SEARCH · PubMed Health
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Current views regarding some aspects of the contraction of muscle and its regulation are reviewed. Recent work bearing on the segmental flexibility of myosin is related to cross-bridge movements and ATP metabolism in living muscle. Interaction of troponin with calcium, the process that initiates activation of actin-myosin interaction, is discussed in terms of Ca-induced conformational changes and protein-protein interactions.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Although muscle contraction is one of the principal themes of biological research, the exact mechanism whereby the chemical free energy of ATP hydrolysis is converted into mechanical work remains elusive. The high thermodynamic efficiency of the process, above all, is difficult to explain on the basis of present theories. A model of the elementary effect in muscle contraction is proposed which aims at high thermodynamic efficiency based on an approximate equilibrium between chemical and mechanical forces throughout the transfer of free energy. The experimental results described in the literature support the assumption that chemimechanic equilibrium is approximated by a free energy transfer system based on the binding of divalent metal ions to the myosin light chains. Muscle contraction demonstrated without light chains is expected to proceed with a considerably lower efficiency. Free energy transfer systems based on the binding of ions to proteins seem to be widespread in the cell. By establishing an approximate chemimechanic equilibrium, they could facilitate biological reactions considerably and save large amounts of free energy. The concept of chemimechanic equilibrium is seen as a supplementation to the concept of chemiosmotic equilibrium introduced for the membrane transport by P. Mitchell.
Unphosphorylated smooth muscle myosin filaments do not disassemble in MgATP, provided that the solution is supplemented either by 25% serum albumin or by 6% polyethylene glycol 6000. These filaments are able to support actomyosin retraction but their ATPase activity is not activated by tropomyosin-decorated F-actin.
Vascular smooth muscle is known to be exposed to an oscillating strain under physiological and patho-physiological conditions as well as in different occupational and environmental situations. The effect of vibrations of smooth muscle seems to be largly unknown. In the present experiments on isolated preparations of the rat portal vein and the rabbit thoracic aorta, imposed sinusoidal changes in length were found to cause prompt reduction in active force, the extent of which was dependent on amplitude (1-10% of tissue length, peak to peak, i.e. approximately plus or minus 50-500 mum) and frequency of vibration (1-400 Hz) as well as on the prevailing level of active and passive forces. Vibration caused only small and inconsistant reductions of passive force of vascular smooth muscle. The results are in accordance with the hypothesis that vibrations exert a direct action on the contractile process by causing an increased rate of detachment of actin-myosin cross-links. It is suggested that, in vivo, vibrations may affect the diameter of conduit arteries locally in the case of turbulent blood flow as seen in post-stenotic dilation and arterio-venous anastomosis. Possibly, even the normal pulse pressure oscillations may sometimes tend to inhibit the smooth muscle activity in such arteries and thereby influence their diameters.
Calcium initiates smooth muscle contraction by binding to calmodulin and activating the enzyme myosin light chain kinase. The activated form of myosin light chain kinase phosphorylates myosin on the 20,000-dalton light chain and contractile activity ensues. Calcium may also enhance smooth muscle contractile activity by binding directly to myosin, the main component of the thick filament. Recent studies raise the possibility that the calcium-calmodulin complex may also modulate smooth muscle contractile activity by removing the inhibition imposed by caldesmon, a protein that is bound to the thin (i.e., actin-containing) filaments of smooth muscle. In vitro studies have demonstrated that the calcium-activated, phospholipid-dependent kinase, protein kinase C, can phosphorylate smooth muscle myosin at a different site than does myosin light chain kinase and down-regulate its actin-activated magnesium adenosine triphosphatase activity. This raises the possibility that protein kinase C phosphorylation of myosin may play a role in modulating vascular contractile activity in vivo.
