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Title: The actomyosin ATPase response to stretch in cardiac muscle
Author: Mansfield, Catherine
ISNI:       0000 0004 2719 8408
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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The aim of this thesis was to examine the molecular mechanism underlying the force response to stretch in the heart. The properties of cardiac muscle were studied in rat trabeculae activated by laser-flash photolysis of NPE-caged ATP at 20°C. The rate of ATP hydrolysis was determined, on a millisecond time scale, using a fluorescently labelled phosphate binding protein to measure the rate of inorganic phosphate release. The results show that an increase in sarcomere length causes an increase in isometric force with a similar response seen upon increasing thin filament activation. ATPase rate increases with thin filament activation, however, the increase in force with sarcomere length is not accompanied by a corresponding increase in ATPase rate. At a lower activation level a more substantial increase in isometric force is seen with increasing sarcomere length, compared to at a higher activation level. The results show that at a longer sarcomere length less ATP is used per unit of force produced. Interestingly, stretch of an active muscle causes a substantial and instantaneous reduction in cross-bridge ATPase activity, even though force remains high. Conversely, active shortening resulted in an increase in the ATPase rate, above that of the isometric level. The stretch applied to the active trabeculae was greater than the reach of the cross-bridges therefore cross-bridge detachment must occur, however as force remains high this must be followed by rapid reattachment. As Pi release is low during the stretch this detachment and reattachment cannot occur via the classical view of the cross-bridge cycle where attachment is preceded by ATP hydrolysis. To explain these results a branched cross-bridge cycle is suggested whereby rapid detachment and reattachment can occur without additional Pi release and ATP hydrolysis.
Supervisor: Ferenczi, Mike Sponsor: National Heart and Lung Institute Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral