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Herzog, Walter; University of Calgary WPI Seminar Room 08.135 Mon, 22. Sep 14, 9:10
A New Model for Muscle Contraction
In 1953, Hugh Huxley proposed that muscle contraction occurred through the sliding of two sets of filamentous proteins, actin and myosin, rather than through the shortening of the centre filament in the sarcomere. This proposal was supported by the two classic papers in the May issue of Nature 1954 by Andrew Huxley and Hugh Huxley. Andrew Huxley then proposed how this sliding of the two sets of filament occurs in 1957, and this has become known as the “cross-bridge theory” of muscle contraction. Briefly, the cross-bridge theory assumes that there are protrusions from the myosin filaments attaching cyclically to the actin filaments and pulling the actin past the myosin filaments using energy from the hydrolysis of adenosine triphosphate (ATP). This two-filament thinking of contraction (involving actin and myosin) has persisted to this day, despite an inability of this model to predict experimental results on stability, force and energetics appropriately for eccentric (active lengthening) muscles. Andrew Huxley reported on this limitation of his cross-bridge model and predicted in 1980, that studying of eccentric contractions would lead to new insights and surprises, and would produce thus far unknown elements that might affect muscle contraction and force production. Here, I would like to propose a new model of muscle contraction, that aside from the contractile proteins, actin and myosin, also includes the structural protein, titin. Titin will not only be a passive player in this new theory, but an activatable spring that changes its stiffness in an activation- and force- dependent manner, thus contributing substantially more titin-based (passive) force in activated muscles than in passive (non-activated) muscles. I will show evidence that titin binds calcium at various sites upon activation (activation in muscles is associated with a steep increase in sarcoplasmic calcium), thereby increasing its inherent spring stiffness, and that titin may bind its proximal segments to actin, thereby shortening its free spring length, and thus increasing its stiffness and force in a second way. Incorporating this third filament, titin, into the two filament model of muscle contraction (actin and myosin) allows for predictions of experimental observations that could not be predicted before while maintaining the power of the cross-bridge theory for isometric (constant length) and concentric (shortening) contractions. For example, the three filament model naturally predicts the energetic efficiency of eccentric contractions, the increase in steady-state force following eccentric contractions, and the stability of sarcomeres on the descending limb of the force-length relationship. Aside from its predictive power, this new three filament model is insofar attractive as it leaves the "historic” cross-bridge model fully intact, it merely adds an element to it, and its conceptual and structural simplicity makes it a powerful theory that, although not fully proven, is intuitively appealing and emotionally satisfying.

Vincenzo Lombardi; University of Florence WPI Seminar Room 08.135 Mon, 22. Sep 14, 10:05
The muscle as a motor and as a brake
Force and shortening in a contracting striated muscle are generated by the dimeric motor protein myosin II pulling the actin filament towards the centre of the sarcomere during cyclical ATP-driven working strokes. The motors in each half-sarcomere are arranged in antiparallel arrays emerging from the two halves of the thick myosin filament and mechanically coupled via their filament attachments. The co-operative action of this coupled system, including the interdigitating actin filaments and other elastic and regulatory proteins, is the basic functional unit of muscle. When the sarcomere load is smaller than the maximum force developed in isometric contraction (T0), the myosin array works as a collective motor, converting metabolic energy into mechanical work at a rate that increases with reduction of the load. When an external load larger than T0 is applied to the active muscle, the sarcomere exerts a marked resistance to lengthening, with reduced metabolic cost. Thus the chemical and mechanical properties of the half-sarcomere machine during generation of force and shortening, when muscle works as a motor, are quite different from those during the response to a load or length stretch, when it works as a brake. Sarcomere-level mechanics and X-ray interferometry in single fibres from frog skeletal muscle have provided detailed information about the mechanical properties of the various components of the half-sarcomere and about kinetics and structural dynamics of the myosin motors as they perform different physiological tasks. The high stiffness of the myosin motor resulting from the analysis of the compliance of half-sarcomere elements indicates that in isometric contraction 20-30% of myosin motors are attached to actin and generate force by a small sub-step of the 11 nm working stroke suggested by the crystallographic model (Fusi et al. 2014, J. Physiol. 592, 1109-1118; Brunello et al. 2014, J. Physiol. 592, 3881-3899). During steady shortening against high to moderate loads (the condition for the maximum power and efficiency), the number of actin-attached motors decreases in proportion to the load, while each attached motor maintains a 5-6 pN force over a 6 nm stroke (Piazzesi et al. 2007, Cell 131, 784-795). The braking action exerted when an active sarcomere resists an increase in load above the isometric force, depends not only on the mechanical properties of the myosin-actin cross-bridges and of the meshwork of cytoskeleton proteins in each half-sarcomere, but also on the rapid attachment to actin of the second motor domain of the myosin dimer that has the first motor domain already attached to actin during the isometric contraction (Brunello et al. 2007, PNAS 104, 20114-20119; Fusi et al. 2010, J. Physiol. 588, 495-510).

