Activation Of Muscle Afferents Research Articles

Central command activation during exercise is essential for the bradycardic response to diving

Mammalian diving response evokes complex cardiovascular adjustments, including bradycardia during sustained muscular activity. This is intriguing because voluntary exercise involves the activation of central command and skeletal muscle afferents, known to provoke tachycardia by reducing vagal outflow and increasing cardiac sympathetic activity. Nonetheless, it is currently unknown how diving-induced bradycardia can override the exercise tachycardia. Given this, we aimed to test the hypothesis that central and peripheral afferent mechanisms interact to modulate this physiological phenomenon. In three visits, 32 healthy subjects (15 women; 22±3 yr) were exposed to trigeminal nerve stimulation (i.e., facial cooling; TGS) to partially activate the diving reflex at rest (semi-recumbent position) and under three protocols: 1) during voluntary light (resting heart rate+20 beats.min−1) and moderate (resting heart rate+50 beats.min−1) steady-state cycling exercise; 2) during isolation of peripheral afferent reflexes via passive exercise (muscle mechanoreceptors) and cold pressor test (nociceptors; CPT), and; 3) during CPT with concurrent light exercise. The exercise intensities were assumed to provide different levels of central command activation, while both passive exercise and CPT were used to provide insights into the contribution of central command to diving bradycardia. TGS was performed for at least 90 seconds in all conditions. Beat-to-beat heart rate (HR, by electrocardiography) and blood pressure (finger photoplethysmography) were continuously measured, and surface electromyography was used to ensure the lack of volitional component during passive exercise. TGS elicited significant bradycardia at rest (Δ-12±0.9 beats·min−1; P<0.001), and this response was increased during voluntary light exercise (Δ-15±1.2 beats·min−1; P=0.002), but unaffected during voluntary moderate exercise when compared to rest (Δ-11±1.3 beats·min−1; P=0.536). In contrast, compared to rest, the HR response to TGS during passive exercise was significantly attenuated (Δ-13±1.2 beats·min−1 vs. Δ-9±1.7 beats·min−1; P=0.039), whereas CPT completely abolish the diving bradycardic response (Δ0±1.6 beats·min−1; P<0.001). However, when the volitional component was restored during CPT with concurrent light exercise, TGS provoked a significant bradycardic response, when compared to CPT condition (Δ1±1.6 beats·min−1 vs. Δ-10±2.1 beats·min−1; P=0.004). Notably, our findings were not affected by sex. In conclusion, these findings suggest that 1) central command activation during cycling exercise is essential for the bradycardic response to diving; 2) isolated peripheral afferent reflexes exert inhibitory feedback to modulate diving-induced bradycardia, and; 3) central and peripheral afferent feedback are important mechanisms by which exercise modulates the dive response. CNPq 307764/2022-2; CAPES (001). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Lower-limb resistance training reduces exertional dyspnea and intrinsic neuromuscular fatigability in individuals with chronic obstructive pulmonary disease.

Skeletal muscle atrophy, dysfunction, and fatigue are important complications of chronic obstructive pulmonary disease (COPD). Greater reliance on glycolytic metabolism and increased type III/IV muscle afferent activity increase ventilatory drive, promote ventilatory constraint, amplify exertional dyspnea, and limit exercise tolerance. To investigate whether muscular adaptation with resistance training (RT) could improve exertional dyspnea, exercise tolerance, and intrinsic neuromuscular fatigability in individuals with COPD (n = 14, FEV1 = 62 ± 21% predicted), we performed a proof-of-concept single-arm efficacy study utilizing 4 wk of individualized lower-limb RT (3 times/wk). At baseline, dyspnea (Borg scale), ventilatory parameters, lung volumes (inspiratory capacity maneuvers), and exercise time were measured during a constant-load test (CLT) at 75% maximal workload to symptom limitation. On a separate day, fatigability was assessed using 3 min of intermittent stimulation of the quadriceps (initial output of ∼25% maximal voluntary force). Following RT, the CLT and fatigue protocols were repeated. Compared with baseline, isotime dyspnea was reduced (5.9 ± 2.4 vs. 4.5 ± 2.4 Borg units, P = 0.02) and exercise time increased (437 ± 405 s vs. 606 ± 447 s, P < 0.01) following RT. Isotime tidal volume increased (P = 0.01), whereas end-expiratory lung volumes (P = 0.02) and heart rate (P = 0.03) decreased. Quadriceps force, relative to initial force, was higher at the end of the stimulation protocol posttraining (53.2 ± 9.1 vs. 46.8 ± 11.9%, P = 0.04). This study provides evidence that 4 wk of RT attenuates exertional dyspnea and improves exercise tolerance in individuals with COPD, which in part, is likely due to delayed ventilatory constraint and reduced intrinsic fatigability. A pulmonary rehabilitation program beginning with individualized lower-limb RT may help mitigate dyspnea before performing aerobic training in individuals with COPD.NEW & NOTEWORTHY This study presents the novel finding that 4-wk resistance training (RT) focused specifically on the lower limbs can reduce exertional dyspnea during constant-load cycling, improve exercise tolerance, and reduce intrinsic fatigability of the quadriceps in individuals with COPD.

