The Sliding Filament Theory Since Andrew Huxley: Multiscale and Multidisciplinary Muscle Research

Two groundbreaking papers published in 1954 laid out the theory of the mechanism of muscle contraction based on force-generating interactions between myofilaments in the sarcomere that cause filaments to slide past one another during muscle contraction. The succeeding decades of research in muscle physiology have revealed a unifying interest: to understand the multiscale processes—from atom to organ—that govern muscle function. Such an understanding would have profound consequences for a vast array of applications, from developing new biomimetic technologies to treating heart disease. However, connecting structural and functional properties that are relevant at one spatiotemporal scale to those that are relevant at other scales remains a great challenge. Through a lens of multiscale dynamics, we review in this article current and historical research in muscle physiology sparked by the sliding filament theory. Expected final online publication date for the Annual Review of Biophysics, Volume 50 is May 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Defects in the Existing Theory of Skeletal Muscle Contraction and Postulation of a New Theory

In 1954 , two independent research teams, one consisting of Andrew F. Huxley and Rolf Niedergerke from the University of Cambridge, and the other consisting of Hugh Huxley and Jean Hanson from the Massachusetts Institute of Technology proposed the theory of skeletal muscle contraction [1]. They used electron microscopy to study the details of muscle filaments. The structure was studied in detail by then, but the mechanism of skeletal muscle contraction was not defined. Based on various assumptions about the actin and myosin filaments of muscle, later they postulated a theory called “sliding filament theory”. When this theory is scrutinized in detail, I find that there are a lot of defects in this theory, which I have pointed out and I have made an attempt to postulate a different mechanism for the skeletal muscle contraction.

Sarcomere length non-uniformities dictate force production along the descending limb of the force–length relation

The force–length relation is one of the most defining features of muscle contraction, and yet a topic of debate in the literature. The sliding filament theory predicts that the force produced by muscle fibres is proportional to the degree of overlap between myosin and actin filaments, producing a linear descending limb of the active force–length relation. However, several studies have shown forces that are larger than predicted, especially at long sarcomere lengths (SLs). Studies have been conducted with muscle fibres, preparations containing thousands of sarcomeres that make measurements of individual SL challenging. The aim of this study was to evaluate force production and sarcomere dynamics in isolated myofibrils and single sarcomeres from the rabbit psoas muscle to enhance our understanding of the theoretically predicted force–length relation. Contractions at varying SLs along the plateau (SL = 2.25–2.39 µm) and the descending limb (SL > 2.39 µm) of the force–length relation were induced in sarcomeres and myofibrils, and different modes of force measurements were used. Our results show that when forces are measured in single sarcomeres, the experimental force–length relation follows theoretical predictions. When forces are measured in myofibrils with large SL dispersions, there is an extension of the plateau and forces elevated above the predicted levels along the descending limb. We also found an increase in SL non-uniformity and slowed rates of force production at long lengths in myofibrils but not in single sarcomere preparations. We conclude that the deviation of the descending limb of the force–length relation is correlated with the degree of SL non-uniformity and slowed force development.

Sir Andrew Fielding Huxley OM. 22 November 1917—30 May 2012

Andrew Huxley was a physiologist, possessing a combination of practical skill, invention and mathematical ability that has few parallels, and is famous for his contributions to the understanding of how nerve and muscle work. He came from an illustrious family: his paternal grandfather was Thomas Henry Huxley, and Julian Huxley and Aldous Huxley were his half-brothers. After completing his undergraduate degree in Cambridge in 1939, he joined Alan Hodgkin in his research on the squid giant axon and they made the first intracellular recording of a nerve action potential. Together, they used the voltage clamp technique to elucidate the ionic mechanism of the action potential; for this they were awarded a share of the Nobel Prize in Physiology or Medicine in 1963. Turning to research on muscle, he elucidated the sliding filament mechanism of contraction (in parallel with Hugh Huxley), and went on to formulate a quantitative account of the steady state properties of muscle based on the interaction between myosin crossbridges and actin sites. Moving to University College London (UCL) in 1960 as Jodrell Professor of Physiology, he provided quantitative evidence for the sliding filament theory through a study of the length–tension relation. His final studies were on the transient mechanical properties of muscle, resulting in a theory of force-generation by crossbridges. During the war, Huxley was engaged in operational research on anti-aircraft artillery and naval gunnery. He was President of the Royal Society in 1980–85, and Master of Trinity College Cambridge in 1984–90.

Sarcomere mechanics in striated muscles: from molecules to sarcomeres to cells

Muscle contraction is commonly associated with the cross-bridge and sliding filament theories, which have received strong support from experiments conducted over the years in different laboratories. However, there are studies that cannot be readily explained by the theories, showing 1) a plateau of the force-length relation extended beyond optimal filament overlap, and forces produced at long sarcomere lengths that are higher than those predicted by the sliding filament theory; 2) passive forces at long sarcomere lengths that can be modulated by activation and Ca2+, which changes the force-length relation; and 3) an unexplained high force produced during and after stretch of activated muscle fibers. Some of these studies even propose “new theories of contraction.” While some of these observations deserve evaluation, many of these studies present data that lack a rigorous control and experiments that cannot be repeated in other laboratories. This article reviews these issues, looking into studies that have used intact and permeabilized fibers, myofibrils, isolated sarcomeres, and half-sarcomeres. A common mechanism associated with sarcomere and half-sarcomere length nonuniformities and a Ca2+-induced increase in the stiffness of titin is proposed to explain observations that derive from these studies.

Weightlifting and the actomyosin cycle

How does a human lift a weight? Can we relate the dynamics of the lift to the molecular actin–myosin interactions responsible for muscle contraction? We address these questions with bench press experiments that we analyse with a theoretical model, based on the sliding filament theory. The agreement is fair, and we discuss its possible extension to medical diagnostics.

Capillary muscle

The contraction of a muscle generates a force that decreases when increasing the contraction velocity. This “hyperbolic” force–velocity relationship has been known since the seminal work of A. V. Hill in 1938 [Hill AV (1938) Proc R Soc Lond B Biol Sci 126(843):136–195]. Hill’s heuristic equation is still used, and the sliding-filament theory for the sarcomere [Huxley H, Hanson J (1954) Nature 173(4412):973–976; Huxley AF, Niedergerke R (1954) Nature 173(4412):971–973] suggested how its different parameters can be related to the molecular origin of the force generator [Huxley AF (1957) Prog Biophys Biophys Chem 7:255–318; Deshcherevskiĭ VI (1968) Biofizika 13(5):928–935]. Here, we develop a capillary analog of the sarcomere obeying Hill’s equation and discuss its analogy with muscles.