Sinusoidal Stretch Research Articles

Attenuation of muscle spindle firing with artificially increased series compliance during stretch of relaxed muscle.

Muscle spindles relay vital mechanosensory information for movement and posture, but muscle spindle feedback is coupled to skeletal motion by a compliant tendon. Little is known about the effects of tendon compliance on muscle spindle feedback during movement, and the complex firing of muscle spindles makes these effects difficult to predict. Our goal was to investigate changes in muscle spindle firing using added series elastic elements (SEEs) to mimic a more compliant tendon, and to characterize the accompanying changes in firing with respect to muscle-tendon unit (MTU) and muscle fascicle displacements (recorded via sonomicrometry). Sinusoidal, ramp-and-hold and triangular stretches were analysed to examine potential changes in muscle spindle instantaneous firing rates (IFRs) in locomotor- and perturbation-like stretches as well as serial history dependence. Added SEEs effectively reduced overall MTU stiffness and generally reduced muscle spindle firing rates, but the effect differed across stretch types. During sinusoidal stretches, peak and mean firing rates were not reduced and IFR was best-correlated with fascicle velocity. During ramp stretches, SEEs reduced the initial burst, dynamic and static responses of the spindle. Notably, IFR was negatively related to fascicle displacement during the hold phase. During triangular stretches, SEEs reduced the mean IFR during the first and second stretches, affecting the serial history dependence of mean IFR. Overall, these results demonstrate that tendon compliance may attenuate muscle spindle feedback during movement, but these changes cannot be fully explained by reduced muscle fascicle length or velocity, or MTU force.

Intrafusal cross-bridge dynamics shape history-dependent muscle spindle responses to stretch.

Computational models can be critical to linking complex properties of muscle spindle organs to the sensory information that they encode during behaviours such as postural sway and locomotion where few muscle spindle recordings exist. Here, we augment a biophysical muscle spindle model to predict the muscle spindle sensory signal. Muscle spindles comprise several intrafusal muscle fibres with varied myosin expression and are innervated by sensory neurons that fire during muscle stretch. We demonstrate how cross-bridge dynamics from thick and thin filament interactions affect the sensory receptor potential at the spike initiating region. Equivalent to the Ia afferent's instantaneous firing rate, the receptor potential is modelled as a linear sum of the force and rate change of force (yank) of a dynamic bag1 fibre and the force of a static bag2/chain fibre. We show the importance of inter-filament interactions in (i) generating large changes in force at stretch onset that drive initial bursts and (ii) faster recovery of bag fibre force and receptor potential following a shortening. We show how myosin attachment and detachment rates qualitatively alter the receptor potential. Finally, we show the effect of faster recovery of receptor potential on cyclic stretch-shorten cycles. Specifically, the model predicts history-dependence in muscle spindle receptor potentials as a function of inter-stretch interval (ISI), pre-stretch amplitude and the amplitude of sinusoidal stretches. This model provides a computational platform for predicting muscle spindle response in behaviourally relevant stretches and can link myosin expression seen in healthy and diseased intrafusal muscle fibres to muscle spindle function.

A New High‐Speed Biaxial Testing System for Rodent Myocardium Viscoelastic Measurement under Dynamic Loadings

IntroductionMyocardium stiffening is well known in heart failure (HF) development, and it contributes to cardiac dysfunction. Myocardium is viscoelastic, which means that both elastic and viscous resistance exist under dynamic loading. There are limited studies of myocardium viscoelasticity, particularly for the right ventricle (RV). Because viscoelasticity is a time‐ and strain‐dependent mechanical behavior, the measurement at physiological rates & non‐linear deformation is critical. This study aims to develop a high‐speed biaxial tester that induces physiological deformation to characterize RV viscoelasticity in rats.MethodsTo enable the viscoelasticity measurement at physiological conditions, we built a biaxial tester that induces non‐linear, cyclic stretch of myocardium at rodent heart rates. Biaxial sinusoidal stretches were induced by actuators (1400mm/s) (Zaber), forces were recorded by load cells (Honeywell) at 1 kHz, and strains were obtained by a high‐speed camera (Baumer) at up to 200 fps. The LabVIEW and MATLAB codes were developed for performing biaxial tests at various frequencies with synchronized force and image data acquisition. To validate the biaxial tester, isotropic polydimethylsiloxane (PDMS) was used due to its similar viscoelasticity to cardiovascular tissues. PDMS sheets were prepared (Sylgard 184) for equibiaxial tests. Then, consistency between different axes’ measurements, synchronization of the axes’ movement, and accurate viscoelastic measurement were evaluated. Next, we performed equibiaxial cyclic sinusoidal tests on healthy rat RVs. After euthanasia, RV free wall was dissected and mounted. The outflow track direction was defined as the longitudinal direction. The RV was placed in a relaxant solution prior to testing, then preloaded by ~0.1 N and preconditioned by 15 cycles. Stress‐strain loops were derived for viscoelastic analysis.ResultsFirst, we examined if the biaxial tester could achieve planar biaxial tests at desired frequencies. The equibiaxial data obtained from PDMS sheets showed that the tester induced cyclic sinusoidal stretch at various frequencies up to 8 Hz (Fig. 1a), and the viscoelastic behavior measured at two axes were very close (Fig. 1b), thus confirming the tester’s accurate biaxial measurement of the isotropic material. The PDMS clearly showed frequency‐dependent changes in the hysteresis loops (Fig. 1c), with trends of increasing elasticity (slope of loop) and viscosity (area of loop) at higher frequencies. We further derived the viscosity by measuring Tan(δ) (Fig. 1d). The frequency‐dependent elasticity and viscosity of the PDMS sheet were consistent with literature data. Next, we obtained preliminary viscoelasticity data of healthy rat RVs (at 0.1‐2 Hz). Our data showed strain‐rate dependent changes in the hysteresis loops (Fig. 2). The dissipated energy (loop area) as well as the stiffness (loop slope) of the RV tended to increase with increasing frequency. The RV tissue showed similar viscoelastic behavior in both directions at all frequencies.ConclusionOur data showed that this novel testing system enables biaxial viscoelastic measurement of myocardium under physiological conditions (0.1‐8Hz) across small and large animal species. The establishment of this system allows further exploration of RV tissues at higher frequencies (5‐8 Hz) and in diseased states, which will improve the understanding of cardiac biomechanics in HF progression.

As the endothelial cell reorients, its tensile forces stabilize

When adherent cells are subjected to uniaxial sinusoidal stretch at frequencies close to physiological, their body and their contractile stress fibers realign nearly perpendicularly to the stretch axis. A common explanation for this phenomenon is that stress fibers reorient along the direction where they are unaffected by the applied cyclic stretch and thus can maintain optimal (homeostatic) tensile force. The ability of cells to achieve tensional homeostasis in response to external disturbances is important for normal physiological functions of cells and tissues and it provides protection against diseases, including cancer and atherosclerosis. However, quantitative experimental data that support the idea that stretch-induced reorientation is associated with tensional homeostasis are lacking. We observed previously that in response to uniaxial cyclic stretch of 10% strain amplitudes, traction forces of single endothelial cells reorient in the direction perpendicular to the stretch axis. Here we carried out a secondary analysis of those data to investigate whether this reorientation of traction forces is associated with tensional homeostasis. Our analysis showed that stretch-induced reorientation of traction forces was accompanied by attenuation of temporal variability of the traction field to the level that was observed in the absence of stretch. These findings represent a quantitative experimental evidence that stretch-induced reorientation of cellular traction forces is associated with the cell’s tendency to achieve tensional homeostasis.

Self-Powered Coiled Carbon-Nanotube Yarn Sensor for Gastric Electronics.

