both groups, but contrastingly they were decreased in fat pads, liver, and kidneys. Both uDNX and UniNX similarly increased noradrenaline content in fat pads and spleen. Melanocortin 4 receptor mRNA levels were increased in the brains of both uDNX and UniNX compared to Sham and may contribute to increased tissue noradrenaline levels. In addition, the farnesoid x receptor (FXR) may contribute to changes in tissue metabolism and inflammation, as anti-inflammatory FXR was decreased in the spleen but increased in other tissues in uDNX and UniNX compared to Sham. In summary, both uDNX and UniNX in rats promote metabolic and immunological alterations by mechanisms that seem to implicate modification of unilateral renal nerve pathways as well as central and peripheral neural pathways.

Severe muscle weakness concomitant with preferential depletion of myosin has been observed in several pathological conditions. Here, we used the steroid-denervation (S-D) rat model, which shows dramatic decrease in myosin content and force production, to test whether electrical stimulation (ES) treatment can prevent these deleterious changes. S-D was induced by cutting the sciatic nerve and subsequent daily injection of dexamethasone for 7 days. For ES treatment, plantarflexor muscles were electrically stimulated to produce four sets of five isometric contractions each day. Plantarflexor in situ isometric torque, muscle weight, skinned muscle fiber force, and protein and mRNA expression were measured after the intervention period. ES treatment partly prevented the S-D-induced decreases in plantarflexor in situ isometric torque and muscle weight. ES treatment fully prevented S-D-induced decreases in skinned fiber force and ratio of myosin heavy chain (MyHC) to actin, as well as increases in the reactive oxygen/nitrogen species-generating enzymes NADPH oxidase (NOX) 2 and 4, phosphorylation of p38 MAPK, mRNA expression of the muscle-specific ubiquitin ligases muscle ring finger-1 (MuRF-1) and atrogin-1, and autolyzed active calpain-1. Thus, ES treatment is an effective way to prevent muscle impairments associated with loss of myosin.

Patients with cancer cachexia (CCX) suffer from muscle wasting, which is often but not always accompanied by selective loss of myosin. Here we examined the effects of CCX on muscle mass and myosin heavy chain (MyHC) expression in denervated (DEN) muscles, especially focusing on the protein synthesis and degradation pathways. Male CD2F1 mice were randomly divided into control (CNT) and CCX groups and their left sciatic nerve was transected. CCX was induced by an intraperitoneal injection of colon 26 cells. After 14 days, the serum concentration of IL-6 and corticosteroid was higher in CCX mice than in CNT mice. The combination of CCX with DEN (CCX + DEN) resulted in a marked reduction of the gastrocnemius muscle weight (-69%) that was significantly lower than DEN (-53%) or CCX (-36%) alone. CCX had no effect on MyHC content, but it elicited a preferential MyHC loss when combined with DEN. The expression levels of autophagy markers cathepsin D and LC3BII/I ratio were markedly higher in the CCX + DEN group than in the CNT + DEN and the CCX groups. Paradoxically, there was an increase in protein synthesis rate and phosphorylation levels of p70S6K and rpS6, markers of mTORC1 signaling, in the CNT + DEN group, and these molecular alterations were inhibited in the CCX + DEN group. Our data indicate that CCX aggravates muscle atrophy in DEN muscles by inducing seletive loss of myosin, which involves inactivity dependent mechanisms that is likely to be a consequence of increased autophagy-mediated protein breakdown coupled with impaired protein synthesis.

Skeletal muscle atrophy is associated with pro-inflammatory cytokines. Salidroside is a biologically active ingredient of Rhodiola rosea, which exhibits anti-inflammatory property. However, there is little known about the effect of salidroside on denervation-induced muscle atrophy. Therefore, the present study aimed to determine whether salidroside could protect against denervation-induced muscle atrophy and to clarify potential molecular mechanisms. Denervation caused progressive accumulation of inflammatory factors in skeletal muscle, especially interleukin 6 (IL6) and its receptor, and recombinant murine IL6 (rmIL6) local infusion could induce target muscle atrophy, suggesting that denervation induced inflammation in target muscles and the inflammation may trigger muscle wasting. Salidroside alleviated denervation-induced muscle atrophy and inhibited the production of IL6. Furthermore, the inhibition of phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the decreased levels of suppressor of cytokine signaling (SOCS3), muscle RING finger protein-1 (MuRF1), atrophy F-box (atrogin-1), microtubule-associated protein light chain 3 beta (LC3B) and PTEN-induced putative kinase (PINK1) were observed in denervated muscles that were treated with salidroside. Finally, all of these responses to salidroside were replicated in neutralizing antibody against IL6. Taken together, these results suggest that salidroside alleviates denervation-induced inflammation response, thereby inhibits muscle proteolysis and muscle atrophy. Therefore, it was assumed that salidroside might be a potential therapeutic candidate to prevent muscle wasting.

