Overlap Of Thick Filaments Research Articles

Muscle active force-length curve explained by an electrophysical model of interfilament spacing

The active isometric force-length relation (FLR) of striated muscle sarcomeres is central to understanding and modeling muscle function. The mechanistic basis of the descending arm of the FLR is well explained by the decreasing thin:thick filament overlap that occurs at long sarcomere lengths. The mechanistic basis of the ascending arm of the FLR (the decrease in force that occurs at short sarcomere lengths), alternatively, has never been well explained. Because muscle is a constant-volume system, interfilament lattice distances must increase as sarcomere length shortens. This increase would decrease thin and thick-filament electrostatic interactions independently of thin:thick filament overlap. To examine this effect, we present here a fundamental, physics-based model of the sarcomere that includes filament molecular properties, calcium binding, sarcomere geometry including both thin:thick filament overlap and interfilament radial distance, and electrostatics. The model gives extremely good fits to existing FLR data from a large number of different muscles across their entire range of measured activity levels, with the optimized parameter values in all cases lying within anatomically and physically reasonable ranges. A local first-order sensitivity analysis (varying individual parameters while holding the values of all others constant) shows that model output is most sensitive to a subset of model parameters, most of which are related to sarcomere geometry, with model output being most sensitive to interfilament radial distance. This conclusion is supported by re-running the fits with only this parameter subset being allowed to vary, which increases fit errors only moderately. These results show that the model well reproduces existing experimental data, and indicate that changes in interfilament spacing play as central a role as changes in filament overlap in determining the FLR, particularly on its ascending arm.

Abstract P315: Shortening The Thick Filament By Partial Deletion Of Titin’S C-zone Alters Cardiac Function By Reducing The Operating Sarcomere Length Range Of The Heart.

Titin’s C-zone is the inextensible part of titin that binds along the thick filament at its cMyBP-C -containing region. Previously it was shown that deletion of titin’s super-repeats C1 and C2 ( Ttn ΔC1-2 mouse model) results in shorter thick filaments and contractile dysfunction, but LV chamber stiffness is normal. Here we studied the contraction-relaxation kinetics from the time-varying elastance of the left ventricle (LV) and from cellular work loops of intact loaded cardiac myocytes. Ca 2+ transients were also measured as well as crossbridge cycling kinetics and Ca 2+ sensitivity of force. It was found that intact cardiomyocytes of Ttn ΔC1-2 mice exhibit systolic dysfunction and impaired relaxation. The time-varying elastance of the LV chamber showed that the kinetics of LV activation are normal but that relaxation is slower in Ttn ΔC1-2 mice. The slowed relaxation was, in part, attributable to an increased myofilament Ca 2+ sensitivity and slower early Ca 2+ reuptake. Dynamic stiffness at the myofilament level showed that cross-bridge kinetics are normal, but that the number of force-generating cross-bridges is reduced. In vivo sarcomere length (SL) measurements in the mid-wall region of the LV revealed that the operating SL range is shifted in Ttn ΔC1-2 mice towards shorter lengths. This normalizes the apparent cell and LV chamber stiffness but reduces the number of force generating cross-bridges due to suboptimal thin and thick filament overlap. Thus the contractile dysfunction in Ttn ΔC1-2 mice is not only due to shorter thick filaments but also to a reduced operating sarcomere length range. Overall these results reveal that for normal cardiac function, thick filament length regulation by titin’s C-zone is critical.

DEVELOPMENT OF A MODEL SYSTEM USING GLYCERINATED MUSCLE FOR THE STUDY OF PHYSICAL PROPERTIES

A model system which duplicates in some of its properties the chemical and physical states of non-glycerinated muscle in its various postmortem states, has been developed using glycerinated muscle at different states of contraction. The state of the muscle was related to sarcomere length, extractable actomyosin, and binding of 1-fluoro-2, 4-dinitrobezene (FDNB) to myofibrillar proteins. It was established that FDNB binding was a more accurate measure of actomyosin formation in situ than was actomyosin extractability. FDNB binding was presumably related to thin and thick filament overlap, even after the Z disc was removed, whereas extraction of actomyosin was not. Results of extensibility with the glycerinated muscle could be predicted based on the model and matched that found with non-glycerinated muscle as described in the literature. The model system offers the following advantages over non-glycerinated muscle: stability, convenience, maintenance of a “pre-rigor” condition indefinitely, and a “pre-rigor” muscle that is not contractile.

Mechanism of Supercontraction in a Striated Muscle Fiber

Cross-striated muscle fibers may contract reversibly to less than 30 percent of their rest length and it is not easy to reconcile this fact with the sliding filament model of muscular contraction. The mechanism of supercontraction has been studied in fibrils obtained from the giant muscle fibers of the barnacle Balanus nubilus. They were examined by phase-contrast light microscopy and electron microscopy. Contraction beyond the 50-percent stage was found to be achieved largely by the passage of thick filaments through the Z-disks, which are perforated. The overlap of thick filaments from adjacent sarcomeres causes the appearance of the contraction bands about the Z-disks. Subsequent contraction is associated with a folding and loose coiling, but not a shortening, of the thick filaments.