The strong peristaltic contraction of the stomach facilitates mixing and emptying of ingested food, which occurs rhythmically at approximately 3 cycles/min (cpm) in humans. Generally, most patients with gastroparesis show gastric electrical dysrhythmia that is disrupted electrical signals controlling gastric contractions. For treatment of gastric electrical dysrhythmia, in vivo electrical impulses to the stomach via an implanted gastric stimulator have been known to restore these gastric deformations. Nevertheless, improved sensors to monitor gastric contractions are still needed in current gastric stimulators. Recently, we have developed a new technology converting mechanical motion to electrical energy by using stretch-induced capacitance changes of a coiled carbon-nanotube (CNT) yarn. For its potential use as a gastric deformation sensor, the performance of a coiled CNT yarn was evaluated in several biological fluids. For a sinusoidal stretch to 30%, the peak-to-peak open-circuit voltage (OCV) was consistently generated at frequencies below 0.1 Hz. This sinusoidal variation in OCV augmented as the strain increased from 10 to 30%. In an in vitro artificial gastric system, the OCV was approximately linearly proportional to the balloon volume, which can monitor periodic deformations of the balloon at 2, 3, and 4 cpm as shown for human gastric deformations. Moreover, stretchy coiled yarns generate the peak electrical voltage and power when deformed. The present study shows that a self-powered CNT yarn sensor can not only monitor the changes in frequency and amplitude of volumetric change but also generate electrical power by periodic deformations of the balloon. Therefore, it seems possible to automatically deliver accurate electrical impulses according to real-time evaluation of a patient's gastric deformation based on information on the frequency, amplitude, and rate of the OCV from CNT yarn.

Mechanical stretch inhibits mesenchymal stem cell adipogenic differentiation through TGFβ1/Smad2 signaling

Mesenchymal stem cells (MSCs) are the common precursors of several functionally disparate cell lineages. A plethora of chemical and physical stimuli contribute to lineage decisions and guidance, including mechanical stretch concomitant with physical movement. Here, we examined how stretch regulates MSC differentiation into adipocytes and the intracellular signaling pathways involved. MSCs were cultured under adipogenic conditions and divided into a control and an experimental group. Cultures in the experimental group were subjected to a sinusoidal stretch regimen delivered via flexible culture bottoms (5% magnitude, 10 times per min, 6h/day, 3 or 5 days). Expression levels of the adipocyte markers PPARγ-2, adiponectin, and C/EBPα were measured as indices of differentiation. Compared to controls, MSCs exposed to mechanical stretch exhibited downregulated PPARγ-2, adiponectin, and C/EBPα mRNA expression. Alternatively, stretch upregulated phosphorylation of Smad2. This stretch-induced increase in Smad2 phosphorylation was suppressed by pretreatment with the TGFβ1/Smad2 pathway antagonist SB-431542. Pretreatment with the TGFβ1/Smad2 signaling agonist TGFβ1 facilitated the inhibitory effect of stretch on the expression levels of PPARγ-2, adiponectin, and C/EBPα proteins, while pretreatment with SB-431542 reversed the inhibitory effects of subsequent stretch on the expression levels of these markers. These results strongly suggest that the anti-adipogenic effects of mechanical stretch on MSCs are mediated, at least in part, by activation of the TGFβ1/Smad2 signaling pathway.

Neck proprioceptors contribute to the modulation of muscle sympathetic nerve activity to the lower limbs of humans

Several different strategies have now been used to demonstrate that the vestibular system can modulate muscle sympathetic nerve activity (MSNA) in humans and thereby contribute to the regulation of blood pressure during changes in posture. However, it remains to be determined how the brain differentiates between head-only movements that do not require changes in vasomotor tone in the lower limbs from body movements that do require vasomotor changes. We tested the hypothesis that neck movements modulate MSNA in the lower limbs of humans. MSNA was recorded in 10 supine young adult subjects, at rest, during sinusoidal stretching of neck muscles (100 cycles, 35° peak to peak at 0.37 ± 0.02 Hz) and during a ramp-and-hold (17.5° for 54 ± 9 s) static neck muscle stretch, while their heads were held fixed in space. Cross-correlation analysis revealed cyclical modulation of MSNA during sinusoidal neck muscle stretch (modulation index 45.4 ± 5.3 %), which was significantly less than the cardiac modulation of MSNA at rest (78.7 ± 4.2 %). Interestingly, cardiac modulation decreased significantly during sinusoidal neck displacement (63.0 ± 9.3 %). By contrast, there was no significant difference in MSNA activity during static ramp-and-hold displacements of the neck to the right or left compared with that with the head and neck aligned. These data suggest that dynamic, but not static, neck movements can modulate MSNA, presumably via projections of muscle spindle afferents to the vestibular nuclei, and may thus contribute to the regulation of blood pressure during orthostatic challenges.