Objective: To determine the effect of renal denervation (RDN) on the severity of atherosclerosis and aortic aneurysm in hypertensive mice. Methods: Hypertension, atherosclerosis and aortic aneurysm were induced by subcutaneous infusion of angiotensin II (1 μg/kg/min) for 28 days in apolipoprotein E-deficient mice. RDN was conducted using combined surgical and local chemical denervation. The norepinephrine concentration in the kidney was measured by high-performance liquid chromatography. Blood pressure was measured by the tail-cuff method. Atherosclerosis was assessed by Sudan IV staining of the aortic arch. The aortic diameter was measured by the morphometric method. The mRNA expression of genes associated with atherosclerosis and aortic aneurysm were analyzed by quantitative PCR. Results: RDN decreased the median norepinephrine content in the kidney by 93.4% (n = 5-7, P = 0.003) 5 days after the procedure, indicating that the RDN procedure was successful. RDN decreased systolic blood pressure in apolipoprotein E-deficient mice. Mice that had RDN had more severe aortic arch atherosclerosis (median percentage of Sudan IV positive area: 13.2% in control mice, n = 12, and 25.4% in mice having RDN, n = 12, P = 0.028). The severity of the atherosclerosis was negatively correlated with the renal norepinephrine content (spearman r = -0.6557, P = 0.005). RDN did not affect the size of aortic aneurysms formed or the incidence of aortic rupture in mice receiving angiotensin II. RDN significantly increased the aortic mRNA expression of matrix metalloproteinase-2 (MMP-2). Conclusion: RDN promoted atherosclerosis in apolipoprotein E-deficient mice infused with angiotensin II associated with upregulation of MMP-2. The higher MMP-2 expression could be the results of the greater amount of atheroma in the RDN mice. The findings suggest further research is needed to assess potentially deleterious effects of RDN in patients.

The aim of the present study was to evaluate the effect of leucine treatment (0.30 mM) on muscle weight and signaling of myoproteins related to synthesis and degradation pathways of soleus muscle following seven days of complete sciatic nerve lesion. Wistar rats (n = 24) of 3-4 months of age (192 ± 23 g) were used. The animals were randomly distributed into four experimental groups (n = 6/group): control, treated with leucine (L), denervated (D) and denervated treated with leucine (DL). Dependent measures were proteins levels of AKT, AMPK, mTOR, and ACC performed by Western blot. Leucine induced a reduction in the phosphorylation of AMPK (p < 0.05) by 16% in the L and by 68% in the DL groups as compared with control group. Denervation increased AMPK by 24% in the D group as compared with the control group (p < 0.05). AKT was also modulated by denervation and leucine treatment, highlighted by the elevation of AKT phosphorylation in the D (65%), L (98%) and DL (146%) groups as compared with the control group (p < 0.05). AKT phosphorylation was 49% higher in the D group as compared with the DL group. Furthermore, denervation decreased mTOR phosphorylation by 29% in the D group as compared with the control group. However, leucine treatment induced an increase of 49% in the phosphorylation of mTOR in the L group as compared with the control group, and an increase of 154% in the DL as compared with the D group (p < 0.05). ACC phosphorylation was 20% greater in the D group than the control group. Furthermore, ACC in the soleus was 22% lower in the in the L group and 50% lower in the DL group than the respective control group (p < 0.05). In conclusion, leucine treatment minimized the deleterious effects of denervation on rat soleus muscle by increasing anabolic (AKT and mTOR) and decreasing catabolic (AMPK) pathways. These results may be interesting for muscle recovery following acute denervation, which may contribute to musculoskeletal rehabilitation after denervation.

