Rate Of Force Generation Research Articles

A FORCE-SENSING MICROSURGICAL INSTRUMENT THAT DETECTS FORCES BELOW HUMAN TACTILE SENSATION

To test the sensitivity and reproducibility of a 25-gauge force-sensing micropick during microsurgical maneuvers that are below tactile sensation. Forces were measured during membrane peeling in a "raw egg" and the chick chorioallantoic membrane models (N = 12) of epiretinal membranes. Forces were also measured during posterior hyaloid detachment and creation of retinal tears during vitrectomy in live rabbits (n = 6). With the raw egg model, 0.5 ± 0.4 mN of force was detected during membrane peeling. In the chorioallantoic membrane model, delaminating the upper membrane produced 2.8 ± 0.2 mN of force. While intentionally rupturing the lower membrane to simulate a retinal tear, 7.3 ± 0.5 mN (range, 5.1-9.2 mN; P < 0.001) of force was generated while peeling the upper membrane. During vitrectomy, the minimum force that detached the posterior hyaloid was 6.7 ± 1.1 mN, which was similar to the force of 6.4 ± 1.4 mN that caused a retinal tear. The rate of force generation, as indicated by the first derivative of force generation, was 3.4 ± 1.2 mN/second during posterior hyaloid detachment, compared with 7.7 ± 2.4 mN/second during the creation of a retinal tear (P = 0.04). Force-sensing microsurgical instruments can detect forces below tactile sensation, and importantly, they can distinguish the forces generated during normal maneuvers from those that cause a surgical complication.

Prevascularization of self-organizing engineered heart tissue by human umbilical vein endothelial cells abrogates contractile performance

Establishing vascularization is a critical obstacle to the generation of engineered heart tissue (EHT) of substantial thickness. Addition of endothelial cells to the formative stages of EHT has been demonstrated to result in prevascularization, or the formation of capillary-like structures. The detailed study of the effects of prevascularization on EHT contractile function is lacking. Here, we evaluated the functional impact of prevascularization by human umbilical vein endothelial cells (HUVECs) in self-organizing EHT. EHT fibers were generated by the self-organization of neonatal rat cardiac cells on a fibrin hydrogel scaffold with or without HUVECs. Contractile function was measured and force-length relationship and rate of force production were assessed. Immunofluorescent studies were used to evaluate arrangement and distribution of HUVECs within the EHT fibers. RT-PCR was used to assess the transcript levels of hypoxia inducible factor-1a (Hif-1α). EHT with HUVECs manifested tubule-like structures at the periphery during fiber formation. After fiber formation, HUVECs were heterogeneously located throughout the EHT fiber and human CD31+ tubule-like structures were identified. The expression level of Hif-1α did not change with the addition of HUVECs. However, maximal force and rate of force generation were not improved in HUVECs containing EHT as compared to control EHT fibers. The addition of HUVECs may result in sparse microvascularization of EHT. However, this perceived benefit is overshadowed by a significant decrease in contractile function and highlights the need for perfused vascularization strategies in order to generate EHT that approaches clinically relevant dimensions.

Contractile and Electrophysiologic Characterization of Optimized Self-Organizing Engineered Heart Tissue

Engineered heart tissue (EHT) is being developed for clinical implantation in heart failure or congenital heart disease and therefore requires a comprehensive functional characterization and scale-up of EHT. Here we explored the effects of scale-up of self-organizing EHT and present detailed electrophysiologic and contractile functional characterization. Fibers from EHT were generated from self-organizing neonatal rat cardiac cells (0.5×10(6) to 3×10(6)/fiber) on fibrin. We characterized contractile patterns and measured contractile function using a force transducer, and assessed force-length relationship, maximal force generation, and rate of force generation. Action potential and conduction velocity of EHT were measured with optical mapping, and transcript levels of myosin heavy chain beta were measured by reverse transcriptase-polymerase chain reaction. Increasing the cell number per construct resulted in an increase in fiber volume. The force-length relationship was negatively impacted by increasing cell number. Maximal force generation and rate of force generation were also abrogated with increasing cell number. This decrease was not likely attributable to a selective expansion of noncontractile cells as myosin heavy chain beta levels were stable. Irregular contractile behavior was more prevalent in constructs with more cells. Engineered heart tissue (1×10(6)/construct) had an action potential duration of 140.2 milliseconds and a conduction velocity of 23.2 cm/s. Engineered heart tissue displays physiologically relevant features shared with native myocardium. Engineered heart tissue scale-up by increasing cell number abrogates contractile function, possibly as a result of suboptimal cardiomyocyte performance in the absence of vasculature. Finally, conduction velocity approaches that of native myocardium without any electrical or mechanical conditioning, suggesting that the self-organizing method may be superior to other rigid scaffold-based EHT.

