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Theories of muscle contraction.

A survey of the mainstream theories in the modern study of the mechanism of muscle contraction is made, with particular emphasis placed on the experimental results which most influenced the progression of ideas. Starting with early elastic and viscoelastic theories of muscle contraction, a chronological organization is used to present, in detail, the results leading up to the swinging crossbridge model. A brief review is made of the experimental results modifying the original crossbridge model such as transient-state mechanics, in vitro kinetics, and kinetic measurements performed on demembranated muscle fibers. Following a brief synopsis of three of the more prevalent alternative models, a summary of the more relevant structural studies is presented. Finally, recent results pertaining to the mechanism of muscle contraction are presented and their promise for the future is discussed.

Animals↗

Alterations in the rheological flow profile in conduit femoral artery during rhythmic thigh muscle contractions in humans.

The present study examined the rheological blood velocity profile in the conduit femoral artery during rhythmic muscle contractions at different muscle forces. Eight healthy volunteers performed one-legged, dynamic knee-extensor exercise at work rates of 5, 10, 20, 30, and 40 W at 60 contractions per minute. The time and space-averaged, amplitude-weighted mean (V(mean)) and maximum (V(max)) blood flow velocities in the common femoral artery were measured during the cardiosystolic phase (CSP) and cardiodiastolic phase (CDP) by the Doppler ultrasound technique. The V(max)/V(mean) ratio was used as a flow profile index, in which a ratio of approximately 1 indicates a "flat velocity flow profile" and a ratio significantly >1 indicates a "parabolic velocity flow profile." At rest, the V(max)/V(mean) ratio was approximately 1.3 and approximately 1.8 during the CSP and CDP, respectively. The V(max)/V(mean) ratio was higher (p < 0.01) during the CDP than during the CSP, both at rest and at all work rates. The V(max)/V(mean) ratio during the CSP was higher (p < 0.01) at 30 and 40 W compared to at rest. The V(max)/V(mean) ratio during the CDP was lower (p < 0.05) at 5 and 10 W compared to at rest. There was a positive linear correlation between blood flow and incremental work rates during both the CSP and CDP, respectively. Thus under resting conditions, the findings indicate a "steeper" parabolic velocity profile during the CDP than during the CSP. The velocity profile during the CDP furthermore shifts to being less "steep" during rhythmic muscle contractions at lower intensities, but to being reelevated and normalized as at rest during higher intensities. The "steepness" of the parabolic velocity profile observed during the CSP at rest increased during muscle contraction at higher intensities. In conclusion, the blood velocity in the common femoral artery is parabolic both at rest and during exercise for both the CSP and CDP, indicating the persistence of laminar flow. The occurrence of any temporary slight disturbance or turbulence in the flow at the sight of measurement in the common femoral artery does consequently not induce a persisting "disturbed" and fully flat "plug-like" velocity profile. Instead, the "steepness" of the parabolic velocity profile is only slightly modified, whereby blood flow is not impaired. Thus the blood velocity profile, besides being influenced by the muscle contraction-relaxation induced mechanical "impedance," seems also to be modulated by the cardiac- and blood pressure-phases, consequently influencing the exercise blood flow response.

Adult↗

[Effect of muscle contraction on heart rate and skin blood flow. Preliminary results].

Evaluation of heart rate variability is an important tool to study several diseases. The most important tests include the variability of the heart rate as a function of time and as function of frequency, variability of blood pressure and pulsatile cutaneous blood flow (PCBF). We studied the effect of a sustained contraction of the quadriceps muscle on the instantaneous heart rate and pulsatile cutaneous blood flow in 10 healthy subjects. We measured the R-R interval and the instantaneous heart rate, in the time domain, 10 beats before the contraction, the R-R interval that coincided with the onset of the contraction, and the 30 R-R intervals after the beginning of the contraction. To measure the PCBF we used a photopletismograph designed for this purpose. We recorded the surface electromyographic activity (EMG) of the quadriceps muscle to determine the onset and end of the muscle contraction, and measured respiratory movements with a belt. We found an increase of the instantaneous heart rate at the first and second beats after the onset of the contraction. There was a decrease of the pulsatile cutaneous blood flow of the finger pad immediately after the contraction, which lasted for approximately eight beats. The findings support the idea of a central command and co-activation of the motor and sympathetic nervous systems. This efferent sympathetic activity seems to act not just on the contracting muscle but also on the heart and the cutaneous blood vessels of the extremities. These findings imply that it is quite likely that the sympathetic efferent effect has a supraspinal origin. This is a test that could be used to study cardiovascular control by the sympathetic nervous system.