Denervation induces skeletal muscle atrophy, accompanied by complex biochemical and physiological changes, with potentially devastating outcomes even an increased mortality. Currently, however, there remains a paucity of effective strategies to treat skeletal muscle atrophy. Therefore, it is required to understand the molecular mechanisms of skeletal muscle atrophy and formulate new treatment strategies. In this study, we investigated the transcriptional profile of denervated skeletal muscle after peripheral nerve injury in rats. The cDNA microarray analysis showed that a huge number of genes in tibialis anterior (TA) muscles were differentially expressed at different times after sciatic nerve transection. Notably, the 24 h of denervation might be a critical time point for triggering TA muscle atrophy. According to the data from self-organizing map (SOM), Pearson correlation heatmap, principal component analysis (PCA), and hierarchical clustering analysis, three nodal transitions in gene expression profile of the denervated TA muscle might partition the period of 0.25 h-28 days post nerve injury into four distinct transcriptional phases. Moreover, the four transcriptional phases were designated as "oxidative stress stage", "inflammation stage", "atrophy stage" and "atrophic fibrosis stage", respectively, which was concluded from Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene ontology (GO) analyses at each transcriptional phase. Importantly, the differentially expressed genes at 24 h post sciatic nerve transection seemed to be mainly involved in inflammation, which might be a critical process in denervation-induced muscle atrophy. Overall, our study would contribute to the understanding of molecular aspects of denervation-induced muscle atrophy, and may also provide a new insight into the time window for targeted therapy.

Background: We previously demonstrated the effectiveness of renal denervation (RDN) to lower blood pressure (BP) at least partially via the reduction of sympathetic stimulation to the kidney. A number of adipocyte-derived factors are implicated in BP control in obesity. Aim: The aim of this study was to examine whether RDN may have salutary effects on the adipokine profile in patients with resistant hypertension (RH). Methods: Fifty seven patients with RH undergoing RDN program have been included in this study (65% males, age 60.8 ± 1.5 years, BMI 32.6 ± 0.7 kg/m2, mean ± SEM). Throughout the study, the patients were on an average of 4.5 ± 2.7 antihypertensive drugs. Automated seated office BP measurements and plasma concentrations of leptin, insulin, non-esterified fatty acids (NEFA), adiponectin and resistin were assessed at baseline and the 3 months after RDN. Results: There was a significant reduction in mean office systolic (168.75 ± 2.57 vs. 155.23 ± 3.17 mmHg, p < 0.001) and diastolic (90.68 ± 2.31 vs. 83.74 ± 2.36 mmHg, p < 0.001) BP 3 months after RDN. Body weight, plasma leptin and resistin levels and heart rate remained unchanged. Fasting insulin concentration significantly increased 3 months after the procedure (20.05 ± 1.46 vs. 29.70 ± 2.51 uU/ml, p = 0.002). There was a significant drop in circulating NEFA at follow up (1.01 ± 0.07 vs. 0.47 ± 0.04 mEq/l, p < 0.001). Adiponectin concentration was significantly higher after RDN (5,654 ± 800 vs. 6,644 ± 967 ng/ml, p = 0.024). Conclusions: This is the first study to demonstrate that RDN is associated with potentially beneficial effects on aspects of the adipokine profile. Increased adiponectin and reduced NEFA production may contribute to BP reduction via an effect on metabolic pathways. Clinical Trial Registration Number: NCT00483808, NCT00888433.

This study aimed to investigate the chronic effects of caudal artery denervation on morphometric parameters of the tail vascular smooth muscle and on physical exercise-induced thermoregulatory and cardiovascular adjustments in rats. Male Wistar rats were subjected to caudal artery denervation or the sham procedure. Approximately 26-28 days after these procedures, their thermoregulatory and cardiovascular parameters were evaluated at rest and during or following a fatiguing treadmill run. At the end of the experiments, the rats were euthanized, and samples of their tails were removed to evaluate morphometric parameters of the vascular smooth muscle surrounding the caudal artery. Denervated rats showed morphological adaptations, including increased arterial wall thickness and wall-to-lumen ratios. In resting rats and following the fatiguing exercise, caudal artery denervation barely affected the thermoregulatory and cardiovascular parameters evaluated. By contrast, caudal artery denervation attenuated the increase in tail skin temperature, decreased the spontaneous baroreflex sensitivity, and exacerbated the increases in mean arterial pressure in exercising rats. The increased wall-to-lumen ratio of denervated rats correlated negatively with the maximum tail skin temperature attained or cutaneous heat loss sensitivity but correlated positively with the maximum diastolic blood pressure attained during exercise. In conclusion, cutaneous denervation induces vascular remodeling characterized by morphological adaptations of the tail vascular smooth muscle. This vascular remodeling likely underlies the impaired tail heat loss and blood pressure adjustments in denervated rats subjected to physical exercise. Therefore, we have highlighted the importance of cutaneous vascular innervation integrity in thermal and cardiovascular control in stress-challenged rats. In this sense, our findings advance the understanding of thermoregulatory and cardiovascular system reactions after a sustained cutaneous vascular innervation injury, which is essential for the treatment of some diseases, such as Parkinson's disease and type 1 and type 2 diabetes mellitus.