Stretch reflexes and joint dynamics in rheumatoid arthritis

In clinically diagnosed rheumatoid arthritis (RA), studies were conducted to investigate the reflex and passive tissue contribution to measured increases in joint stiffness in the resting upper limb and during constant contractions of an attached muscle. The tonic stretch reflex was induced by a servo-controlled sinusoidal stretch perturbation of the metacarpophalangeal joint of RA patients, and age- and sex-matched controls. The resulting reflexes and mechanical changes in the RA affected joint were explored. Surface electromyographic (EMG) measurements were obtained from first dorsal interosseus muscle. Reflex gain (EMG/joint angle amplitude ratio), phase difference (reflex delay after stretch), coherence square (proportion of EMG variance accounted for by joint angle changes), joint mechanical gain (torque-joint angle amplitude ratio) and mechanical phase difference (torque response delay after stretch) were determined. RA patients showed decreased reflex gain that was partly due to coexistent severe muscle weakness, as determined from maximum voluntary contraction and grip pressure estimates. The decreased reflex gain was most evident at high stretch frequency suggesting a disproportionate loss of the large diameter afferent response and also increased reflex delay in the patients. These changes ensemble suggest significant loss of neural drive to the motor unit population. Patients also showed increased joint stiffness (measured as torque gain) in the contracting muscle, but there was no evidence of reflex activity or increased stiffness at rest. This suggests that the increased joint stiffness in RA was due to changes in the mechanical properties of the active muscle-joint system rather than changes in reflex properties.

Age‐related physiological and morphological changes of muscle spindles in rats

Age-related physiological and morphological changes of muscle spindles were examined in rats (male Fischer 344/DuCrj: young, 4-13 months; middle-aged, 20-22 months; old, 28-31 months). Single afferent discharges of the muscle spindles in gastrocnemius muscles were recorded from a finely split dorsal root during ramp-and-hold (amplitude, 2.0 mm; velocity, 2-20 mm s(-1)) or sinusoidal stretch (amplitude, 0.05-1.0 mm; frequency, 0.5-2 Hz). Respective conduction velocities (CVs) were then measured. After electrophysiological experimentation, the muscles were dissected. The silver-impregnated muscle spindles were teased and then analysed using a light microscope. The CV and dynamic response to ramp-and-hold stretch of many endings were widely overlapped in old rats because of the decreased CV and dynamic response of primary endings. Many units in old rats showed slowing of discharge during the release phase under ramp-and-hold stretch and continuous discharge under sinusoidal stretch, similarly to secondary endings in young and middle-aged rats. Morphological studies revealed that primary endings of aged rat muscle spindles were less spiral or non-spiral in appearance, but secondary endings appeared unchanged. These results suggest first that primary muscle spindles in old rats are indistinguishable from secondary endings when determined solely by previously used physiological criteria. Secondly, these physiological results reflect drastic age-related morphological changes in spindle primary endings.

Biomechanical and electromyogram characterization of neuroleptic-induced rigidity in the rat

Rodent models of Parkinson’s disease (PD) are usually assessed using measures of akinesia, but other important parkinsonian symptoms such as rigidity are only rarely quantified. This is in part due to technical difficulties in obtaining such measures in small animals. In the present study we developed quantitative methods to provide time-course assessment of the alternations of muscle tone of parkinsonian rats. A portable and miniature biomechanical stretching device was established to manually stretch the hindlimb of awake rats with muscle rigidity induced by dopamine D2-receptor antagonist raclopride (5 mg/kg, i.p.). From the measured angular displacement angle and reactive torque of sinusoidal stretches at five varied frequencies, viscoelastic components of the muscle tone can be derived. In addition, non-invasive multielectrode was applied to record the tonic and phasic components of the gastrocnemius muscle electromyogram (EMG). Our biomechanical measurements showed not only increase in stiffness (P<0.05) but also increase in viscous components (P<0.05) that matched the time course of increased amplitude of EMG activity (P<0.05). There was a significant positive correlation between all of these measures and akinesia, as measured by the conventional bar-test for catalepsy (with a correlation coefficient of 0.87 at stiffness, 0.92 at viscosity and 0.96 at amplitude of EMG). Phasic contraction counts (PCC) of voluntary EMG exhibited a significantly negative correlation with the bar test scores (correlation coefficient=−0.78). These results confirm that akinesia induced by D2-receptor blockade also induces a rigidity that shares many features with human PD. These novel techniques for quantifying biomechanical and electromyographic parameters provide objective assessment methods for investigating the time-course changes of abnormal muscle tone in rat models of PD that will be useful for evaluating novel treatments.

Mathematical Models of Proprioceptors. I. Control and Transduction in the Muscle Spindle

We constructed a physiologically realistic model of a lower-limb, mammalian muscle spindle composed of mathematical elements closely related to the anatomical components found in the biological spindle. The spindle model incorporates three nonlinear intrafusal fiber models (bag(1), bag(2), and chain) that contribute variously to action potential generation of primary and secondary afferents. A single set of model parameters was optimized on a number of data sets collected from feline soleus muscle, accounting accurately for afferent activity during a variety of ramp, triangular, and sinusoidal stretches. We also incorporated the different temporal properties of fusimotor activation as observed in the twitchlike chain fibers versus the toniclike bag fibers. The model captures the spindle's behavior both in the absence of fusimotor stimulation and during activation of static or dynamic fusimotor efferents. In the case of simultaneous static and dynamic fusimotor efferent stimulation, we demonstrated the importance of including the experimentally observed effect of partial occlusion. The model was validated against data that originated from the cat's medial gastrocnemius muscle and were different from the data used for the parameter determination purposes. The validation record included recently published experiments in which fusimotor efferent and spindle afferent activities were recorded simultaneously during decerebrate locomotion in the cat. This model will be useful in understanding the role of the muscle spindle and its fusimotor control during both natural and pathological motor behavior.

Role of Occlusal Vertical Dimension in Spindle Function

Several studies have suggested the jaw-muscle spindle as the receptor responsible for regulating and maintaining the occlusal vertical dimension (OVD). However, to challenge this assumption, we hypothesized that long-term changes in OVD could affect the sensory inputs from jaw-muscle spindles. In this study, we investigated changes in masseter muscle spindle function under an increased OVD (iOVD) condition. Responses of primary and secondary endings of masseter muscle spindles to cyclic sinusoidal stretches were investigated. Twenty barbiturate-anesthetized female Wistar rats were divided into control and iOVD groups. Rats in the iOVD group received a 2.0-mm composite resin build-up to the maxillary molars. After iOVD, masseter muscle spindle sensitivity gradually decreased. Primary and secondary spindle endings were affected differently. We conclude that iOVD caused reduction in masseter muscle spindle sensitivity. This result suggests that peripheral sensory plasticity may occur following changes in OVD. Such changes may provide a basis for physiological adaptation to clinical occlusal adjustments.

Validation of portable muscle tone measurement device for quantifying velocity-dependent properties in elbow spasticity

The objective of this study is to develop a portable device for quantifying the velocity-dependent properties of spastic elbow muscles. Based on a motor-driven system, validation tests of the portable system such as accuracy and response of sensors were first examined. Furthermore, simulated modules (inertia, damper and spring) as well as elbow joints (15 control and 15 hemiplegic subjects) were manually stretched under four different frequencies (1/3, 1/2, 1 and 3/2 Hz) through 60° range of motion. Joint resistance and displacement during sinusoidal stretch were collected for further analysis. Two quantitative parameters (i.e., viscous components under each frequency and averaged viscosity across four frequencies) were derived to estimate the velocity-dependent properties of elbow joint. Tests of simulated modules confirm the manual stretch protocol and data analysis are valid in estimating the velocity-dependent component during a sinusoidal stretch. Compared to normal control, viscous component in each stretch frequency and averaged viscosity were significantly higher in subjects with spasticity ( P<0.001). The viscous component and averaged viscosity were found highly correlated with the modified Ashworth scale. These findings suggest that measurements of viscous component and averaged viscosity during manual sinusoidal stretching using the portable device could be clinically useful in evaluating spasticity.

Effects of hypodynamia-hypokinesia on the muscle spindle discharges of rat soleus muscle.

The aim of this study was to determine whether Ia and II fiber discharges of soleus muscle spindles were modified after a 14-day period of hypodynamia (absence of weight bearing) and hypokinesia (reduction of motor activity). Fifty-one and 38 afferent fibers were studied, respectively, in control and hypodynamia-hypokinesia (HH) groups. Under deep anesthesia (pentobarbital, 30 mg/kg), a L3-L6 laminectomy was performed. Unitary potentials from the L5 dorsal root were recorded in response to ramp-and-hold stretches applied at two stretch amplitudes (3 and 4 mm) and four stretch velocities (6, 10, 15, and 30 mm/s) and to sinusoidal stretches applied at four stretch amplitudes (0.12, 0.25, 0.5, and 1 mm) and six stretch frequencies (0.5, 1, 2, 3, 6, and 10 Hz). In both animal groups, the Ia fibers showed higher dynamic index values, smaller linear range, and higher vibration sensitivity than the II fibers. They also exhibited a pause in their discharges during the stretch release contrary to II fibers, which displayed no pause in their responses. After HH, our results showed that for both fiber types all parameters measured under ramp-and-hold stretches (except the static sensitivity) were significantly increased and under sinusoidal stretches, the vibration sensitivity increased, and the response amplitude only increased at 0.12-mm stretch amplitude. The linear range of Ia afferents was limited to 0.12 mm, whereas it was unchanged for the II fibers. After HH, the stretches could be better transmitted to the muscle spindles, probably resulting from changes in passive mechanical properties of the soleus.

Characterization of spindle afferents in rat soleus muscle using ramp-and-hold and sinusoidal stretches.

The discharge properties of 51 afferents were studied in the rat soleus muscle spindles. Under deep anesthesia using a pentobarbital sodium solution (30 mg/kg), a laminectomy was performed and the right L(4) and L(5) dorsal and ventral roots were transected near their entry into the spinal cord. In situ, the minimal (L(min)) muscle length [3 +/- 0.08 (SE) cm] of the soleus was measured at full ankle extension. Unitary potentials from the L(5) dorsal root were recorded in response to ramp-and-hold stretches applied at 3 mm (S3) and 4 mm (S4) amplitudes and four stretch velocities (6, 10, 15, and 30 mm/s), sinusoidal stretches performed at four amplitudes (0.12, 0.25, 0.5, and 1 mm) and six stretch frequencies (0.5, 1, 2, 3, 6, and 10 Hz), and vibrations applied at 50-, 100-, and 150-Hz frequencies. These two kinds of stretches were performed at three different muscle lengths (L(min+10%), L(min+15%), and L(min+20%)), whereas vibrations were applied at L(min+20%) muscle length. Conduction velocity of the fibers was calculated but did not allow to discriminate different fiber types. However, the mean conduction velocity of the first fiber group (43.3 +/- 0.8 m/s) was significantly higher than that of the second fiber group (33.9 +/- 0.9 m/s). Three parameters allowed to differentiate the responses of primary and secondary endings: the dynamic index (DI), the discharge during the stretch release from the ramp-and-hold stretches, and the linear range and the vibration sensitivity from sinusoidal stretches. The slope histogram of the linear regression based on the DI and the stretch velocity was clearly bimodal. Therefore the responses were separated into two groups. During the stretch release at a velocity of 3 mm/s, the first response group (n = 26) exhibited a pause, whereas the second (n = 25) did not. The linear range of the second ending group (0.12-1 mm) was broader than that of the first (0.12-0.25 mm). The first ending group showed a higher sensitivity to high-vibration frequencies of small amplitude than the second. In comparison with the literature, we can assert that the first and the second ending groups corresponded to the primary and secondary endings, respectively. In conclusion, our study showed that in rat soleus muscle spindles, it was possible to immediately classify the discharge of Ia and II fibers by using some parameters measured under ramp-and-hold and sinusoidal stretches.

Effects of the calcium antagonist nifedipine on the afferent impulse activity of isolated cat muscle spindles

The impulse activity of muscle spindles isolated from the cat tenuissimus muscle was investigated under varying concentrations of the L-type calcium channel blocker nifedipine. At a concentration of 25 μM nifedipine impulse activity was clearly diminished in both primary and secondary endings. However, low concentrations of the drug (5–10 μM) exerted unexpected excitatory effects. The dynamic properties of primary endings in particular were augmented; those of secondary endings were also increased, although only slightly. A detailed analysis of the afferent discharge patterns obtained under ramp-and-hold stretches yielded the following effects of 10 μM nifedipine. (1) The initial burst at the beginning of the ramp phase of a stretch was increased in primary endings; (2) the peak dynamic discharge frequency at the end of the ramp phase was considerably increased in most primary endings; (3) the sensitivity of the peak dynamic discharge value to varying amplitudes and velocities of stretch was significantly enhanced in primary endings, and also increased, although only slightly, in secondary endings; (4) the rise in the discharge frequency during the ramp phase of a stretch was augmented in both types of ending, the effect being again stronger in primary endings; (5) the fast adaptive decay of the impulse frequency following the ramp phase of a ramp-and-hold stretch was significantly increased in primary endings, but remained unaffected in secondary endings. The enhanced dynamic properties of primary endings were also observed under small sinusoidal stretch stimuli (10 μm, 40 Hz), where nifedipine induced a significant shift in the position of the 1:1 driven action potentials toward smaller phase values. In view of an increase in tension in the isolated muscle spindle and an increased initial burst in primary endings in the presence of nifedipine, it is suggested that the drug facilitates the attachment of cross-bridges in the poles of the intrafusal muscle fibers. The increase in the dynamic properties of primary endings points to the possibility that the drug preferentially affects the nuclear bag 1 fiber. The inhibitory effect on the afferent discharge rate at high doses of the drug is interpreted as the consequence of a calcium channel block in the membranes of the sensory endings. The membrane potential of sensory endings appears to be highly dependent on sustained Ca 2+ conductance.

Toe flexor muscle spindle discharge and stretch modulation during locomotor activity in the decerebrate cat.

In order to investigate the nature (i.e. static or dynamic) of fusimotor drive to the flexor hallucis longus (FHL) and flexor digitorum longus (FDL) muscles during locomotion we recorded Ia and group II muscle spindle afferent responses to sinusoidal stretch (0.25 and 1 mm amplitude, respectively, 4-5 Hz) in a decerebrate cat preparation. FHL Ia and group II afferents generally had increased discharge rates and decreased modulation to stretch throughout the step cycle, compared to rest, suggesting raised static gamma drive at all locomotor phases. Although the modulation of Ia afferents was reduced during locomotion, most (13 of 18) showed a clear increasing trend during homonymous muscle activity (extension). This was consistent with phasic dynamic gamma drive to FHL spindles linked with alpha drive. In agreement with previous reports, FHL gave a single burst of EMG activity during the step cycle while FDL alpha drive had two components. One was related to extension while the other comprised a brief burst around the end of this phase. Typically FDL Ia and group II afferents also had elevated firing rates and reduced modulation at all locomotor phases, again implicating static gamma drive. Half the afferents (seven Ia, three group II) showed increased discharge during extension, suggesting phasic static gamma drive. There was no gamma drive associated with the late FDL alpha burst. In conclusion, the gamma drives to FHL and FDL differed during locomotion. FHL, which has the alpha drive of a classic extensor, received gamma drive that closely resembled other extensors. The gamma drive of FDL, which exhibits both extensor and flexor alpha synergies, did not match either muscle type. These observations are compatible with the view that fusimotor drive varies in different muscles during locomotion according to the prevailing sensorimotor requirements.