Adult↗

The influence of motor axon misdirection on muscle contraction force in early nerve repair in a rat sciatic nerve model.

We examined the influence of misdirection of regenerating motor axons toward the distal sensory Schwann tubes on the muscle contraction force in early nerve repair using a rat sciatic nerve model. At 0, 1, 2, 4 and 8 weeks after severing the tibial, peroneal and sural nerves, the proximal stump of the tibial nerve was anastomosed with the distal stumps of both the peroneal and sural nerves using tubulisation (n=10 in each of five groups). We intentionally used the distal stump of the sural nerve (a sensory nerve) to induce regeneration in motor axons from the proximal tibial nerve stump toward the distal sensory nerve stump. Twenty-four weeks after nerve repair, isometric contraction force and wet weight of the anterior tibial muscle were measured, and the numbers of regenerated myelinated axons (motor and sensory) in the distal sural and peroneal nerves were counted. The rates of sural nerve regeneration were significantly higher at weeks 0 and 1 than at the later repair times. However, muscle contraction force and muscle wet weight did not differ significantly between groups in which nerves were repaired within four weeks of severance. These results indicate that peripheral nerve repair within four weeks of severance does not influence the muscle contraction force of single muscle despite the misdirection of motor axons toward the distal sensory Schwann tubes.

Anastomosis, Surgical↗

Conformational changes of contractile proteins accompanying modulation of skeletal muscle contraction. Polarized microfluorometry investigations.

Results of studies on the modulation of skeletal muscle contraction by phosphorylation of myosin regulatory light chains and by exchange of magnesium for calcium in myosin heads were reviewed. The polarized fluorescence method was used in these studies, and conformational changes of contractile proteins accompanying modulation of skeletal muscle contraction were investigated. It was found that both the exchange of bound magnesium for calcium on myosin heads and the phosphorylation of myosin regulatory light chains control the ability of myosin heads to induce, upon binding to actin, conformational changes of thin filament leading to decrease or increase of its flexibility. The changes in actin filament flexibility may be caused by alteration of both the inter- and the intramonomer structural organization.

Actins↗

Arachidonic acid is responsible for the smooth muscle-contracting activity of G-acid.

G-acid, a smooth-muscle-contracting substance isolated from human blood plasma, was previously identified as 3-octadecenoic acid. Synthetic cis- and trans-3-octadecenoic acid, however, are biologically inactive. G-acid actually consists of a mixture of fatty acids, characteristic of animal tissues. The biological activity is caused by arachidonic acid, which contracts smooth muscle upon in situ conversion to prostaglandins.

Animals↗

ONO-1078 antagonizes diarrhea-causing changes in ion transport and smooth muscle contraction induced by peptidoleukotrienes in rat and human colon in vitro.

Leukotrienes play important roles in inflammatory bowel diseases. Previous studies have revealed the effects of peptidoleukotrienes on smooth muscle contraction and transmucosal ion transport, which may cause hyperactive bowel movement and the loss of electrolytes and water, i.e., diarrhea. The purpose of the present study was to evaluate the effects of the peptidoleukotrienes antagonist ONO-1078 and to assess its possible future clinical use. We examined the effects of ONO-1078 on peptidoleukotrienes-induced changes in electrolyte transport and muscle contraction in the rat colon, with the Ussing and Magnus techniques. Human biopsy specimens obtained at colonoscopy were also used for ion transport studies. Transmucosal ion transport in both rats and humans, and smooth muscle contractions in the rat colon, were induced by similar doses of peptidoleukotrienes at estimated interstitial concentrations (1 nM-100 nM). The time course of changes in short circuit current had two phases, a rapid and transient decrease and a subsequent transient increase, which seemed to be due mainly to Na+ and Cl-, respectively. Rat colon smooth muscle contracted transiently after the addition of peptidoleukotrienes. These effects of peptidoleukotrienes, which could be related to the diarrhea in inflammatory bowel diseases, were inhibited by ONO-1078. ONO-1078 is expected to be effective in clinical use against peptidoleukotrienes-related diarrhea in mild to moderate inflammatory bowel diseases.