Modulation of Cerebral Function by Muscle Afferent Activity, with Reference to Intravenous Succinylcholine.

Cerebral Function and Muscle Afferent Activity Following Intravenous Succinylcholine in Dogs Anesthetized with Halothane: The Effects of Pretreatment with a Defasciculating Dose of Pancuronium. By WL Lanier, PA Iaizzo, and JH Milde. Anesthesiology 1989; 71:87-95. Reprinted with permission. By the mid-1980s, it was widely assumed that if the depolarizing muscle relaxant, succinylcholine, given IV, produced increases in intracranial pressure, it did so because fasciculations produced increases in intrathoracic and central venous pressures that were transferred to the brain; however, there was no direct evidence that this was true. In contrast, we explored the possibility that the succinylcholine effect on the brain was explained by the afferentation theory of cerebral arousal, which predicts that agents or maneuvers that stimulate muscle stretch receptors will tend to stimulate the brain. Our research in tracheally intubated, lightly anesthetized dogs discovered that IV succinylcholine (which does not cross the blood-brain barrier) produced a doubling of cerebral blood flow that lasted for 30 min and corresponded to activation of the electroencephalogram and increases in intracranial pressure. Later, in our Classic Paper, we were able to assess simultaneously cerebral physiology and afferent nerve traffic emanating from muscle stretch receptors (primarily muscle spindles). We affirmed that the cerebral arousal response to succinylcholine was indeed driven by muscle afferent traffic and was independent of fasciculations or increases in intrathoracic or central venous pressures. Later research in complementary models demonstrated that endogenous movement (e.g., coughing, hiccups) produced a cerebral response very similar to IV succinylcholine, apparently as a result of the same muscle afferent mechanisms, independent of intrathoracic and central venous pressures. Thus, the importance of afferentation theory as a driver of the cerebral state of arousal and cerebral physiology during anesthesia was affirmed.

Group III/IV Afferent Activation During Prolonged Sitting With Mild-Hypercapnia In Middle-Aged Adults: A Pilot Study

Prolonged sitting (PS) and sedentarism in the US has significantly increased in recent decades, leading many adults to spend a majority of their workday sedentary. Uninterrupted PS has been shown to cause endothelial dysfunction in the lower limbs, leading to an increased risk for cardiovascular disease such as peripheral arterial disease. Additionally, elevations in carbon dioxide (hypercapnia), commonly observed in crowded environments such as workplaces and/or classrooms, have been known to impair cardiovascular function. Interruptions to PS by muscular contraction can prevent the negative effects attributed to PS. However, the underlying mechanisms of these muscle contractions in the prevention of the negative effects of PS within a hypercapnic condition in middle-aged adults, is currently unknown. PURPOSE: Examine the impacts of muscle contraction, specifically, group III/IV muscle afferent activation via passive and active leg movement in middle aged adults during prolonged sitting in a mild hypercapnic environment. METHODS: Healthy sedentary middle-aged adults (n =4, 48± 7 years old) participated. Utilizing a randomized control design participants completed 2 visits: control (CON) and active (group III/IV muscle afferent activation, ACT). Each visit included 2.5 hours of PS in a mild-hypercapnic environment to determine how activation of group III (mechanosensitive reflex) and/or group IV (metabosensitive reflex) afferents affect cardiovascular function respectively. RESULTS: Responses to ACT between 0-min and 250-min showed a 12% increase in blood flow (BF) and a 27.74% increase in shear rate (SR), while CON showed a 0.23% decrease in BF and an 8.9% increase in SR. Flow mediated dilation (FMD) of the popliteal artery increased following ACT (2.45 ± 0.82%) and decreased in CON (-1.45 ± 1.21%) while brachial artery FMD found increases in both conditions (ACT: 4.075 ± 0.92%, CON: 0.76 ± 0.54%). CONCLUSION: The findings from this study provide a novel insight towards the cardiovascular effects of PS within mild hypercapnia in sedentary middle-aged adults and the role of group III and IV muscle afferent activation for the mechanism(s) behind the preservation of vascular function via muscular contraction. Supported by the University of Nebraska at Omaha Graduate Research and Creative Activity grant.

Yoda1-induced Piezo1 Channel Activity In Group Iv Muscle Afferents Of Type 2 Diabetic Rats

Yoda1-induced Piezo1 Channel Activity In Group Iv Muscle Afferents Of Type 2 Diabetic Rats

NaV1.9 current in muscle afferent neurons is enhanced by substances released during muscle activity.

Skeletal muscle contraction triggers the exercise pressor reflex (EPR) to regulate the cardiovascular system response to exercise. During muscle contraction, substances are released that generate action potential activity in group III and IV afferents that mediate the EPR. Some of these substances increase afferent activity via G-protein-coupled receptor (GPCR) activation, but the mechanisms are incompletely understood. We were interested in determining if tetrodotoxin-resistant (TTX-R) voltage-dependent sodium channels (NaV) were involved and investigated the effect of a mixture of such compounds (bradykinin, prostaglandin, norepinephrine, and ATP, called muscle metabolites). Using whole cell patch-clamp electrophysiology, we show that the muscle metabolites significantly increased TTX-R NaV currents. The rise time of this enhancement averaged ∼2 min, which suggests the involvement of a diffusible second messenger pathway. The effect of muscle metabolites on the current-voltage relationship, channel activation and inactivation kinetics support NaV1.9 channels as the target for this enhancement. When applied individually at the concentration used in the mixture, only prostaglandin and bradykinin significantly enhanced NaV current, but the sum of these enhancements was <1/3 that observed when the muscle metabolites were applied together. This suggests synergism between the activated GPCRs to enhance NaV1.9 current. When applied at a higher concentration, all four substances could enhance the current, which demonstrates that the GPCRs activated by each metabolite can enhance channel activity. The enhancement of NaV1.9 channel activity is a likely mechanism by which GPCR activation increases action potential activity in afferents generating the EPR.NEW & NOTEWORTHY G-protein-coupled receptor (GPCR) activation increases action potential activity in muscle afferents to produce the exercise pressor reflex (EPR), but the mechanisms are incompletely understood. We provide evidence that NaV1.9 current is synergistically enhanced by application of a mixture of metabolites potentially released during muscle contraction. The enhancement of NaV1.9 current is likely one mechanism by which GPCR activation generates the EPR and the inappropriate activation of the EPR in patients with cardiovascular disease.

The impact of postexercise blood flow restriction on local muscle endurance of a remote limb.

Studies have examined the influence of postexercise blood flow restriction as a mechanism to activate muscle afferents and assess nonlocal muscle fatigue. Althoughthese studies have assessed fatigue during maximal contractions, less is known about how these afferents may impact submaximal local muscle endurance, which was the purpose of the present study. Individuals completed two testing visits which involved completing a set of elbow flexion exercises to volitional failure on the nondominant followed by the dominant arm. During both trials, a pneumatic cuff was placed at the top of the nondominant arm before exercise. This cuff was inflated to either 0% (control) or 70% (experimental) of the individual's arterial occlusion pressure immediately after the set was completed. We then evaluated how this impacted local muscle endurance of the dominant arm using a Bayesian paired samples t-test with an uninformed prior width of 0.707 centred on 0. A total of 36 individuals completed the study (18 females). There was a greater discomfort present in the experimental trial when compared to the control trial (control: 4.5 standard deviation [SD]: 2.4); experimental: 5.8 [SD: 1.9]; BF10 = 61.46), but there were no differences in repetitions completed on the dominant arm (control: 43 [SD: 9], experimental: 43 [SD: 10]; BF10 = 0.179). Applying blood flow restriction postexercise induced sensations of discomfort but did not alter the local muscle endurance of the contralateral limb. These results suggest that increasing the activation of muscle afferents does not appear to alter the submaximal muscle endurance of a remote limb.

Arterial Baroreceptor Denervation Enhances Muscle Metaboreflex Induced Increases in Effective Arterial Elastance Without Worsening Stoke Work During Dynamic Exercise in Heart Failure

Optimal energy transfer from the left ventricle to the systemic circulation is paramount to the maintenance of workload performance during exercise. This interaction between the heart and circulation is quantified by the ventricular‐vascular coupling relationship which is the ratio of direct assessments of arterial and ventricular elastance. During exercise, increases in both arterial and ventricular elastance occur as a result of sympatho‐excitatory efferent responses brought about by activation of metabosensitive skeletal muscle afferents ‐ termed the muscle metaboreflex. In heart failure, ventricular elastance is reduced and arterial elastance is increased causing ventricular‐vascular uncoupling at rest and further sympatho‐activation elicited by the muscle metaboreflex worsens this relationship through profound systemic vasoconstriction. Recent studies have concluded that the arterial baroreflex substantially buffers vasoconstriction within peripheral vascular beds. In heart failure, the arterial baroreflex buffering capacity is significantly reduced and muscle metaboreflex induced vasoconstriction is enhanced. To what extent this shift in metaboreflex control of peripheral sympathetic tone affects ventricular‐vascular coupling is unknown. We examined the effect of sino‐aortic baroreceptor denervation (SAD) on the ventricular‐vascular relationship at rest and during moderate dynamic exercise (6.4 km/h 10% grade) in chronically instrument conscious canines before and after the induction of heart failure to determine whether loss of baroreflex buffering engendered further uncoupling of the ventricular‐vascular relationship in heart failure. Increases in effective arterial elastance (Ea), were significantly enhanced during muscle metaboreflex activation after SAD (0.5 ± 0.1 mmHg/ml to 2.0 ± 0.4 mmHg/mL). Furthermore, SAD elicited a significant increase in the ability to improve stroke work during muscle metaboreflex activation (2.7 ± 0.1 L*mmHg to 3.5 ± 0.1 L*mmHg) suggesting that even without the arterial baroreflex muscle metaboreflex activation in healthy subjects maintains ventricular‐vascular coupling. In heart failure, SAD elicited a 2‐fold increase in Ea during muscle metaboreflex activation (0.9 ± 0.2 mmHg/ml to 1.8 ± 0.2 mmHg/ml). Stroke work did not improve during muscle metaboreflex activation in heart failure with SAD. Thus, enhanced increases in Ea are likely not matched by ventricular elastance thereby exacerbating the already uncoupled ventricular‐vascular relationship. We conclude that the arterial baroreflex actively restrains increases in Ea and stroke work during muscle metaboreflex activation and SAD does not appear to significantly impact the ventricular‐vascular relationship in healthy subjects. In heart failure, the arterial baroreflex retains some degree of restraint over metaboreflex induced increases in Ea and thus is likely a mechanism which prevents worsening of the already impaired energy transfer from the left ventricle to the systemic circulation.

Arterial Baroreflex Inhibits Muscle Metaboreflex Induced Increases in Effective Arterial Elastance: Implications for Ventricular-Vascular Coupling.

The ventricular-vascular relationship assesses the efficacy of energy transferred from the left ventricle to the systemic circulation and is quantified as the ratio of effective arterial elastance to maximal left ventricular elastance. This relationship is maintained during exercise via reflex increases in cardiovascular performance raising both arterial and ventricular elastance in parallel. These changes are, in part, due to reflexes engendered by activation of metabosensitive skeletal muscle afferents—termed the muscle metaboreflex. However, in heart failure, ventricular-vascular uncoupling is apparent and muscle metaboreflex activation worsens this relationship through enhanced systemic vasoconstriction markedly increasing effective arterial elastance which is unaccompanied by substantial increases in ventricular function. This enhanced arterial vasoconstriction is, in part, due to significant reductions in cardiac performance induced by heart failure causing over—stimulation of the metaboreflex due to under perfusion of active skeletal muscle, but also as a result of reduced baroreflex buffering of the muscle metaboreflex-induced peripheral sympatho-activation. To what extent the arterial baroreflex modifies the metaboreflex-induced changes in effective arterial elastance is unknown. We investigated in chronically instrumented conscious canines if removal of baroreflex input via sino-aortic baroreceptor denervation (SAD) would significantly enhance effective arterial elastance in normal animals and whether this would be amplified after induction of heart failure. We observed that effective arterial elastance (Ea), was significantly increased during muscle metaboreflex activation after SAD (0.4 ± 0.1 mmHg/mL to 1.4 ± 0.3 mmHg/mL). In heart failure, metaboreflex activation caused exaggerated increases in Ea and in this setting, SAD significantly increased the rise in Ea elicited by muscle metaboreflex activation (1.3 ± 0.3 mmHg/mL to 2.3 ± 0.3 mmHg/mL). Thus, we conclude that the arterial baroreflex does buffer muscle metaboreflex induced increases in Ea and this buffering likely has effects on the ventricular-vascular coupling.

Influence of Family History of Hypertension on Muscle Metaboreflex Activation in Young Healthy Non‐Hispanic White and Black Men

Activation of skeletal muscle afferents (i.e., the muscle metaboreflex) contributes importantly to the blood pressure and muscle sympathetic nerve activity (MSNA) responses evoked during exercise. Previous studies have demonstrated that non-Hispanic Black (BK) individuals have a heightened pressor response during exercise compared to White (WH) individuals. In addition, there is evidence to suggest that normotensive individuals with a family history of hypertension (+FHH) have exaggerated increases in blood pressure and MSNA during exercise. However, the mechanism(s) contributing to exaggerated responses during exercise in BK individuals and those with a +FHH remain unclear. Therefore, we tested the hypothesis that individuals with a +FHH would have an exaggerated muscle metaboreflex activation compared to those with a -FHH and these responses would be further augmented in BK individuals with a +FHH. Twenty-three WH (-FHH, n=12; +FHH, n=11) and twenty-two BK (-FHH n=10; +FHH, n=12) healthy young men performed 2 min of static handgrip at 40% of maximal voluntary contraction, followed by 2 min of post-exercise ischemia (PEI) to isolate muscle metaboreflex activation. Beat-to-beat arterial blood pressure (finger photoplethysmography), heart rate (ECG), and MSNA (peroneal nerve microneurography) were measured. Resting mean arterial pressure (MAP, p=0.89) and MSNA burst frequency (p=0.76) were similar between all groups. During PEI, WH+FHH had significantly exaggerated MAP (-FHH: Δ23±2 vs +FHH: Δ33±3 mmHg, p=0.01) and MSNA (-FHH: Δ17±2 vs +FHH: Δ28±3 bursts/min, p=0.02) responses compared to WH-FHH. In contrast, PEI responses were similar between BK-FHH and BK+FHH for both MAP (-FHH: Δ26±1 vs +FHH: Δ25±2 mmHg, p=0.79) and MSNA (-FHH: Δ25±3 vs +FHH: Δ20±3 bursts/min, p=0.26). In summary, in contrast to our hypothesis, +FHH did not appear to affect responses in BK individuals, whereas WH men with a +FHH exhibited heightened muscle metaboreflex-mediated pressor and sympatho-excitatory responses compared to WH men with a -FHH.

Muscle metaboreflex-induced increases in effective arterial elastance: effect of heart failure.

Dynamic exercise elicits robust increases in sympathetic activity in part due to muscle metaboreflex activation (MMA), a pressor response triggered by activation of skeletal muscle afferents. MMA during dynamic exercise increases arterial pressure by increasing cardiac output via increases in heart rate, ventricular contractility, and central blood volume mobilization. In heart failure, ventricular function is compromised, and MMA elicits peripheral vasoconstriction. Ventricular-vascular coupling reflects the efficiency of energy transfer from the left ventricle to the systemic circulation and is calculated as the ratio of effective arterial elastance (Ea) to left ventricular maximal elastance (Emax). The effect of MMA on Ea in normal subjects is unknown. Furthermore, whether muscle metaboreflex control of Ea is altered in heart failure has not been investigated. We utilized two previously published methods of evaluating Ea [end-systolic pressure/stroke volume (EaPV)] and [heart rate × vascular resistance (EaZ)] during rest, mild treadmill exercise, and MMA (induced via partial reductions in hindlimb blood flow imposed during exercise) in chronically instrumented conscious canines before and after induction of heart failure via rapid ventricular pacing. In healthy animals, MMA elicits significant increases in effective arterial elastance and stroke work that likely maintains ventricular-vascular coupling. In heart failure, Ea is high, and MMA-induced increases are exaggerated, which further exacerbates the already uncoupled ventricular-vascular relationship, which likely contributes to the impaired ability to raise stroke work and cardiac output during exercise in heart failure.

The Sexes Do Not Differ for Neural Responses to Submaximal Elbow Extensor Fatigue.

To investigate possible sex-related differences in group III/IV muscle afferent feedback with isometric fatigue, we aimed to assess the effect of a sustained submaximal elbow extensor contraction on motoneuronal excitability (cervicomedullary motor evoked potential [CMEP]) and voluntary activation (VA). Twenty-four participants (12 females) performed a 15-min contraction at the level of EMG activity recorded at 15% of maximal torque. Each minute, CMEP were elicited by cervicomedullary stimulation with and without conditioning transcranial magnetic stimulation (TMS) delivered 100 ms earlier. Unconditioned and conditioned motor evoked potentials (MEP) in response to TMS were also recorded to assess motor cortical excitability. CMEP and MEP were normalized for changes in downstream excitability and expressed as percentage of their prefatigue (control) values. Postfatigue, VA was calculated from superimposed and resting tetani evoked by stimulation over triceps brachii. Males were twice as strong as females, but the sexes did not differ for any variable during the fatigue protocol. On a 0-10 scale, RPE increased from ~2.5 to 9. The unconditioned CMEP did not change, whereas the conditioned CMEP was reduced by ~50%. By contrast, the unconditioned and conditioned MEP increased to ~200% and ~320% of the control values, respectively. At task termination, maximal torque was reduced ~40%, and VA was ~80%, down from a prefatigue value of ~96%. Results support the scant published data on the elbow extensors and indicate no sex-related differences for isometric fatigue of this muscle group. The motoneuronal and VA data suggest that metabolite buildup and group III/IV muscle afferent activity were similar for females and males.

Control of exercise hyperpnoea: Contributions from thin-fibre skeletal muscle afferents.

What is the topic of this review? In this review, we examine the evidence for control mechanisms underlying exercise hyperpnoea, giving attention to the feedback from thin-fibre skeletal muscle afferents, and highlight the frequently conflicting findings and difficulties encountered by researchers using a variety of experimental models. What advances does it highlight? There has been a recent resurgence of interest in the role of skeletal muscle afferent involvement, not only as a mechanism of healthy exercise hyperpnoea but also in the manifestation of breathlessness and exercise intolerance in chronic disease. The ventilatory response to dynamic submaximal exercise is immediate and proportional to metabolic rate, which maintains isocapnia. How these respiratory responses are controlled remains poorly understood, given that the most tightly controlled variable (arterial partial pressure of CO2 /H+ ) provides no error signal for arterial chemoreceptors to trigger reflex increases in ventilation. This review discusses evidence for different postulated control mechanisms, with a focus on the feedback from groupIII/IV skeletal muscle mechanosensitive and metabosensitive afferents. This concept is attractive, because the stimulation of muscle mechanoreceptors might account for the immediate increase in ventilation at the onset of exercise, and signals from metaboreceptors might be proportional to metabolic rate. A variety of experimental models have been used to establish the contribution of thin-fibre muscle afferents in ventilatory control during exercise, with equivocal results. The inhibition of afferent feedback via the application of lumbar intrathecal fentanyl during exercise suppresses ventilation, which provides the most compelling supportive evidence to date. However, stimulation of afferent feedback at rest has no consistent effect on respiratory output. However, evidence is emerging for synergistic interactions between muscle afferent feedback and other stimulatory inputs to the central respiratory neuronal pool. These seemingly hyperadditive effects might explain the conflicting findings encountered when using different experimental models. We also discuss the increasing evidence that patients with certain chronic diseases exhibit exaggerated muscle afferent activation during exercise, resulting in enhanced cardiorespiratory responses. This might provide a neural link between the well-established limb muscle dysfunction and the associated exercise intolerance and exertional dyspnoea, which might offer therapeutic targets for these patients.

Insulin potentiates the response to mechanical stimuli in small dorsal root ganglion neurons and thin fibre muscle afferents in vitro.

Insulin is known to activate the sympathetic nervous system centrally. A mechanical stimulus to tissues activates the sympathetic nervous system via thin fibre afferents. Evidence suggests that insulin modulates putative mechanosensitive channels in the dorsal root ganglion neurons of these afferents. In the present study, we report the novel finding that insulin augments the mechanical responsiveness of thin fibre afferents not only at dorsal root ganglion, but also at muscle tissue levels. Our data suggest that sympathoexcitation is mediated via the insulin-induced mechanical sensitization peripherally. The present study proposes a novel physiological role of insulin in the regulation of mechanical sensitivity in somatosensory thin fibre afferents. Insulin activates the sympathetic nervous system, although the mechanism underlying insulin-induced sympathoexcitation remains to be determined. A mechanical stimulus to tissues such as skin and/or skeletal muscle, no matter whether the stimulation is noxious or not, activates the sympathetic nervous system via thin fibre afferents. Evidence suggests that insulin modulates putative mechanosensitive channels in the dorsal root ganglion (DRG) neurons of these afferents. Accordingly, we investigated whether insulin augments whole-cell current responses to mechanical stimuli in small DRG neurons of normal healthy mice. We performed whole-cell patch clamp recordings using cultured DRG neurons and observed mechanically-activated (MA) currents induced by mechanical stimuli applied to the cell surface. Local application of vehicle solution did not change MA currents or mechanical threshold in cultured DRG neurons. Insulin (500mU mL-1 ) significantly augmented the amplitude of MA currents (P<0.05) and decreased the mechanical threshold (P<0.05). Importantly, pretreatment with the insulin receptor antagonist, GSK1838705, significantly suppressed the insulin-induced potentiation of the mechanical response. We further examined the impact of insulin on thin fibre muscle afferent activity in response to mechanical stimuli in normal healthy rats in vitro. Using a muscle-nerve preparation, we recorded single group IV fibre activity to a ramp-shaped mechanical stimulation. Insulin significantly decreased mechanical threshold (P<0.05), although it did not significantly increase the response magnitude to the mechanical stimulus. In conclusion, these data suggest that insulin augments the mechanical responsiveness of small DRG neurons and potentially sensitizes group IV afferents to mechanical stimuli at the muscle tissue level, possibly contributing to insulin-induced sympathoexcitation.

Impaired sensorimotor control of the hand in congenital absence of functional muscle spindles.

Patients with hereditary sensory and autonomic neuropathy type III (HSAN III) exhibit marked ataxia, including gait disturbances. We recently showed that functional muscle spindle afferents in the leg, recorded via intraneural microelectrodes inserted into the peroneal nerve, are absent in HSAN III, although large-diameter cutaneous afferents are intact. Moreover, there is a tight correlation between loss of proprioceptive acuity at the knee and the severity of gait impairment. We tested the hypothesis that manual motor performance is also compromised in HSAN III, attributed to the predicted absence of muscle spindles in the intrinsic muscles of the hand. Manual performance in the Purdue pegboard task was assessed in 12 individuals with HSAN III and 11 age-matched healthy controls. The mean (±SD) pegboard score (number of pins inserted in 30 s) was 8.1 ± 1.9 and 8.6 ± 1.8 for the left and right hand, respectively, significantly lower than the scores for the controls (15.0 ± 1.3 and 16.0 ± 1.1; P < 0.0001). Performance was not improved after kinesiology tape was applied over the joints of the hand. In 5 patients we inserted a tungsten microelectrode into the ulnar nerve at the wrist. No spontaneous or stretch-evoked muscle afferent activity could be identified in any of the 11 fascicles supplying intrinsic muscles of the hand, whereas touch-evoked activity from low-threshold cutaneous mechanoreceptor afferents could readily be recorded from 4 cutaneous fascicles. We conclude that functional muscle spindles are absent in the short muscles of the hand and most likely absent in the long finger flexors and extensors, and that this largely accounts for the poor manual motor performance in HSAN III. NEW & NOTEWORTHY We describe the impaired manual motor performance in patients with hereditary sensory and autonomic neuropathy type III (Riley-Day syndrome), who exhibit congenital insensitivity to pain, poor proprioception, and marked gait ataxia. We show that functional muscle spindles are absent in the intrinsic muscles of the hand, which we argue contributes to their poor performance in a task involving the precision grip.