183 ROLE OF MYOSIN LIGHT CHAIN PHOSPHORYLATION IN PARTIAL BLADDER OUTLET OBSTRUCTION: COMPENSATED VERSUS DECOMPENSATED

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology I1 Apr 2010183 ROLE OF MYOSIN LIGHT CHAIN PHOSPHORYLATION IN PARTIAL BLADDER OUTLET OBSTRUCTION: COMPENSATED VERSUS DECOMPENSATED Joseph Hypolite, Shaohua Chang, Stephen Zderic, Alan Wein, Stephan Butler, and Samuel Chacko Joseph HypoliteJoseph Hypolite Lansdowne, PA More articles by this author , Shaohua ChangShaohua Chang Glenolden, PA More articles by this author , Stephen ZdericStephen Zderic Philadelphia, PA More articles by this author , Alan WeinAlan Wein Philadelphia, PA More articles by this author , Stephan ButlerStephan Butler Philadelphia, PA More articles by this author , and Samuel ChackoSamuel Chacko Glenolden, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.239AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Benign prostatic hyperplasia (BPH) in men can lead to bladder outlet obstruction(BOO). We have reported previously that BOO in the rabbit model can be categorized into compensated and decompensated based on bladder function studies obtained from metabolic cage data and in vitro biochemical and physiological studies. The compensated group maintains their function close to normal whereas the decompensated group demonstrates higher frequency of urination and low void volume. The bladder dysfunction is also associated with changes in contractile and regulatory proteins which control myosin phosphorylation, and can affect force generation of the bladder smooth muscle. In the present study, we ask what role myosin light chain (MLC20) phosphorylation plays in BOO-induced compensation and decompensation at the resting level, and upon activation with carbachol (50μM) and KCl (125mM). METHODS Adult male New Zealand white rabbits were partially obstructed by surgical ligation of the urethra, and sham-operated rabbits served as controls. Metabolic cage data analysis was used to segregate bladders into compensated and decompensated groups based on the frequency of urination and void volume over a 24 hour period. In vitro muscle strip studies and two-dimensional gel electrophoresis were used to study contractile function and MLC20 phosphorylation, respectively, in sham-operated and two week obstructed rabbit bladders. RESULTS Decompensated bladders showed a significant reduction in maximum force, and the rate of force generation in response to both KCl (47%) and carbachol (41%) compared to compensated and sham bladders. Both the resting level of MLC20 phosphorylation (13%) and the level at maximum force generation (23%) were significantly less in decompensated bladders compared to sham and compensated bladders (23% at resting level and 36% at maximum force). There was no significant difference in the basal, or maximal phosphorylation level in response to KCl and carbachol between sham and compensated bladders. The mean weights of the bladders were, 2.2, 4.8 and 10.4 grams for sham, compensated and decompensated respectively. CONCLUSIONS Since MLC20 phosphorylation is the primary mechanism involved in smooth muscle contraction, the data suggests that the reduced levels of MLC20 phosphorylation both at rest and upon activation, in the decompensated bladders may be a major contributing factor to the contractile dysfunction seen in these bladders. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e73 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joseph Hypolite Lansdowne, PA More articles by this author Shaohua Chang Glenolden, PA More articles by this author Stephen Zderic Philadelphia, PA More articles by this author Alan Wein Philadelphia, PA More articles by this author Stephan Butler Philadelphia, PA More articles by this author Samuel Chacko Glenolden, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Effect of stimulation frequency on force, net power output, and fatigue in mouse soleus muscle in vitro