The contractile state of smooth muscle is regulated primarily by the sarcoplasmic (cytosolic) free Ca2+ concentration. A variety of stimuli that induce smooth muscle contraction (e.g., membrane depolarization, alpha-adrenergic and muscarinic agonists) trigger an increase in sarcoplasmic free [Ca2+] from resting levels of 120-270 to 500-700 nM. At the elevated [Ca2+], Ca2+ binds to calmodulin, the ubiquitous and multifunctional Ca(2+)-binding protein. The interaction of Ca2+ with CaM induces a conformational change in the Ca(2+)-binding protein with exposure of a site(s) of interaction with target proteins, the most important of which in the context of smooth muscle contraction is the enzyme myosin light chain kinase. The interaction of calmodulin with myosin light chain kinase results in activation of the kinase that catalyzes phosphorylation of myosin at serine-19 of each of the two 20-kDa light chains (native myosin is a hexamer composed of two heavy chains (230 kDa each) and two pairs of light chains (one pair of 20 kDa each and the other pair of 17 kDa each)). This simple phosphorylation reaction triggers cycling of myosin cross-bridges along actin filaments and the development of force. Relaxation of the muscle follows removal of Ca2+ from the sarcoplasm, whereupon calmodulin dissociates from myosin light chain kinase regenerating the inactive kinase; myosin is dephosphorylated by myosin light chain phosphatase(s), whereupon it dissociates and remains detached from the actin filament and the muscle relaxes. A substantial body of evidence has been accumulated in support of this central role of myosin phosphorylation-dephosphorylation in the regulation of smooth muscle contraction. However, a wide range of physiological and biochemical studies supports the existence of additional, secondary Ca(2+)-dependent mechanisms that can modulate or fine-tune the contractile state of the smooth muscle cell. Three such mechanisms have emerged: (i) the actin-, tropomyosin-, and calmodulin-binding protein, calponin; (ii) the actin-, myosin-, tropomyosin-, and calmodulin-binding protein, caldesmon; and (iii) the Ca(2+)- and phospholipid-dependent protein kinase (protein kinase C).
A model of single muscle contraction is proposed. The kinetics of two reactions have been used: interaction between the excitation mediator and the muscle membrane receptor, and the reaction of enzymatic mediator splitting. The muscle contraction parameters have been correlated with the concentration of the mediator-receptor complex.
The cellular and molecular mechanisms underlying smooth muscle contraction are reviewed in the light of recent studies of smooth muscle ultrastructure and of the role of polyphosphoinositide turnover and protein kinase C function in smooth muscle contraction. A new model of smooth muscle contraction is proposed that differs radically from accepted views, particularly the latch bridge hypothesis, in terms of both Ca2+ messenger function and the molecular events underlying this process. A coordinate fibrillar domain model of contraction is proposed in which the initial and sustained phases of contraction are mediated by different cellular and molecular events. The initial phase of response is mediated by a rise in [Ca2+]c and the resulting calmodulin-dependent activation of both myosin light chain kinase and the dissociation of caldesmon from the actin-caldesmon-tropomyosin-myosin fibrillar domain. These events lead to an interaction between actin and the phosphorylated light chains of myosin just as in previous models. However, this initial phase is followed by a sustained phase in which a rise in [Ca2+]sm stimulates the plasma membrane-associated, Ca2+-sensitive form of protein kinase C that results in the phosphorylation of both structural and regulatory components of the filamin-actin-desmin fibrillar domain. These events underlie the tonic phase of contraction.
Human urine contains a small molecular weight natriuretic substance and similar material isolated from the kidney inhibits Na/K ATPase. Such action on blood vessels would cause contraction. Human urinary natriuretic material isolated from a Sephadex G-25 column contracted smooth muscle in the rat anococcygeus muscle. Known vasoactive substances could not explain the activity of the natriuretic fraction on the anococcygeus muscle. In subsequent studies the natriuretic fraction from the Sephadex G-25 column was run on a Sephadex G-10 column and natriuretic activity was found before the sodium was eluted. The same fractions inhibited Na/K ATPase but did not cause contraction of the anococcygeus muscle. The fractions which did cause contraction of the anococcygeus muscle were eluted long after the salts and these fractions did not inhibit Na/K ATPase and were not natriuretic. The postulated defect in sodium excretion in hypertensive patients might be related to their low kallikrein excretion. Since ANP stimulates increased kallikrein release in rats and does not inhibit Na/K ATPase, it is suggested that the natriuretic pathway via inhibition of renal Na/K ATPase is independent in the kidney of the kallikrein/kinin natriuretic pathway.
A sliding filament model for muscle contraction is extended by including an activation mechanism based on the hypothesis that the binding of calcium by a regulating protein in the myofibrils must occur before the rate constant governing the making of interactions between cross-bridges and thin filament sites can take on nonzero values. The magnitude of the rate constant is proportional to the amount of bound calcium. The model's isometric twitch and rise of force in an isometric tetanus are similar to the curves produced by real muscles. It redevelops force after a quick release in an isometric tetanus faster than the initial rise. Quick release experiments on the model during an isometric twitch show that the "active state" curve produced is different from the postulated calcium binding curve. The force developed by the model can be increased by a small quick stretch delivered soon after activation to values near the maximum generated in an isometric tetanus. Following the quick stretch, the force remains near the tetanic maximum for a long time even though the calcium binding curve rises to a peak and subsequently decays by about 50%. The model satisfies the constraint of shortening with a constant velocity under a constant load. Modifications can be made in the model so that it produces the delayed force changes following step length changes characteristic of insect fibrillar muscle.
Cardiomyoplasty, or the use of skeletal muscle to assist the failing heart, has been studied for many years but has enjoyed only minimal success. It has been suggested that a delay in the start of skeletal muscle contraction relative to the QRS complex would enhance aortic flow. To study the effects of simulated changes in the relative timing of skeletal muscle contraction, heart rate and skeletal muscle contraction duration, a mathematical model was used to predict the vascular pressures and flows during cardiomyoplasty. The vascular pressures and cardiac output generated by the model for both the normal and heart failure state were similar to previously published canine data. Skeletal muscle contraction synchronous with cardiac mechanical systole (i.e., delayed approximately 50-75 ms from the QRS) was able to provide improvements in cardiac output, arterial blood pressure and aortic flow velocity up to 40% over the baseline heart failure state. A delay in the start of skeletal muscle contraction, prolonged skeletal muscle contraction duration or an increase in the heart rate from 90 to 120/min reduced this benefit. Thus, mechanical synchrony of skeletal and cardiac muscle contraction optimizes hemodynamics during cardiomyoplasty.
Intrauterine instillations of oil or saline distended the uterus in ovariectomized mice treated with progesterone + oestrogen to sensitize the uterus to a decidualizing stimulus. Saline does not induce decidualization, and therefore uterine distension per se is not the trigger to decidual induction. Oil induces decidualization, but does not involve gross damage to the epithelium, penetration of oil into the stroma or release of epithelial lipid into the stroma. Instillation (oil, saline or sham) induced a contraction of the circular muscles along the length of the uterus which closed the uterine lumen, expelled most of the oil and located the remainder primarily in the antimesometrial cleft of the lumen. Progesterone inhibited longitudinal muscle contraction and facilitated circular muscle contraction. These effects are discussed in relation to the spacing and implantation of blastocysts.
Halothane directly relaxes airway smooth muscle. To determine the direct inhibitory mechanisms of halothane on canine tracheal smooth muscle contraction, the effects of this anesthetic on the levels of several intracellular second messengers were investigated by measuring intracellular Ca2+ concentration ([Ca2+]i), Ca2+/phospholipid-dependent protein kinase (PKC) translocation, and intracellular cyclic adenosine monophosphate concentration ([cAMP]i). When carbachol (1 microM) was used to increase [Ca2+]i to the same concentration as that induced by high-K+ (72.7 mM), the carbachol-induced contraction was more than twice as great, indicating that carbachol enhances the sensitivity of contractile elements to Ca2+ or activates a Ca(2+)-independent mechanism. Similarly, 12-deoxyphorbol 13-isobutylate, a potent PKC activator, markedly potentiated high-K(+)-induced muscle contraction without an increase of [Ca2+]i. The addition of halothane (0.33, 0.75, 1.15, and 1.47 mM) decreased [Ca2+]i and the muscle tension induced by carbachol. However, the decrease of muscle tension was more marked than that of [Ca2+]i at the higher concentrations. Although [Ca2+]i in the presence of verapamil and carbachol was not affected by halothane, the anesthetic markedly decreased muscle force by decreasing the "Ca2+ sensitization" or the Ca(2+)-independent enhancement of tension observed with carbachol. Halothane (0.75 and 1.47 mM) significantly released the membrane-associated PKC to cytosol, which decreased PKC activity. [cAMP]i of the smooth muscle stimulated by carbachol was moderately but significantly increased by halothane. However, when equivalent relaxation was induced with forskolin, which acts via adenylate cyclase activation, a much higher [cAMP]i was observed, which suggests that halothane acts via an additional pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
Hysteretic after-effects of muscle contraction were studied on unanaesthetized cats during intracortical microstimulation of two sites in the motor cortex. Equilibrium in the joint-external load system was shown to be dependent on the order of stimulation of the sites in the motor cortex. Coactivation of antagonistic muscles led to an increase in both the joint stiffness and uncertainty of the equilibrium value of the joint angle.