Sarcopenia, or age-related skeletal muscle atrophy and weakness, imposes significant clinical and economic burdens on affected patients and societies. Neurological degeneration, such as motoneuron death, has been recognized as a key contributor to sarcopenia. However, little is known about how aged/sarcopenic muscle adapts to this denervation stress. Here, we show that mice at 27months of age exhibit clear signs of sarcopenia but no accelerated denervation-induced muscle atrophy when compared to 8-month-old mice. Surprisingly, aging lends unique atrophy resistance to tibialis anteria muscle, accompanied by an increase in the cascade of mammalian target of rapamycin complex 1 (mTORC1)-independent anabolic events involving Akt signaling, rRNA biogenesis, and protein synthesis during denervation. These results expand our understanding of age-dependent stress responses and may help develop better countermeasures to sarcopenia.

Carotid bodies (CBs) are metabolic sensors whose dysfunction is involved in the genesis of dysmetabolic states. Ageing induces significant alterations in CB function also prompting to metabolic deregulation. On the other hand, metabolic disease can accelerate ageing processes. Taking these into account, we evaluated the effect of long-term hypercaloric diet intake and CSN resection on age-induced dysmetabolism and CB function. Experiments were performed in male Wistar rats subjected to 14 or 44 weeks of high-fat high-sucrose (HFHSu) or normal chow (NC) diet and subjected to either carotid sinus nerve (CSN) resection or a sham procedure. After surgery, the animals were kept on a diet for more than 9 weeks. Metabolic parameters, basal ventilation, and hypoxic and hypercapnic ventilatory responses were evaluated. CB type I and type II cells, HIF-1α and insulin receptor (IR), and GLP-1 receptor (GLP1-R)-positive staining were analyzed by immunofluorescence. Ageing decreased by 61% insulin sensitivity in NC animals, without altering glucose tolerance. Short-term and long-term HFHSu intake decreased insulin sensitivity by 55 and 62% and glucose tolerance by 8 and 29%, respectively. CSN resection restored insulin sensitivity and glucose tolerance. Ageing decreased spontaneous ventilation, but short-term or long-term intake of HFHSu diet and CSN resection did not modify basal ventilatory parameters. HFHSu diet increased hypoxic ventilatory responses in young and adult animals, effects attenuated by CSN resection. Ageing, hypercaloric diet, and CSN resection did not change hypercapnic ventilatory responses. Adult animals showed decreased type I cells and IR and GLP-1R staining without altering the number of type II cells and HIF-1α. HFHSu diet increased the number of type I and II cells and IR in young animals without significantly changing these values in adult animals. CSN resection restored the number of type I cells in HFHSu animals and decreased IR-positive staining in all the groups of animals, without altering type II cells, HIF-1α, or GLP-1R staining. In conclusion, long-term hypercaloric diet consumption exacerbates age-induced dysmetabolism, and both short- and long-term hypercaloric diet intakes promote significant alterations in CB function. CSN resection ameliorates these effects. We suggest that modulation of CB activity is beneficial in exacerbated stages of dysmetabolism.