The effects of electrical stimulation frequency on force, work loop power output, and fatigue of mouse soleus muscle were investigated in vitro at 35 degrees C. Increasing stimulation frequency did not significantly affect maximal isometric tetanic stress (overall mean +/- SD, 205 +/- 16.6 kN.m-2 between 70 and 160 Hz) but did significantly increase the rate of force generation. The maximal net power output during work loops significantly increased with stimulation frequency: 18.2 +/- 3.7, 22.5 +/- 3.3, 26.8 +/- 3.7, and 28.6 +/- 3.4 W.kg(-1) at 70, 100, 130, and 160 Hz, respectively. The stimulation frequency that was used affected the pattern of fatigue observed during work loop studies. At stimulation frequencies of 100 and 130 Hz, there were periods of mean net negative work during the fatigue tests due to a slowing of relaxation rate. In contrast, mean net work remained positive throughout the fatigue test when stimulation frequencies of 70 and 160 Hz were used. The highest cumulative work during the fatigue test was performed at 70 and 160 Hz, followed by 130 Hz, then 100 Hz. Therefore, stimulation frequency affects power output and the pattern of fatigue in mouse soleus muscle.

Sexual dimorphism of murine masticatory muscle function

Objective To determine if gender distinctions of force generating capacity existed in murine masticatory muscles. Design In order to investigate the effect of sex on force generating capacity in this muscle group, an isolated muscle preparation was developed utilising the murine anterior deep masseter. Age-matched male and female mice were utilized to assess function, muscle fibre type and size in this muscle. Results Maximum isometric force production was not different between age-matched male and female mice. However, the rate of force generation and relaxation was slower in female masseter muscles. Assessment of fibre type distribution by immunohistochemistry revealed a three-fold decrease in the proportion of myosin heavy chain 2b positive fibres in female masseters, which correlated with the differences in contraction kinetics. Conclusions These results provide evidence that masticatory muscle strength in mice is not affected by sex, but there are significant distinctions in kinetics associated with force production between males and females.

BAPTA Induces Frequency Shifts in vivo of Spontaneous Otoacoustic Emissions of the Bobtail Lizard

Spontaneous otoacoustic emissions (SOAEs) are indicators of active processes in the inner ear and are found in all classes of land vertebrates. In the Australian bobtail lizard, earlier work showed that otoacoustic emissions are generated by an active motility process in the hair-cell bundle. This is likely to be driven by calcium-sensitive mechanisms implicated in other non-mammalian hair cell systems. If so, it should be fundamentally influenced by the extracellular calcium concentration. In in vitro studies, the rate of force generation in hair cell stereovilli is linked to the extracellular calcium concentration. In such preparations, low-calcium solutions, buffered by the calcium chelator BAPTA, were reported to change the frequency of hair cell bundle oscillations. In the present study, BAPTA was iontophoresed into the endolymph of the bobtail skink in vivo, and SOAEs were monitored. Application of BAPTA resulted in a prolonged downward shift in the frequency of individual SOAE spectral peaks. Recovery took more than 1 h, consistent with a slow clearance of BAPTA from endolymph. SOAE peak amplitudes were most often enhanced, suggesting there was no functional disruption of tip links. The direction and degree of frequency shifts were consistent with in vitroand in vivo data showing the effects of changing calcium concentrations in the endolymph directly.

Effects of slope, substrate, and temperature on forces associated with locomotion of the ornate box turtle, Terrapene ornata

In spite of several studies of the locomotor performances of reptiles, we know as yet relatively little about the mechanical forces involved. The present investigation examined the effects of substrate, slope and temperature on the pulling forces exerted by ornate box turtles tethered to a force transducer. These forces increased with body mass in a nearly isometric manner. The forces exerted during the initial effort were greatest on a styrofoam substrate, whereas maximum forces generated were greatest on pea gravel. Both forces progressively increased as slope decreased from +30° to − 30°. The rate of force generation (N/s) was greatest at intermediate slopes. Contact force tended to increase as normal force increased, and was strongly influenced by slope, increasing from −30° to +30°. Surprisingly, we found no significant effects of temperature on tether forces, contraction times, or rates. This evaluation of pulling forces associated with box turtle locomotion revealed some interesting, and at times unexpected, relationships.

Hearts from mice lacking desmin have a myopathy with impaired active force generation and unaltered wall compliance.

Desmin intermediate filaments are key structures in the cytoskeleton of cardiac muscle. Since they are associated with Z-discs and intercalated discs, they may have a role in sarcomere alignment or force transmission. We have explored the mechanical function of the desmin filaments in the cardiac wall by comparing desmin-deficient (Des-/-) and wild-type (Des+/+) mice. The Langendorff technique was used to examine the contractility of the whole heart. Rate of force generation, Ca(2+)-sensitivity and force per cross-sectional area were measured in skinned ventricle muscle preparations. Des-/- mice have a cardiomyopathy with increased heart weight. Diastolic pressure was increased at all filling volumes in the Des-/- group. Since passive wall stress (i.e. force per area) was unchanged, the alteration in diastolic pressure is a consequence of the thicker ventricle wall. Developed pressure, rate of pressure increase and developed wall stress were significantly reduced, suggesting that active force generation of the contractile apparatus is reduced in Des-/-. Concentrations of actin and myosin in the ventricle were unaltered. Measurements in skinned muscle preparations showed a lower active force development with unaltered Ca(2+)-sensitivity and rate of tension development. It is suggested that the intermediate filaments have a role in active force generation of cardiac muscle, possibly by supporting sarcomere alignment or force transmission. The desmin filaments do not contribute the passive elasticity of the ventricle wall. Des-/- mice provide a model for genetic cardiomyopathy where the main factor contributing to altered cardiac performance is a decrease in active force generation, possibly in combination with a loss of functional contractile units.

Modulation of Contractile Activation in Skeletal Muscle by a Calcium-insensitive Troponin C Mutant

Calcium controls the level of muscle activation via interactions with the troponin complex. Replacement of the native, skeletal calcium-binding subunit of troponin, troponin C, with mixtures of functional cardiac and mutant cardiac troponin C insensitive to calcium and permanently inactive provides a novel method to alter the number of myosin cross-bridges capable of binding to the actin filament. Extraction of skeletal troponin C and replacement with functional and mutant cardiac troponin C were used to evaluate the relationship between the extent of thin filament activation (fractional calcium binding), isometric force, and the rate of force generation in muscle fibers independent of the calcium concentration. The experiments showed a direct, linear relationship between force and the number of cross-bridges attaching to the thin filament. Further, above 35% maximal isometric activation, following partial replacement with mixtures of cardiac and mutant troponin C, the rate of force generation was independent of the number of actin sites available for cross-bridge interaction at saturating calcium concentrations. This contrasts with the marked decrease in the rate of force generation when force was reduced by decreasing the calcium concentration. The results are consistent with hypotheses proposing that calcium controls the transition between weakly and strongly bound cross-bridge states.

Supine lower body negative pressure exercise simulates metabolic and kinetic features of upright exercise

Exercise within an artificial gravity environment may help prevent microgravity-induced deconditioning. We hypothesized that supine lower body negative pressure (LBNP) exercise simulates physiological and biomechanical features of upright exercise. Walking (4.5 +/- 0.3 km/h) and running (8.0 +/- 1.0 km/h) while supine within a LBNP exerciser were compared with walking and running while upright. Eight healthy subjects exercised for 5 min at each of the four posture/gait conditions. LBNP of 52 +/- 4 mmHg generated one body weight of supine ground reaction force (GRF). Gait parameters and GRFs were measured during the third minute of exercise, and heart rate and oxygen consumption were measured during the fifth minute. Oxygen consumption during supine LBNP treadmill exercise [walking: 14.6 +/- 0.9; running: 32.2 +/- 1.6 (SE) ml. min(-1). kg(-1)] was similar to that during upright treadmill exercise (walking: 15.1 +/- 0.9; running: 34.0 +/- 1.9 ml. min(-1). kg(-1)). Heart rate for supine LBNP exercise (grand mean: 133 +/- 11 beats/min) was also similar to that for upright exercise (136 +/- 11 beats/min). Footward forces integrated over each stride (330.5 +/- 34.4 vs. 319. 1 +/- 29.6 N. s) and rate of force generation (26,483 +/- 4,310 vs. 25,634 +/- 4,434 N/s) were similar for upright and LBNP exercise, respectively. Our collective results indicate that supine exercise within LBNP can simulate the physiological stress and GRFs that are generated during upright gait.

Minor role of a Ca2+-depleted sarcoplasmic reticulum in heterologous desensitization of smooth muscle to K+.

