Myosin isoforms and the mechanochemical cross-bridge cycle

Abstract

At the latest count the myosin family includes 35 distinct groups, all of which have the conserved myosin motor domain attached to a neck or lever arm, followed by a highly variable tail or cargo binding region. The motor domain has an ATPase activity that is activated by the presence of actin. One feature of the myosin ATPase cycle is that it involves an association/dissociation with actin for each ATP hydrolysed. The cycle has been described in detail for a large number of myosins from different classes. In each case the cycle is similar, but the balance between the different molecular events in the cycle has been altered to produce a range of very different mechanical activities. Myosin may spend most of the ATPase cycle attached to actin (high duty ratio), as in the processive myosin (e.g. myosin V) or the strain-sensing myosins (e.g. myosin 1c). In contrast, most muscle myosins spend 80% of their ATPase cycle detached from actin. Within the myosin IIs found in human muscle, there are 11 different sarcomeric myosin isoforms, two smooth muscle isoforms as well as three non-muscle isoforms. We have been exploring how the different myosin isoforms have adapted the cross-bridge cycle to generate different types of mechanical activity and how this goes wrong in inherited myopathies. The ideas are outlined here.

Hypertrophic Cardiomyopathy

“…Consequently, to study the human MYH7 mutation, it had to be transposed into MYH6 in the mouse models. The problem with this approach is the presence of major differences between MYH6 and MYH7 proteins in their ATPase activities and acto-myosin kinetics 103 . The ATPase activity of the MYH6 protein and the velocity of actin displacement are several folds higher than those of MYH7 protein 100, 104, 105 .…”

Overview of the Muscle Cytoskeleton

“…To accommodate the difference in energy requirements between muscle groups and during development, multiple striated muscle MHC and MLC isoforms exist [reviewed in (584, 728, 740)]. In cardiac muscle of small mammals (e.g., mice), MHC-β ( MYH7 ) is the predominant isoform during development and is replaced by MHC-α ( MYH6 ) in the adult (394).…”

Thick Filament Protein Network, Functions, and Disease Association

“…To date, 35 distinct myosin families have been characterized in mammalian genomes (581). Herein, we will focus on the myosin isoforms that are expressed in striated muscles and discuss their preferential expression during embryogenesis and at maturity.…”

“…Fast-twitch skeletal myofibers are subclassified as Type-IIx, -IIb, and -IIa, and primarily express MyHC-2X encoded by MYH1 , MyHC-2B encoded by MYH4 , and MyHC-2A encoded by MYH2 , respectively, recently reviewed in (501, 581). Similar to cardiac ventricles, slow-twitch skeletal myofibers (Type-I) mainly express MYH7, along with low levels of MYH1, MYH2, MYH4, and MYH6 (403, 536).…”

“…Generally, fast-twitch muscles exhibit intense power output with high-contraction rate mediated by fast ATPase hydrolysis; they are therefore suitable for short bursts of contractility under anaerobic conditions (536, 581). Conversely, slow-twitch muscles display slow(er) shortening velocity and reduced ATP usage compared to fast-twitch muscles, thereby sustaining tension for longer periods of time (581). …”