Induction of apoptosis in vascular smooth muscle cells by mechanical stretch.

We studied the response of porcine vascular smooth muscle cells (PVSMCs) to cyclic sinusoidal stretch at a frequency of 1 Hz. Cyclic stretch with an area change of 25% caused an increase in PVSMC apoptosis, which was accompanied by sustained activation of c-Jun NH(2)-terminal kinases (JNK) and the mitogen-activated protein kinase p38. Cyclic stretch with an area change of 7% had no such effect. Infection of PVSMCs with recombinant adenoviruses expressing constitutively active forms of upstream molecules that activate JNK and p38 also led to apoptosis. The simultaneous blockade of both JNK and p38 pathways with adenovirus-mediated expression of dominant-negative mutants of c-Jun and p38 caused a significant decrease (to 1/2) of the apoptosis induced by 25% cyclic stretch. The 25% stretch also caused sustained clustering of tumor necrosis factor-alpha (TNF-alpha) receptor-1 and its association with TNF-alpha receptor-associated factor-2 (TRAF-2). Overexpressing the wild-type TRAF-2 in PVSMCs caused an increase in apoptosis. In contrast, the expression of a dominant-negative mutant of TRAF-2 attenuated stretch-induced apoptois. These results support the hypothesis that circumferential overload under hypertensive conditions induces a clustering of death receptors that cause vascular smooth muscle cell apoptosis.

Structural model of the muscle spindle.

A model of the muscle spindle was developed based on its anatomical structure. The model contains three intrafusal fibers (bag1, bag2, and chain), two efferents (dynamic gamma efferent to the bag1 fiber and static gamma efferent to bag2 and chain fibers), and two afferents [primary (Ia) and secondary (II)]. As in the real muscle spindle, the spindle model, under the modulation of gamma efferents, responds to the extrafusal muscle fiber length. Both outputs (Ia and II afferents) of the model were compared extensively with published data, under both sinusoidal stretch (with different stretch amplitudes and frequencies) and ramp and hold stretch (with different stretch amplitudes and velocities) in three different fusimotor activation conditions (dynamic gamma stimulation, static gamma stimulation, and without gamma stimulation). Model Ia afferent responses fit the published data well with active gamma input, but less well in the passive state. Model II afferent responses also fit the published data, although less quantitative data were available for comparison. The model correctly predicted the fractional power dependence of the primary and secondary ending responses on stretch velocity. The current model provides a powerful tool for simulation studies of neuromusculoskeletal systems, and demonstrates the feasibility of using a structural approach to model complex neurophysiological systems.

Comparison of the effects of stimulating groups of static gamma axons with different conduction velocity ranges on cat spindles.

In cat peroneus tertius muscles, static gamma axons were prepared in groups of three to four according to the conduction velocity of their axons (fast, intermediate, or slow). Effects of stimulating these groups (at 20, 30, and 50 Hz) on spindle ensemble discharges during sinusoidal stretch (peak-to-peak amplitude, 0.5 mm; frequency linearly increasing from 0.5 to 8 Hz in 10 s) were compared. Ensemble discharges were obtained by digital treatment of the discharges in afferent fibers from all the spindles in peroneus tertius as recorded from the muscle nerve. Stimulation of each group prevented ensemble discharges from falling to very low levels during shortening phases. However, this effect was clearly larger when the group of fast-conducting axons was stimulated. In view of the known effects of the activation of bag(2) and chain fibers (either separately or together) on single primary ending discharges during comparable sinusoidal stretches, this stronger effect supports the view that static gamma axons with faster conduction velocities are more likely to supply more bag(2) fibers than slower ones. Possibly the proportions of bag(2) and chain fibers activated during motor activity are determined by a recruitment of static gamma motoneurons related to their size.