Exposure of porcine carotid artery smooth muscle (PCASM) to histamine was followed by a large reduction in the rate of force generation in response to 40 mM KCl. This was shown to be a manifestation of slow attainment of a steady-state myoplasmic Ca2+ concentration ([Ca2+]i). We hypothesized that if net transsarcolemmal Ca2+ flux into the depolarized PCASM cells is the same before and after a desensitizing histamine treatment, then the transient attenuation of the increase in [Ca2+]i may be due to accelerated uptake of Ca2+ by a partially depleted sarcoplasmic reticulum (SR) acting as a Ca2+ sink or superficial buffer barrier. We tested this hypothesis by eliciting responses of "desensitized PCASM" to 40 mM KCl in the presence of cyclopiazonic acid (CPA), an SR Ca2+-ATPase inhibitor. Contractions of CPA-treated tissues were attenuated less than those of tissues not treated with CPA, but they were not abolished. CPA-insensitive mechanism(s) dominated the desensitization. We conclude that histamine pretreatment reduced net transsarcolemmal Ca2+ flux into PCASM in response to 40 mM KCl.

The rate of force generation by the myocardium is not influenced by afterload.

The influence of afterload on the rate of force generation by the myocardium was investigated using two types of preparations: the in situ dog heart (dP/dt) and isolated papillary muscle of rats (dT/dt). Thirteen anesthetized, mechanically ventilated and thoracotomized dogs were submitted to pharmacological autonomic blockade (3.0 mg/kg oxprenolol plus 0.5 mg/kg atropine). A reservoir connected to the left atrium permitted the control of left ventricular end-diastolic pressure (LVEDP). A mechanical constriction of the descending thoracic aorta allowed to increase the systolic pressure in two steps of 20 mmHg (conditions H1 and H2) above control values (condition C). After arterial pressure elevations (systolic pressure C: 119 +/- 8.1; H1: 142 +/- 7.9; H2: 166 +/- 7.7 mmHg; P < 0.01), there were no significant differences in heart rate (C: 125 +/- 13.9; H1: 125 +/- 13.5; H2: 123 +/- 14.1 bpm; P > 0.05) or LVEDP (C: 6.2 +/- 2.48; H1: 6.3 +/- 2.43; H2: 6.1 +/- 2.51 mmHg; P > 0.05). The values of dP/dt did not change after each elevation of arterial pressure (C: 3,068 +/- 1,057; H1: 3,112 +/- 996; H2: 3,086 +/- 980 mmHg/s; P > 0.05). In isolated rat papillary muscle, an afterload corresponding to 50% and 75% of the maximal developed tension did not alter the values of the maximum rate of tension development (100%: 78 +/- 13; 75%: 80 +/- 13; 50%: 79 +/- 11 g mm-2 s-1, P > 0.05). The results show that the rise in afterload per se does not cause changes in dP/dt or dT/dt.

Substrate-dependent alteration in O2 consumption and energy metabolism in vascular smooth muscle.

Energy metabolism and the substrate utilization pattern of intact porcine carotid artery were investigated in the presence or absence of glucose and/or octanoate during the phases of isometric contraction induced by K+ depolarization. During the early phase of contraction, there was a rapid increase in the rate of O2 uptake that was independent of the rate of force generation but dependent on the availability of intracellular pyruvate, the source of which was glucose and not glycogen. Lactate production increased linearly from the onset of contractile stimulation and was not suppressed by octanoate oxidation. There was no alteration from the basal resting state in the concentrations of the metabolites of the tricarboxylic acid cycle in the presence or absence of octanoate. During the phase of steady-state force maintenance, O2 consumption was increased compared with the basal unstimulated rate but was not increased when glucose and octanoate were present, which is consistent with the Crabtree effect. This was associated with increased aerobic lactic acid production and inhibition of the tricarboxylic acid cycle at the citrate synthase step. Alteration of the high-energy phosphate content could not account for the pattern of O2 consumption during contraction under different substrate conditions. In the absence of glucose, the energy from octanoate oxidation could substitute for the energy ordinarily derived from aerobic glycogen and lactic acid production. It is concluded that energy metabolism of vascular smooth muscle is coordinated during contraction by integration of the pathways of aerobic glycolysis and oxidative phosphorylation.