Adult↗

Angle of active site of myosin heads in contracting muscle during sudden length changes.

The change in orientation of myosin crossbridges in contracting muscle during sudden length changes was examined by fluorescence polarization. This study used a fluorescent ATP analogue, 1,N6-etheno-2-aza-ATP(epsilon-2-aza-ATP) as a probe. Its fluorescence is considerably enhanced upon binding with myosin and is dependent on the chemical state of the myosin-nucleotide complex in muscle. The results showed that nucleotides bound to crossbridges in the intermediate attached state (presumably AM-epsilon-2-aza-ADP-Pi) during isometric contraction are highly oriented at the same angle as that of AM in rigor with bound epsilon-2-aza-ADP. Furthermore the orientation of nucleotides bound to crossbridges in the attached state is not altered during sudden changes in length of isometrically contracting muscle. The results of this time-resolved measurement support the conclusion obtained from a previous steady-state experiment that change in axial orientation of the active site of the myosin head is not involved in force generation.

Animals↗

PAF-like lipids- and PAF-induced gallbladder muscle contraction is mediated by different pathways in guinea pigs.

H2O2 stimulates gallbladder muscle contraction and scavengers of free radicals through the generation of PGE2. Oxidative stress causes lipid peroxidation and generation of platelet-activating factor (PAF) or PAF-like lipids. The present studies therefore were aimed at determining whether either one induced by H2O2 mediates the increased generation of PGE2. Dissociated muscle cells of guinea pig gallbladder were obtained by enzymatic digestion. Both PAF-like lipids and PAF-induced muscle contraction was blocked by the PAF receptor antagonist CV-3988. This antagonist also blocked the increased PGE2 production caused by PAF-like lipids or PAF. Actions of PAF-like lipids were completely inhibited by indomethacin, but those of PAF were only partially reduced by indomethacin or by nordihydroguaiaretic acid and completely blocked by their combination. PAF-like lipids-induced contraction was inhibited by AACOCF3 (cystolic phospholipase A2 inhibitor), whereas the actions of PAF were blocked by MJ33 (secretory phospholipase A2 inhibitor). Receptor protection studies showed that pretreatment with PAF-like lipids before N-ethylmaleimide protected the contraction induced by a second dose of PAF-like lipids or PGE2 but not by PAF. In contrast, pretreatment with PAF protected the actions of PAF and PGE2 but not that of PAF-like lipids. Both PAF-like lipids and PAF-induced contractions were inhibited by anti-Galphaq/11 antibody and by inhibitors of MAPK and PKC. In conclusion, PAF-like lipids seem to activate a pathway different from that of PAF probably by stimulating a different PAF receptor subtype.

Animals↗

Muscle contraction increases the in vivo structural strength to the same degree in osteopenic and normal rat tibiae.

