Modulation of Skeletal Muscle Contraction by Myosin Phosphorylation

Abstract

The striated muscle sarcomere is a highly organized and complex enzymatic and structural organelle. Evolutionary pressures have played a vital role in determining the structure-function relationship of each protein within the sarcomere. A key part of this multimeric assembly is the light chain-binding domain (LCBD) of the myosin II motor molecule. This elongated "beam" functions as a biological lever, amplifying small interdomain movements within the myosin head into piconewton forces and nanometer displacements against the thin filament during the cross-bridge cycle. The LCBD contains two subunits known as the essential and regulatory myosin light chains (ELC and RLC, respectively). Isoformic differences in these respective species provide molecular diversity and, in addition, sites for phosphorylation of serine residues, a highly conserved feature of striated muscle systems. Work on permeabilized skeletal fibers and thick filament systems shows that the skeletal myosin light chain kinase catalyzed phosphorylation of the RLC alters the "interacting head motif" of myosin motor heads on the thick filament surface, with myriad consequences for muscle biology. At rest, structure-function changes may upregulate actomyosin ATPase activity of phosphorylated cross-bridges. During activation, these same changes may increase the Ca2+ sensitivity of force development to enhance force, work, and power output, outcomes known as "potentiation." Thus, although other mechanisms may contribute, RLC phosphorylation may represent a form of thick filament activation that provides a "molecular memory" of contraction. The clinical significance of these RLC phosphorylation mediated alterations to contractile performance of various striated muscle systems are just beginning to be understood. © 2017 American Physiological Society. Compr Physiol 7:171-212, 2017.

Thick Filament Protein Network, Functions, and Disease Association

“…The effects of phosphorylation of RLC MYL2 at Ser15 by the cardiac and skeletal myosin light chain kinases (MLCK) have been extensively examined (89, 126, 624). Accordingly, it was demonstrated that it renders the lever arm of MyHC stiffer, potentiates isometric and concentric force production, and increases myofilament Ca 2+ sensitivity in both cardiac and skeletal muscles, reviewed in (514, 573, 574, 618). Consistent with these findings, constitutive expression of phosphomimetic Myl2 (i.e., Ser15Asp) in myocardia prevented the development of HCM in transgenic mice carrying the HCM-linked Asp166Val MYL2 missense mutation (620).…”

Nonlocalized postactivation performance enhancement (PAPE) effects in trained athletes: a pilot study

“…The magnitude and time history of the enhancement depends on whether performance is assessed in electrically evoked or voluntary contractions. Enhancements of electrically evoked contractions are typically large (>20%) increases in twitch torque during the first minute after the CA and decline rapidly (Tillin and Bishop 2009;Vandenboom 2016). In contrast, enhancements of voluntary contractions are typically small (<5%) effects observable after a significant rest period, peaking 7-10 minutes after the CA (Maloney et al 2014;Tillin and Bishop 2009;Wilson et al 2013), a time when there is effectively no remaining enhancement of electrically evoked contractions.…”

Role of Proton Motive Force in Photoinduction of Cytoplasmic Streaming in Vallisneria Mesophyll Cells

“…In muscle cells, Ca 2+ -sensitive regulatory mechanisms for the actomyosin-dependent generation of motive force have been extensively investigated, and a number of actin-linked and myosin-linked components responsible for the Ca 2+ sensitivity have been identified [11,12]. Moreover, it is well documented that Ca 2+ fluxes across the plasma membrane (PM) and the sarcoplasmic reticulum membrane of those motile cells function to control the cytoplasmic concentration of Ca 2+ and excitation-contraction coupling [13].…”