Small molecule studies: the fourth wave of muscle research

Abstract

The study of muscle and contractility is an unusual scientific endeavour since it has from the start been focussed on one problem-What makes muscle work?-and yet has needed a vast range of different approaches and techniques to study it. Its uniqueness lies in the fundamental fascination of a large scale molecular machine that converts chemical energy into mechanical energy at ambient temperature and with high efficiency that is also controlled by an exquisitely intricate yet utterly reliable regulatory system and is an essential component of animal life. The investigation of muscle is as innovative as any other field of research. As soon as one approach appears to be played out another comes along. It is instructive to consider this as a series of waves of novel and heightened activity starting in the 1950s. The thesis of this article is that we are approaching the fourth wave with the recent rise of interest in small molecules as research tools and possible therapies for muscle diseases.

Keywords: Actin; Contraction; Myosin; Regulation; Small molecules; Tropomyosin; Troponin.

Fig. 1

The crossbridge cycle and its regulation by troponin-tropomyosin and by the SRX/DRX equilibrium. The chemomechanical crossbridge cycle is represented in the blue circle. The availability of actin-binding sites is controlled by troponin–tropomyosin (top left). Ca²⁺ controls the equilibrium between blocked (no myosin binding) and closed (weak myosin binding) states. Myosin heads cooperatively regulate the closed-open equilibrium. Only the open state may participate in the crossbridge cycle. Small molecules that interact with each transition are shown. The availability of myosin heads is controlled by the SRX-DRX equilibrium; only the DRX state can enter the crossbridge cycle. Small molecules and physiological regulators that modulate the transition are shown. Diagram modified from Spudich (, Fig. 5). (Color figure online)