The increase in structural capacity due to muscle contraction in the lower leg was investigated in osteopenic and normal rats. Osteopenia was induced by ovariectomy combined with a low-calcium diet (0.01%). The control rats were sham operated and fed a diet containing 1.1% calcium. After 7 weeks the right lower leg of all animals were fractured in three-point ventral cantilever bending during muscle contraction induced by electrical stimulation of the ischiatic nerve. The left tibiae were resected and fractured as each animal's control. During muscle contraction in vivo, the ultimate bending moment, energy absorption, bending stiffness, and deflection were significantly lower in the osteopenic than in the sham-operated animals. However, the increase in mechanical parameters due to muscle contraction comparing the in vivo and resected tibiae in each animal were equally high in the osteopenic and sham-operated animals. Ultimate bending moment in the resected tibiae was 10% higher in the sham-operated animals compared with the ovariectomized, proving mechanically weaker tibiae in the osteopenic rats. In accordance with this, the medullary area of the osteopenic rats was 46% larger in the distal tibial diaphysis, and the ultimate stress the tibiae could withstand was 15% lower in the osteopenic compared with the sham-operated rats. The trabecular bone volume in the distal tibial metaphysis of the osteopenic rats was reduced by 70% compared with the sham operated. This study shows that muscle protection against fracture can be substantial in osteopenic tibia and that it is of the same magnitude as in rats with normal bone mass.

Animals↗

Analysis of GLUT4 distribution in whole skeletal muscle fibers: identification of distinct storage compartments that are recruited by insulin and muscle contractions.

The effects of insulin stimulation and muscle contractions on the subcellular distribution of GLUT4 in skeletal muscle have been studied on a preparation of single whole fibers from the rat soleus. The fibers were labeled for GLUT4 by a preembedding technique and observed as whole mounts by immunofluorescence microscopy, or after sectioning, by immunogold electron microscopy. The advantage of this preparation for cells of the size of muscle fibers is that it provides global views of the staining from one end of a fiber to the other and from one side to the other through the core of the fiber. In addition, the labeling efficiency is much higher than can be obtained with ultracryosections. In nonstimulated fibers, GLUT4 is excluded from the plasma membrane and T tubules. It is distributed throughout the muscle fibers with approximately 23% associated with large structures including multivesicular endosomes located in the TGN region, and 77% with small tubulovesicular structures. The two stimuli cause translocation of GLUT4 to both plasma membrane and T tubules. Quantitation of the immunogold electron microscopy shows that the effects of insulin and contraction are additive and that each stimulus recruits GLUT4 from both large and small depots. Immunofluorescence double labeling for GLUT4 and transferrin receptor (TfR) shows that the small depots can be further subdivided into TfR-positive and TfR-negative elements. Interestingly, we observe that colocalization of TfR and GLUT4 is increased by insulin and decreased by contractions. These results, supported by subcellular fractionation experiments, suggest that TfR-positive depots are only recruited by contractions. We do not find evidence for stimulation-induced unmasking of resident surface membrane GLUT4 transporters or for dilation of the T tubule system (Wang, W., P.A. Hansen, B.A. Marshall, J.O. Holloszy, and M. Mueckler. 1996. J. Cell Biol. 135:415-430).

Animals↗

Effect of electrically induced muscle contractions on posttraumatic edema formation in frog hind limbs.

We tested the hypothesis that repeated muscle contractions induced by high voltage pulsed current (HVPC) would limit volume increases in traumatized frog hind limbs. Twelve frogs were anesthetized, and both hind limbs of each frog were traumatized by impact. Limb volumes were measured via water displacement over a 24-hour period. Four 30-minute treatments of continuous 1-pulse per second HVPC were applied to one limb selected randomly. Stimulation produced muscle contractions that resulted in minimal joint movements. Volume changes from pretrauma limb volumes (in milliliters per kilogram) were analyzed by an analysis of variance for repeated measures. Our hypothesis was rejected (ie, repeated muscle contractions, as induced in this study, did not limit posttraumatic edema formation in frogs). Further investigation of the relative influences of limb position and varying pulse rates, pulse durations, and intensities of HVPC on edema formation may provide valuable insights on effective treatment of edema in humans.

Animals↗

A comparison of the regularity of involuntary muscle contractions in vascular chorea with that in Huntington's chorea, hemiballism and parkinsonian tremor.