Skeletal muscle atrophy occurs under various conditions, such as disuse, denervation, fasting, aging, and various diseases. Although the underlying molecular mechanisms are still not fully understood, skeletal muscle atrophy is closely associated with reactive oxygen species (ROS) overproduction. In this study, we aimed to investigate the involvement of ROS in skeletal muscle atrophy from the perspective of gene regulation, and further examine therapeutic effects of antioxidants on skeletal muscle atrophy. Microarray data showed that the gene expression of many positive regulators for ROS production were up-regulated and the gene expression of many negative regulators for ROS production were down-regulated in mouse soleus muscle atrophied by denervation (sciatic nerve injury). The ROS level was significantly increased in denervated mouse soleus muscle or fasted C2C12 myotubes that had suffered from fasting (nutrient deprivation). These two muscle samples were then treated with N-acetyl-L-cysteine (NAC, a clinically used antioxidant) or pyrroloquinoline quinone (PQQ, a naturally occurring antioxidant), respectively. As compared to non-treatment, both NAC and PQQ treatment (1) reversed the increase in the ROS level in two muscle samples; (2) attenuated the reduction in the cross-sectional area (CSA) of denervated mouse muscle or in the diameter of fasted C2C12 myotube; (3) increased the myosin heavy chain (MHC) level and decreased the muscle atrophy F-box (MAFbx) and muscle-specific RING finger-1 (MuRF-1) levels in two muscle samples. Collectively, these results suggested that an increased ROS level was, at least partly, responsible for denervation- or fasting-induced skeletal muscle atrophy, and antioxidants might resist the atrophic effect via ROS-related mechanisms.

Heart failure (HF) has been proposed as a potential indication of renal denervation (RDN). However, the mechanisms enabling RDN to attenuate HF are not well understood, especially the central effects of RDN. The aim of this study was to decipher the mode of operation of RDN in the treatment of HF using a canine model of right ventricular rapid pacing-induced HF. Accordingly, 24 Chinese Kunming dogs were randomly grouped to receive sham procedure (sham-operated group), bilateral RDN (RDN group), rapid pacing to induce HF (HF-control group), and bilateral RDN plus rapid pacing (RDN + HF group). Echocardiography, plasma brain natriuretic peptide (BNP), and norepinephrine (NE) concentrations of randomized dogs were measured at baseline and 4 weeks after interventions, followed by histological and molecular analyses. Twenty dogs completed the research successfully and were enrolled for data analyses. Results showed that the average optical density of renal efferent and afferent nerves were significantly lower in the RDN and RDN + HF groups than in the sham-operated group, with a significant reduction of renal NE concentration. Rapid pacing in the RDN + HF and HF-control groups, compared with the sham-operated group, induced a significant increase in left ventricular end-diastolic volume and decrease in left ventricular ejection fraction and correspondingly resulted in cardiac fibrosis and dysfunction. Cardiac fibrosis evaluated by Masson's trichrome staining and the expression of transforming growth factor-β1 (TGF-β1) were significantly higher in the HF-control group than in the sham-operated group, which were remarkably attenuated by the application of the RDN technique in the RDN + HF group. In terms of central renin-angiotensin system (RAS), the expression of angiotensin II (AngII)/angiotensin-converting enzyme (ACE)/AngII type 1 receptor (AT1R) in the hypothalamus of dogs in the HF-control group, compared with the sham-operated group, was upregulated and that of the angiotensin-(1-7) [Ang-(1-7)]/ACE2 was downregulated. Furthermore, both of them were significantly attenuated by the RDN therapy in the RDN + HF group. In conclusion, the RDN technique could damage renal nerves and suppress the cardiac remodeling procedure in canine with HF while concomitantly attenuating the overactivity of central RAS in the hypothalamus.

Sympathetic innervation of the ovary in rodents occurs via two routes: the superior ovarian nerve (SON), which runs along the ovarian ligament, and the plexus nerve (PN), which is mainly associated with the vasculature. SON and ovarian norepinephrine (NE) levels play a major role in regulating ovarian cystic health. Although it was previously described that the polycystic ovarian phenotype (PCO) is causally related to hyperstimulation of the sympathetic nerves of the ovary, much less is known, however, regarding the role of PN in ovarian physiology. We studied the role of SON and PN in relation to the maintenance of the PCO phenotype induced in the rat by exposure to estradiol valerate (EV). EV exposure at 24 days old (juvenile exposure) increases NE in the ovary for up to 90 days after EV injection. SON or PN denervation (SONX and PNX) decreased NE. SONXreversed the acyclic condition from 30 days after surgery (p < 0.05), but PNXdid not. SONX was more effective than PNX to downregulate the increased number of cysts induced by EV, with the presence of the corpora lutea (CL, signifying ovulation) in the SONX group. Seventy percent of SONX rats presented with pregnancy at 60 days post-EV (6 of the 7 sperm-positive rats were pregnant); however, SONX rats had a reduced number (half) of pups compared with vehicle-treated rats and 60% more pups than EV rats. These data suggest that the SON plays a predominant role in follicular development, ovulation and pregnancy during ovarian diseases.

