Hill’s equation of muscle performance and its hidden insight on molecular mechanisms

Muscles shorten faster against light loads than they do against heavy loads. The hyperbolic equation first used by A.V. Hill over seven decades ago to illustrate the relationship between shortening velocity and load is still the predominant method used to characterize muscle performance, even though it has been regarded as purely empirical and lacking precision in predicting velocities at high and low loads. Popularity of the Hill equation has been sustained perhaps because of historical reasons, but its simplicity is certainly attractive. The descriptive nature of the equation does not diminish its role as a useful tool in our quest to understand animal locomotion and optimal design of muscle-powered devices like bicycles. In this Review, an analysis is presented to illustrate the connection between the historic Hill equation and the kinetics of myosin cross-bridge cycle based on the latest findings on myosin motor interaction with actin filaments within the structural confines of a sarcomere. In light of the new data and perspective, some previous studies of force–velocity relations of muscle are revisited to further our understanding of muscle mechanics and the underlying biochemical events, specifically how extracellular and intracellular environment, protein isoform expression, and posttranslational modification of contractile and regulatory proteins change the interaction between myosin and actin that in turn alter muscle force, shortening velocity, and the relationship between them.