|Ph.D Student||Amiad Pavlov Daria|
|Subject||The Effects of Muscle Length and Shortening Velocity on|
Cross-Bridge Dynamics; Deciphering the
Mechanisms Underlying the Regulation of
Cardiac Sarcomere Mechanics
|Department||Department of Biomedical Engineering||Supervisor||Professor Amir Landesberg|
|Full Thesis text|
Introduction: The cardiac muscle has a remarkable ability to adjust function to changes in demands as described by the fundamental properties of the Frank-Starling law, the pressure-volume relationship, the Fenn effect, and the constant linear relationship between energy consumption and the generated mechanical energy. The loading conditions determine the rate of energy consumption via intracellular mechanisms of control of contraction. The length, stress, and velocity of shortening were suggested as possible modulators of cross-bridge (XB) dynamics, in response to changes in the loading conditions.
Methods: The study utilized intact rat cardiac trabeculae and analyzed their force response to length perturbations under tight control of the loading conditions to isolate the effects of length, velocity and activation level on the force per XB and the rates of XB cycling. Sarcomere length was measured by laser diffraction, and controlled ramp shortenings were induced by fast servomotor. The stress responses were analyzed with phase plots of the rate of change in the stress against the instantaneous stress (ds(t)/dt-s(t) plane). The experimental results were evaluated against the theoretical predictions.
Results and Discussion: Stress responses of all experimental conditions have revealed two distinct phases: 1. A rapid and short phase that relates to the fast physical acto-myosin interactions that determine the force per XB. 2. A slow phase that reflects the slower biochemical process of XB cycling between the weak and the strong conformations. The rapid kinetics is faster by a factor >5 than the slow kinetics.
Both the rapid and the slow rate coefficients are independent of the sarcomere length. Alternatively, both rate coefficients increase linearly with the shortening velocity. The results indicate that XB dynamics is modulated by shortening velocity, and not by the instantaneous sarcomere length or stress level.
The study further reveals that the short scale (<20msec) stress response to ramp length perturbations during isometric twitch contraction is also biphasic. Both rate coefficients show linear dependence on the shortening velocity. The rate coefficients were practically unaffected by different ramp onset times. These findings indicate that the short scale response is dominated by changes in XB dynamics while Ca2 activation dependent changes in the rates of XB recruitment are slower and do not affect XB cycling kinetics.
Conclusions and Significance:
The velocity of shortening imposes real time control on cardiac muscle contraction by modulation of the force per XB and the rate of XB cycling. Hence, the velocity plays a key role in synchronizing the contraction of the 10 billion myocytes on the opposite walls of the whole heart. The length and activation level have no direct effect on XB dynamics, but modulate force generation by changing the rate of XB recruitment, in a separate mechanism from XB cycling. This observation strongly indicates that the Frank-Starling mechanism is not mediated by changes in XB dynamics, and that the cardiac muscle operates at constant economy under different preloads. These findings can explain global cardiac mechanic and energetic phenomena and have immense importance for understanding physiological and pathological cardiac adaptation to changing loads.