The Role of the Thick Filaments in the Regulation of Muscle Contraction

Abstract

Contraction of skeletal and heart muscle is triggered by a calcium-dependent structural change in the actin-containing thin filaments that permits binding of myosin motors from the neighbouring thick filaments. In resting muscle, however, most of the myosin motors are packed into helical tracks on the surface of the thick filaments, making them unavailable for actin binding or ATP hydrolysis, and implying additional thick filament-based mechanisms in the control of muscle contraction. Structurally, the OFF state of the thick filament is characterized by a myosin conformation with motors folded back against their tails, stabilized by a network of intra- and inter-molecular interactions. These features are largely conserved across muscle types and species, including myosin-regulated muscles. In vertebrate striated muscles, the regulatory transition in thick filament structure controls both the number of myosin heads available for actin interaction and the dynamics of activation. The thick filament regulatory transition is highly co-operative, and the regulatory states of the thick and thin filaments are positively coupled through multiple mechanisms. One such mechanism recently described in skeletal muscle is direct activation of thick filaments by mechanical stress (Linari et al., Nature 2015; Fusi et al., Nat. Commun. 2016). During muscle activation, this mechanism relies on a small population of constitutively ON motors outside thick filament control which are sufficient to drive unloaded shortening when the thin filament is ON. At higher load, these motors generate sufficient stress to switch the thick filament ON, releasing the remaining motors from their OFF conformation. This mechano-sensing mechanism seems to determine both the rate of force development and the classic force-velocity relationship of skeletal muscle. Related mechanisms are likely to operate in heart muscle, adapted to its distinct functional requirements (Kampourakis et al., PNAS 2016).