A New State of Myosin in Cardiac Muscles with Very Slow ATP Turnover: A Potential Cardio-Protective Mechanism in the Heart

Abstract

We used quantitative epi-fluorescence of mant-nucleotides to measure single nucleotide turnovers in small bundles of permeable rabbit ventricle cells. In relaxed cells nucleotide turnover occurs in two phases one with a short time constant, 14 ± 1 seconds, and a second with a much longer time constant, 144 ± 10 seconds. The first is compatible with the normal relaxed state and the second arises from myosin heads in the Super Relaxed State (SRX). Approximately 60% of the myosin heads were in the SRX. Recent work identified a similar state with a slow nucleotide turnover time constant, 230 seconds, in relaxed vertebrate skeletal muscle (Stewart et.al. PNAS, 2010). The SRX appears to play a similar role in relaxed skeletal fibers and cardiac cells providing a state with a very low metabolic rate. However, in active fibers the properties of the SRX differ dramatically. There is a rapid transition of myosin heads out of the SRX in active skeletal fibers. In contrast, in cardiac muscle, the population of myosin heads in the SRX is not changed when the muscle, is activated. This property allows the SRX to play a very different role in cardiac cells than in skeletal fibers. The mechanisms that control cardiac contractility are complex, leading to an output that can vary from highly active to very quiescent. The ability of myosin heads to remain in the SRX, while other heads are generating tension, allows this state to play a role in the regulation of cardiac output. In particular, the super relaxed state could provide a mechanism for decreasing the metabolic load on the heart, being cardioprotective, particularly in time of stress such as ischemia.