T48. Hypersensitivity of the persistent inward current

Motor cortex controls movements but a sensitive mechanism called persistent inward current (PIC) at the spinal cord plays a major role in adjusting the strength. The PIC is subject to descending neuromodulatory systems but also peripheral sensory afferent activity. Hypersensitivity of PIC may cause spasms which are stimulation sensitive. We describe a 46-year old male patient who had frequent and severe but relatively short-lasting bouts of stimulus-sensitive spasms after a suspected myelitis 10 years earlier. Stiff person syndrome and channelopathy of the muscle membrane were closed out. The spasms were very therapy resistant and intrathecal baclofen therapy was planned. A six-channel surface EMG recording of the right upper extremity (muscles: opponens pollicis, abductor digiti minimi, flexor carpi radialis, extensor carpi radialis, biceps brachii, triceps brachii) and repeated serial electrical stimuli of the radial nerve (30 Hz, 10 mA, 50 stimuli) and the median nerve at wrist (30 Hz, 6 mA, 50 stimuli) and vibratory stimulation of muscles. H-reflex measurements of the median nerve and needle EMG recordings during spasms. The serial, but not single, electrical stimuli caused activation of all the recorded muscles with different delay times ranging from 250 to 2500 ms. We saw augmentation of the responses with shortening delay times with repeated serial stimuli. Vibratory stimulation of the abductor digiti minimi muscle also caused activation of all the muscles recorded but with little augmentation. Vibratory stimulus of the biceps brachii muscle caused a very strong contraction of all the muscles recorded. This stimulus could not be repeated because of the strong response. The post-stimulus contractions were confined to the right upper extremity. EMG recorded with needle during spasms resembled normal muscle activity. When measuring the median nerve H-reflex, getting an M-response increased the amplitude of H-reflex. With this patient we could reveal typical behavior of PIC hypersensitivity to peripheral stimuli. The delay times of stimulus-sensitive motor reactions of different muscles varied but they were relatively long indicating the involvement of a neuromodulatory system (G-proteins, intracellular cascades) instead of the ionotrophic activation. The responses were confined to one extremity. Serial stimuli of both A beta and A alpha sensory axons caused reactions. We saw augmentation of the responses and shortening of the delay times with repeated serial or vibratory stimuli. The motor contractions lasted for a few minutes at most and were mainly tonic. Measurements of H-reflex showed that even a small muscle afferent activation caused an increased PIC response. EMG during spasms resembled normal muscle activation. With these features hypersensitivity of PIC can be diagnosed and differentiated from other syndromes with sustained motor symptoms.

Emergence of gamma motor activity in an artificial neural network model of the corticospinal system.

Muscle spindle discharge during active movement is a function of mechanical and neural parameters. Muscle length changes (and their derivatives) represent its primary mechanical, fusimotor drive its neural component. However, neither the action nor the function of fusimotor and in particular of γ-drive, have been clearly established, since γ-motor activity during voluntary, non-locomotor movements remains largely unknown. Here, using a computational approach, we explored whether γ-drive emerges in an artificial neural network model of the corticospinal system linked to a biomechanical antagonist wrist simulator. The wrist simulator included length-sensitive and γ-drive-dependent type Ia and type II muscle spindle activity. Network activity and connectivity were derived by a gradient descent algorithm to generate reciprocal, known target α-motor unit activity during wrist flexion-extension (F/E) movements. Two tasks were simulated: an alternating F/E task and a slow F/E tracking task. Emergence of γ-motor activity in the alternating F/E network was a function of α-motor unit drive: if muscle afferent (together with supraspinal) input was required for driving α-motor units, then γ-drive emerged in the form of α-γ coactivation, as predicted by empirical studies. In the slow F/E tracking network, γ-drive emerged in the form of α-γ dissociation and provided critical, bidirectional muscle afferent activity to the cortical network, containing known bidirectional target units. The model thus demonstrates the complementary aspects of spindle output and hence γ-drive: i) muscle spindle activity as a driving force of α-motor unit activity, and ii) afferent activity providing continuous sensory information, both of which crucially depend on γ-drive.

Fatigue and Exhaustion in Hypoxia: The Role of Cerebral Oxygenation.

Fan, Jui-Lin, and Bengt Kayser. Fatigue and exhaustion in hypoxia: the role of cerebral oxygenation. High Alt Med Biol. 17:72-84, 2016.-It is well established that ascent to high altitude is detrimental to one's aerobic capacity and exercise performance. However, despite more than a century of research on the effects of hypoxia on exercise performance, the underlying mechanisms remain incompletely understood. While the cessation of exercise, or the reduction of its intensity, at exhaustion, implies reduced motor recruitment by the central nervous system, the mechanisms leading up to this muscular derecruitment remain elusive. During exercise in normoxia and moderate hypoxia (∼1500-2500 m), peripheral fatigue and activation of muscle afferents probably play a major role in limiting exercise performance. Meanwhile, studies suggested that cerebral tissue deoxygenation may play a pivotal role in impairing aerobic capacity during exercise in more severe hypoxic conditions (∼4500-6000 m). However, recent studies using end-tidal CO2 clamping, to improve cerebral tissue oxygenation during exercise in hypoxia, failed to demonstrate an improvement in exercise performance. In light of these recent findings, which seem to contradict the hypothetical role of cerebral tissue deoxygenation as a performance limiting factor at high altitude, this short review aims to provide a critical reappraisal of the extant literature and ends exploring some potential avenues for further research in this field.

Long-Term Effects of Botulinum Toxin Complex Type A Injection on Mechano- and Metabo-Sensitive Afferent Fibers Originating from Gastrocnemius Muscle.

The aim of the present study was to investigate long term effects of motor denervation by botulinum toxin complex type A (BoNT/A) from Clostridium Botulinum, on the afferent fibers originating from the gastrocnemius muscle of rats. Animals were divided in 2 experimental groups: 1) untreated animals acting as control and 2) treated animals in which the toxin was injected in the left muscle, the latter being itself divided into 3 subgroups according to their locomotor recovery with the help of a test based on footprint measurements of walking rats: i) no recovery (B0), ii) 50% recovery (B50) and iii) full recovery (B100). Then, muscle properties, metabosensitive afferent fiber responses to potassium chloride (KCl) and lactic acid injections and Electrically-Induced Fatigue (EIF), and mechanosensitive responses to tendon vibrations were measured. At the end of the experiment, rats were killed and the toxin injected muscles were weighted. After toxin injection, we observed a complete paralysis associated to a loss of force to muscle stimulation and a significant muscle atrophy, and a return to baseline when the animals recover. The response to fatigue was only decreased in the B0 group. The responses to KCl injections were only altered in the B100 groups while responses to lactic acid were altered in the 3 injected groups. Finally, our results indicated that neurotoxin altered the biphasic pattern of response of the mechanosensitive fiber to tendon vibrations in the B0 and B50 groups. These results indicated that neurotoxin injection induces muscle afferent activity alterations that persist and even worsen when the muscle has recovered his motor activity.

The ventilatory response to muscle afferent activation during concurrent hypercapnia in humans: central and peripheral mechanisms.

What is the central question of this study? During hypercapnia but not normocapnia, activation of muscle afferents by postexercise circulatory occlusion increases ventilation, possibly due to additional activation of metabolite-stimulated muscle afferents. Alternatively, chemoreflex activation caused by hypercapnia may have a synergistic interaction with muscle afferent feedback, so stimulating breathing. What is the main finding and its importance? Muscle afferent activation during muscle hypercapnia with concurrent systemic normocapnia did not increase breathing. With systemic hypercapnia, there was a response that did not change with hyperoxic hypercapnia. A synergistic interaction between central chemoreception and muscle afferent feedback is therefore indicated. During hypercapnia, activation of thin-fibre muscle afferents using postexercise circulatory occlusion (PECO) provokes a ventilatory response not seen in normocapnia. We investigated the ventilatory responses to PECO when hypercapnia was restricted to the active muscle ('Local' trial) or during systemic hypercapnia ('Systemic' trial). In the Local trial, a hypercapnic gas mixture (5% CO2 in air) was inhaled for 5min when circulation to the active calf muscle was open, then rapidly closed by thigh-cuff inflation (200mmHg), immediately before a return to breathing room air and performance of isometric exercise and PECO. In the Systemic trial, circulation through the muscle was closed throughout the exercise and PECO phases, performed during the hypercapnic gas inhalation. In a third trial, in Systemic conditions a hyperoxic hypercapnic gas mixture (95% O2 and 5% CO2 ) was breathed for 1min during PECO ('Hyperoxia' trial). The increase in ventilation during calf muscle exercise was not different between trials. In the Local trial, ventilation fell to pre-exercise levels during PECO, but in the Systemic trial it remained at end-exercise levels (4.9±0.8 lmin(-1) ) and was equally well maintained throughout the Hyperoxia trial (4.3±1lmin(-1) ). Cardiovascular responses during PECO were not different in the three trials, indicating similar activation of muscle afferents. Sustained elevation of ventilation during PECO in the Systemic but not the Local trial suggests that ventilation is stimulated via an interaction between muscle afferent feedback and hypercapnia-induced chemoreceptor activation. The similar ventilatory responses in Systemic and Hyperoxia conditions further suggest that in this respect, central rather than peripheral chemoreceptors play the major role.