Spinal cord injury (SCI) disconnects supraspinal micturition centers from the lower urinary tract resulting in immediate and long-term changes in bladder structure and function. While cervical and high thoracic SCI have a greater range of systemic effects, clinical data suggest that those with lower (suprasacral) injuries develop poorer bladder outcomes. Here we assess the impact of SCI level on acute changes in bladder activity. We used two SCI models, T3 and L2 complete transections in male Wistar rats, and compared bladder pressure fluctuations to those of naïve and bladder-denervated animals. By 2 days after L2 transection, but not T3 transection or bladder denervation, small amplitude rhythmic contractions (1 mmHg, 0.06 Hz) were present at low intravesical pressures (<6 mmHg); these were still present 1 month following injury, and at 3 months, bladders from L2 SCI animals were significantly larger than those from T3 SCI or naïve animals. Low-pressure contractions were unaffected by blocking ganglionic signaling or bladder denervation at the time of measurements. L2 (and sham surgery) but not T3 transection preserves supraspinal adrenal control, and by ELISA we show lower plasma adrenal catecholamine concentration in the latter. When an adrenalectomy preceded the L2 transection, the aberrant low-pressure contractions more closely resembled those after T3 transection, indicating that the increased bladder activity after lumbar SCI is mediated by preserved adrenal function. Since ongoing low-pressure contractions may condition the detrusor and exacerbate detrusor-sphincter dyssynergia, moderating bladder catecholamine signaling may be a clinically viable intervention strategy.

Leptin is an adipose-derived hormone that plays an important role in the regulation of breathing. It has been demonstrated that obesity-related hypoventilation or apnea is closely associated with leptin signaling pathways. Perturbations of leptin signaling probably contribute to the reduced sensitivity of respiratory chemoreceptors to hypoxia/hypercapnia. However, the underlying mechanism remains incompletely understood. The present study is to test the hypothesis that leptin signaling contributes to modulating a hypoxic ventilatory response. The respiratory function was assessed in conscious obese Zucker rats or lean littermates treated with an injection of leptin. During exposure to hypoxia, the change in minute ventilation was lower in obese Zucker rats than chow-fed lean littermates or high fat diet-fed littermates. Such a change was abolished in all groups after carotid body denervation. In addition, the expression of phosphorylated signal transducers and activators of transcription 3 (pSTAT3), as well as putative O2-sensitive K+ channels including TASK-1, TASK-3 and TASK-2 in the carotid body, was significantly reduced in obese Zucker rats compared with the other two phenotype littermates. Chronic administration of leptin in chow-fed lean Zucker rats failed to alter basal ventilation but vigorously increased tidal volume, respiratory frequency, and therefore minute volume during exposure to hypoxia. Likewise, carotid body denervation abolished such an effect. In addition, systemic leptin elicited enhanced expression of pSTAT3 and TASK channels. In conclusion, these data demonstrate that leptin signaling facilitates hypoxic ventilatory responses probably through upregulation of pSTAT3 and TASK channels in the carotid body. These findings may help to better understand the pathogenic mechanism of obesity-related hypoventilation or apnea.

Aerobic exercise training improves the autonomic control of the circulation. Emerging evidence has shown that exercise induces neuroplastic adaptive changes in preautonomic circuitry controlling sympathetic/parasympathetic outflow to heart and vessels. The mechanisms underlying neuronal plasticity are, however, incompletely understood. Knowing that sinoaortic denervation blocks training-induced cardiovascular benefits, we investigate whether baroreceptors' and chemoreceptors' signaling are able to drive neuronal plasticity within medullary and supramedullary pathways controlling autonomic outflow. Male Wistar rats submitted to sinoaortic denervation (SAD) or dopamine β-hydroxylase-saporin lesion (DBHx) and respective controls (SHAM) were allocated to training (T) or sedentary (S) protocols for 8 weeks. After hemodynamic measurements at rest, rats were deeply anesthetized for brain harvesting. The density of DBH and oxytocin (OT) cell bodies and terminals were analyzed in brainstem and hypothalamic brain areas (double immunofluorescence reactions, optic and confocal microscopy). In SHAM rats training augmented the density of DBH+ neurons in the nucleus of solitary tract, increased the density of ascending NORergic projections and the number of DBH+ boutons contacting preautonomic OT+ neurons into paraventricular hypothalamic preautonomic nuclei, augmented the density of local OTergic neurons and enhanced the density of OT+ terminals targeting brainstem autonomic areas. These plastic changes occurred simultaneously with reduced sympathetic/increased parasympathetic activity, augmented baroreflex sensitivity and reduced resting heart rate. SAD reduced the density of both DBH+ fibers ascending from brainstem to paraventricular nucleus of hypothalamus and preautonomic OT+ neurons projecting to the brainstem, abrogated training-induced plastic changes and autonomic adaptive responses without changing the treadmill performance. Minor neuroplastic changes with preserved baroreflex sensitivity were observed in trained rats after partial selective disruption of ascending NORergic projections. Our data indicated that afferent inputs conveyed by arterial baroreceptors and chemoreceptors are the main stimuli to drive both inactivity-induced and activity-dependent neuroplasticity within the autonomic circuitry.

Treatment options for denervated skeletal muscle atrophy are limited, in part because the underlying molecular mechanisms are not well understood. Unlike previous transcriptomics studies conducted in rodent models of peripheral nerve injury, in the present study, we performed high-throughput sequencing with denervated atrophic biceps muscle and normal (non-denervated) sternocleidomastoid muscle samples obtained from four brachial plexus injury (BPI) patients. We also investigated whether Ficus carica L. (FCL.) extract can suppress denervated muscle atrophy in a mouse model, along with the mechanism of action. We identified 1471 genes that were differentially expressed between clinical specimens of atrophic and normal muscle, including 771 that were downregulated and 700 that were upregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the differentially expressed genes were mainly enriched in the GO terms "structural constituent of muscle," "Z disc," "M band," and "striated muscle contraction," as well as "Cell adhesion molecules," "Glycolysis/Gluconeogenesis," "Peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway," and "P53 signaling pathway." In experiments using mice, the reduction in wet weight and myofiber diameter in denervated muscle was improved by FCL. extract compared to saline administration, which was accompanied by downregulation of the proinflammatory cytokines interleukin (IL)-1β and IL-6. Moreover, although both denervated groups showed increased nuclear factor (NF)-κB activation and PPARα expression, the degree of NF-κB activation was lower while PPARα and inhibitor of NF-κB IκBα expression was higher in FCL. extract-treated mice. Thus, FCL. extract suppresses denervation-induced inflammation and attenuates muscle atrophy by enhancing PPARα expression and inhibiting NF-κB activation. These findings suggest that FCL. extract has therapeutic potential for preventing denervation-induced muscle atrophy caused by peripheral nerve injury or disease.

Introduction: During heart transplantation (HTx), cardiac denervation is inevitable, thus typically resulting in chronic resting tachycardia and chronotropic incompetence with possible consequences in patient quality of life and clinical outcomes. To this date, knowledge of hemodynamic changes early after HTx is still incomplete. This study aims at providing a model-based description of the complex hemodynamic changes at rest and during exercise in HTx recipients (HTxRs). Materials and Methods: A numerical model of early HTxRs is developed that integrates intrinsic and autonomic heart rate (HR) control into a lumped-parameter cardiovascular system model. Intrinsic HR control is realized by a single-cell sinoatrial (SA) node model. Autonomic HR control is governed by aortic baroreflex and pulmonary stretch reflex and modulates SA node activity through neurotransmitter release. The model is tuned based on published clinical data of 15 studies. Simulations of rest and exercise are performed to study hemodynamic changes associated with HTxRs. Results: Simulations of HTxRs at rest predict a substantially increased HR [93.8 vs. 69.5 beats/min (bpm)] due to vagal denervation while maintaining normal cardiac output (CO) (5.2 vs. 5.6 L/min) through a reduction in stroke volume (SV) (55.4 vs. 82 mL). Simulations of exercise predict markedly reduced peak CO (13 vs. 19.8 L/min) primarily resulting from diminished peak HRs (133.9 vs. 169 bpm) and reduced ventricular contractility. Yet, the model results show that HTxRs can maintain normal CO for low- to medium-intensity exercise by increased SV augmentation through the Frank-Starling mechanism. Conclusion: Relevant hemodynamic changes occur after HTx. Simulations suggest that (1) increased resting HRs solely result from the absence of vagal tone; (2) chronotropic incompetence is the main limiting factor of exercise capacity whereby peripheral factors play a secondary role; and (3) despite the diminished exercise capacity, HTxRs can compensate chronotropic incompetence by a preload-mediated increase in SV augmentation and thus maintain normal CO in low- to medium-intensity exercise.