Campbell, Kenneth; University of Kentucky WPI Seminar Room 08.135 Mon, 22. Sep 14, 11:30
Myocardial strain rate modulates the speed of relaxation in dynamically loaded twitch contractions
Slow myocardial relaxation is an important clinical problem in about 50% of patients who have heart failure. Prior experiments had suggested that the slow relaxation might be a consequence of high afterload (hypertension) but clinical trials testing this hypothesis have failed; lowering blood pressure in patients with slow relaxation does not help their condition. We performed new experiments using mouse, rat, and human trabeculae and showed that it is not afterload but the strain rate at end systole that determines the subsequent speed of relaxation. To investigate the molecular mechanisms that drive this behavior, we ran simulations of our experiments using the freely available software MyoSim (http://www.myosim.org). This software simulates the mechanical properties of dynamically activated half-sarcomeres by extending A.F.Huxley’s cross-bridge distribution technique with Ca2+ activation and cooperative effects. We discovered that our experimental data could be reproduced using a relatively simple framework consisting of a single half-sarcomere pulling against a series elastic spring. Further analysis of the simulations suggested that quick stretches speed myocardial relaxation by detaching myosin heads and thereby disrupting the cooperative mechanisms that would otherwise prolong thin filament activation. The simulations therefore identify myofilament kinetics and tissue strain rate as potential therapeutic targets for heart failure attributed to slow relaxation.

Lorz, Alexander; Laboratoire Jacques-Louis Lions WPI Seminar Room 08.135 Tue, 23. Sep 14, 11:30
Population dynamics and therapeutic resistance: mathematical models
Motivated by the theory of mutation-selection in adaptive evolution, we propose a model based on a continuous variable that represents the expression level of a resistance phenotype. This phenotype influences birth/death rates, effects of chemotherapies (both cytotoxic and cytostatic) and mutations in healthy and tumor cells. We extend previous work by demonstrating how qualitatively different actions of cytostatic (slowing down cell division) and cytostatic (actively killing cells) treatments may induce different levels of resistance.

Latos, Evangelos; University of Mannheim WPI Seminar Room 08.135 Wed, 24. Sep 14, 10:05
Existence and Blow-up of Solutions for Semilinear Filtration Problems
We examine the local existence and uniqueness of solutions to the semi-linear filtration equation, with positive initial data and appropriate boundary conditions. Our main result is the proof of blow-up of solutions. Moreover, we discuss about the existence of solutions for the corresponding steady-state problem. It is found that there exists a critical value, above which the problem has no stationary solution of any kind, while below that critical value there exist classical stationary solutions. Exactly this critical value of the parameter acts as a threshold also for the corresponding parabolic problem between blow-up and global existence

Laamri, El-Haj; Institut Elie Cartan de Lorraine WPI , OMP 1, Seminar Room 08.135 Wed, 24. Sep 14, 11:30
Global existence for some reaction-di usion systems with nonlinear di usion
In this talk, we present new results concerning global existence for some reaction-diff usion systems. This is joint work with Michel Pierre (ENS de Rennes).
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