The endothermic ATP hydrolysis and crossbridge attachment steps drive the increase of force with temperature in isometric and shortening muscle

Abstract

Key points: Muscle performance increases with temperature in a wide variety of animals but has been studied most fully in frogs and mammals. While it has been previously proposed that the tension-generating step in the muscle crossbridge cycle is temperature-sensitive, this does not explain why tension increases after a rapid temperature rise much more slowly than after a length step. We have developed a model of an unbranched crossbridge cycle that simulates the effects of temperature on the tension and force-velocity relationship of frog muscle and the tension rise after a rapid temperature rise. We conclude that the increased tension produced by raising temperature is principally due to enhancement of the two steps before the tension-generating step. By integrating the interpretation of several key physiological experiments, this simplifies our understanding of the crossbridge cycle and the effect of temperature on human muscle performance. The isometric tetanic tension of skeletal muscle increases with temperature because attached crossbridge states bearing a relatively low force convert to those bearing a higher force. It was previously proposed that the tension-generating step(s) in the crossbridge cycle was highly endothermic and was therefore itself directly targeted by changes in temperature. However, this did not explain why a rapid rise in temperature (a temperature jump) caused a much slower rate of rise of tension than a rapid length step. This led to suggestions that the step targeted by a temperature rise is not the tension-generating step but is an extra step in the attached pathway of the crossbridge cycle, perhaps located on a parallel pathway. This enigma has been a major obstacle to a full understanding of the operation of the crossbridge cycle. We have now used a previously developed mechano-kinetic model of the crossbridge cycle in frog muscle to simulate the temperature dependence of isometric tension and shortening velocity. We allowed all five steps in the cycle to be temperature-sensitive. Models with different starting combinations of enthalpy changes and activation enthalpies for the five steps were refined by downhill simplex runs and scored by their ability to fit experimental data on the temperature dependence of isometric tension and the relationship between force and shortening velocity in frog muscle. We conclude that the first tension-generating step may be weakly endothermic and that the rise of tension with temperature is largely driven by the preceding two strongly endothermic steps of ATP hydrolysis and attachment of M.ADP.Pi to actin. The refined model gave a reasonable fit to the available experimental data and after a temperature jump the overall rate of tension rise was much slower than after a length step as observed experimentally. The findings aid our understanding of the crossbridge cycle by showing that it may not be necessary to include an additional temperature-sensitive step.