Effects of Troponin-I Extraction with Vanadate and of the Calcium Sensitizer EMD 53998 on the Rate of Force Generation in Skinned Cardiac Muscle

The rate of tension development following release of ATP from caged-ATP in the presence of calcium was studied in skinned cardiac fibres from swine. A low-force rigor state was obtained by using butanedione monoxime (BDM) during the induction of rigor. BDM was washed out and following release of ATP in the presence of Ca2+ (pCa 4.3), the muscles contracted with an apparent rate of about 2 s-1 at 22 degrees C. After treatment with 10 mM vanadate to extract troponins I and C the fibres contracted independently of calcium. The rate of contraction upon release of ATP was slower than prior to extraction and was independent of [Ca2+]. Since treatment with vanadate has been shown to extract about 90% of troponin-I the results suggest that the muscles under these conditions are partially activated by removal of an inhibition of cross-bridge interaction by troponin I. A partial recovery of force was obtained by prolonged incubation in DTT containing solutions possibly reflecting reconstitution with troponin I still present in the fibre bundle. Treatment with a solution containing whole troponin caused almost complete recovery of calcium sensitivity and rate of force development. The calcium sensitizer EMD 53998 increased rates of contraction in a dose dependent manner, suggesting that this compound increases force and calcium sensitivity by increasing the cross-bridge attachment rates.

A component analysis of the generation and release of isometric force in Parkinson's disease.

Paradigms of isometric force control allow study of the generation and release of movement in the absence of complications due to disordered visuomotor coordination. The onset and release of isometric force in Parkinson's disease (PD) was studied, using computerised determinants of latency of response and rate of force generation and release. Components of isometric force control were related to measures of cognitive, affective and clinical motor disability. The effects of treatment were determined by longitudinal study of de novo patients. Patients with PD showed impairment in latency and rate of force change for movement release as well as onset. Rate of force change correlated with depression, clinical motor disability and memory quotient but latency showed no correlation with any of these measures. Treatment improved rate of force release, in concert with clinical motor disability, but not latency. These results suggest dissociations between latency and rate of force change that may be linked to different neurochemical deficits. Further, they demonstrate akinetic deficits in force release that argue against the "neural energy hypothesis" of akinesia.

The cross-bridge cycle in muscle. Mechanical, biochemical, and structural studies on single skinned rabbit psoas fibers to characterize cross-bridge kinetics in muscle for correlation with the actomyosin-ATPase in solution.

A characteristic and important feature of myocardium is the modulation of tension when stimulated or possibly even when unstimulated. In addition, resistance to stretch and its variation in unstimulated heart muscle is an important factor in myocardial function. These features may occur in some new light when viewed from some recent advances in understanding of cross-bridge action and regulation of muscle. For this reason we give a short review of such advances. Firstly, we summarize some of our earlier results obtained in experiments designed to see whether and to what extent actomyosin ATPase data obtained in solution might apply in muscle. Secondly, we present a recently developed experimental approach to estimate the rate constants that determine the cycling of cross-bridges between weak-binding, 'non-force-generating' states and strong-binding, 'force-generating' states. The estimated rate constants confirm the prediction of cross-bridge models derived from in vitro studies that the step which is rate-limiting in solution also determines the rate of force-generation in the cross-bridge cycle in muscle. Experiments at various Ca++ concentrations imply that a major mechanism of regulation is the control of the transition from the weak-binding, 'non-force-generating' states to the strong-binding, 'force-generating' states while the number of activated interaction sites appears unchanged and always at its maximum. This implies that changes in the force-pCa relation cannot be interpreted without detailed analysis of cross-bridge kinetics, and that factors other than Ca++ may have the potential to modulate muscle activity, both in stimulated and unstimulated muscle, by affecting cross-bridge kinetics.

On the isometric equation of the sarcomere.

A model of the sarcomere is described, which is based upon (a) the sliding filament theory ofHuxley, (b) the ultrastructure of the sarcomere, (c) the biochemical mechanisms responsible for mechanical coupling and uncoupling of myosin and actin, (d) the constancy of the volume of the sarcomere and (e) a statistical analysis of random forces acting on myosin cross-bridges, constrained by flexible and extensible heavy meromyosin subfragments. The results can be fitted to experimental Frank-Starling diagrams. Maximal velocity of contraction, derived from the theory, is independent of sarcomere length, while the rate of force generation is predicted to increase with increasing sarcomere length. The relationship of the new model with the older three-element models is discussed and a new definition of the series elastic element is proposed representing the series component as being distributed over the thin and elongated heavy meromyosin subfractions which connect the crossbridges to the myosin backbone.