We compared the regularity of involuntary muscle contractions in patients with Huntington's disease, vascular chorea, hemiballism and parkinsonian tremor to clarify the nature of phasic involuntary movements caused by lesions in the basal ganglia. Rectified and smoothed electromyograms (EMGs) in involuntary contractions of the predominantly affected muscles were analyzed. After detecting the muscle whose EMG waves showed the most regular rhythm, the frequency, coefficients of variation of interval, amplitude and rise time of the successive EMG waves were compared. The regularity of the intervals of the EMG waves in vascular chorea was significantly greater than that in Huntington's chorea, and some patients with vascular chorea showed a regular rhythm the degree of which approximated that of parkinsonian tremor. The regularity of the intervals of the EMG waves in hemiballism was greater than that in Huntington's chorea, but lower than that in vascular chorea. The regularities of interval, amplitude and rise time all showed the same ordering across the patient groups. The high regularity of muscle contraction intervals in vascular chorea and hemiballism may arise from neural circuits that are abnormally activated as well as those producing tremor.

Adult↗

Behavioral intervention with muscle-contraction headache: a review.

Studies involving behavioral intervention with muscle-contraction headache are reviewed. Intervention approaches have most frequently involved frontal electromyographic feedback and relaxation instructions. Although behavioral intervention packages have been more effective than control procedures in reducing headache activity, identification of active components of these packages is difficult. Specifically,, the contribution of placebo, expectancy and demand factors, reactive effects of self-monitoring, and home practice have not been adequately assessed. The importance of assessing individual differences in etiology and in response to intervention is stressed. The results of some studies are congruent with the hypothesized muscle tension etiology of muscle-contraction headaches but the results from others suggest that factors other than muscle-tension may be involved. Supportive laboratory research on the intervention procedures and cost-efficiency of electromyographic feedback and relaxation instructions are discussed.

Attitude↗

The double peak-to-peak analysis for determining EMG onset of muscle contraction.

PURPOSE: Identification of the onset of muscle contraction with EMG signal amplitude double of the baseline value (DP-P) has been recently reported for determining the temporal parameters of muscular activity. Due to its convenience, it is suitable for clinical application. However, there is a lack of report on the reliability and comparability of this method to other established methods. Therefore, this study examined the test-retest reliability of the DP-P method and compared it with an established method that used the mean + 3 standard deviations (mean + 3 s.d.) over the baseline value for muscles of the knee. METHODS: The onset of contraction of vastus medialis obliquus (VMO) and vastus lateralis (VL) of eleven able-bodied volunteers performing isometric knee extension at 50%, 75% and 100% of MVC in 30-minute and 7-day intervals were analyzed with both the DP-P and mean + 3 s.d. methods. RESULTS: The ICC for within-day measurements of DP-P method ranged from 0.64 to 0.86 and that for between-day measurements ranged from 0.63-0.81. The ICC values were higher with submaximal than maximal contractions. There was a consistent delay of about 3 ms in EMG onset detection with the DP-P as compared to the mean + 3 s.d method. CONCLUSION: The DP-P method is a reliable method for muscle onset determination but the absolute onset time of muscle contraction obtained from this method should not be directly compared with other methods such as the mean + 3 s.d.

Adult↗

Phosphorylation of the regulatory light chains of myosin affects Ca2+ sensitivity of skeletal muscle contraction.

The role of phosphorylation of the myosin regulatory light chains (RLC) is well established in smooth muscle contraction, but in striated (skeletal and cardiac) muscle its role is still controversial. We have studied the effects of RLC phosphorylation in reconstituted myosin and in skinned skeletal muscle fibers where Ca2+ sensitivity and the kinetics of steady-state force development were measured. Skeletal muscle myosin reconstituted with phosphorylated RLC produced a much higher Ca2+ sensitivity of thin filament-regulated ATPase activity than nonphosphorylated RLC (change in -log of the Ca2+ concentration producing half-maximal activation = approximately 0.25). The same was true for the Ca2+ sensitivity of force in skinned skeletal muscle fibers, which increased on reconstitution of the fibers with the phosphorylated RLC. In addition, we have shown that the level of endogenous RLC phosphorylation is a crucial determinant of the Ca2+ sensitivity of force development. Studies of the effects of RLC phosphorylation on the kinetics of force activation with the caged Ca2+, DM-nitrophen, showed a slight increase in the rates of force development with low statistical significance. However, an increase from 69 to 84% of the initial steady-state force was observed when nonphosphorylated RLC-reconstituted fibers were subsequently phosphorylated with exogenous myosin light chain kinase. In conclusion, our results suggest that, although Ca2+ binding to the troponin-tropomyosin complex is the primary regulator of skeletal muscle contraction, RLC play an important modulatory role in this process.

Actins↗

Depolarization of membrane potential and the smooth muscle contraction by isothiocyanatobenzyl imidazoline in guinea-pig stomach circular muscle.

Isothiocyanatobenzyl imidazoline (IBI) produces characteristic slowly developing contraction of many smooth muscle preparations including the circular smooth muscle of the guinea-pig stomach. Changes in the membrane potential were recorded intracellularly, and the muscle contraction induced by IBI was investigated. IBI at 100 micromol/l slowly produced a sustained depolarization of the membrane with a maximum change of approximately 15 mV. This depolarization could not be blocked by 1-hyoscyamine, 100 nmol/l. An imidazoline analogue, oxymetazoline at 1 micromol/l, did not change the resting membrane potential as observed after IBI. Significant membrane depolarization after IBI still occurred in Ca2+-free medium. During IBI-induced depolarization, sudden reduction of Na+ to 30 mmol/l in the medium reduced the depolarization slightly. IBI-induced depolarization was additive with that produced by 20 mmol/l K+ in the medium. In the presence of tetraethylammonium chloride or levcromakalim or nifedipine, IBI continued to depolarize the membrane although functional pharmacological experiments showed that the contractile effects of IBI were significantly inhibited by 30 micromol/l levcromakalim and abolished by 100 nmol/l nifedipine. At 100 micromol/l phentolamine (reported by others as an inhibitor of ATP-sensitive potassium channels) completely blocked IBI-induced contraction. Phentolamine (30 micromol/l) blocked the contractile effects of IBI by 50%. On the other hand, S(-)-Bay K 8644, a voltage-dependent calcium channel activator, was additive with the contractile response of IBI. These results indicated that IBI produced membrane depolarization and contraction of the guinea-pig stomach circular muscle, by a mechanism not involving muscarinic receptors or alpha-adrenoceptors. Even though levcromakalim, an ATP-sensitive potassium channel opener, could not inhibit IBI-induced depolarization, the ATP-sensitive potassium channel and the voltage-dependent calcium channel may be intrinsically linked with the action of IBI.

Animals↗

Abnormal regulation of muscle contraction in horses with recurrent exertional rhabdomyolysis.

OBJECTIVE: To determine whether abnormal regulation of muscle contraction similar to that associated with malignant hyperthermia (MH) was evident in intact external intercostal muscle cells from Thoroughbreds with recurrent exertional rhabdomyolysis (RER). ANIMALS: 5 adult Thoroughbred horses with RER and 7 clinically normal adult Thoroughbred or mixed-breed horses. PROCEDURES: Twitch time course variables and contracture responses to various concentrations of potassium, caffeine, and halothane were measured in small bundles of intact external intercostal muscle cells from clinically normal horses and horses with RER. RESULTS: Threshold for significant contracture induced by potassium depolarization was lower for RER-affected muscles, compared with normal muscles, although the relationship between potassium concentration and membrane potential were not different. Thresholds for contracture induced by caffeine and halothane were also lower for RER-affected muscles, compared with normal muscles. Lower thresholds for caffeine- and halothane-induced contractures, as well as depolarization-elicited contractures, in RER-affected muscles suggest a defect in myoplasmic calcium regulation. CONCLUSIONS AND CLINICAL RELEVANCE: Regulation of muscle contraction is abnormal in Thoroughbreds with RER. The specific defect may be attributable to abnormal intracellular calcium regulation. Knowledge of the specific defect involved in RER may lead to improved prevention and treatment of RER-affected horses.

Anesthetics, Inhalation↗