Mechanical stress-induced sarcomere assembly for cardiac muscle growth in length and width

Abstract

A ventricular myocyte experiences changes in length and load during every beat of the heart and has the ability to remodel cell shape to maintain cardiac performance. Specifically, myocytes elongate in response to increased diastolic strain by adding sarcomeres in series, and they thicken in response to continued systolic stress by adding filaments in parallel. Myocytes do this while still keeping the resting sarcomere length close to its optimal value at the peak of the length-tension curve. This review focuses on the little understood mechanisms by which direction of growth is matched in a physiologically appropriate direction. We propose that the direction of strain is detected by differential phosphorylation of proteins in the costamere, which then transmit signaling to the Z-disc for parallel or series addition of thin filaments regulated via the actin capping processes. In this review, we link mechanotransduction to the molecular mechanisms for regulation of myocyte length and width.

Figure 1. Anisotropic mechanotransduction

Neonatal cardiac myocytes have distinct molecular responses to different directions of extrinsically-applied mechanical strain. Myocytes are aligned by culture in microgrooves and subjected to either (A) transverse strain (TS) or (B) longitudinal strain (LS) (B) relative to the long axis of myocytes [17]. Costameres encircle the myocyte at every Z-disc. FAK is a costameric protein whose unfolding by local mechanics may be crucial for detecting and initiating differential growth in myocyte length or width. FAK is perhaps found more often in its unfolded, active state when strained transversely than when at rest or when strained longitudinally. (C) The table shows major changes between spontaneously beating neonatal myocytes in this culture system compared to those with TS or LS strain. Increased phosphorylation of FAK (at Y397) was found in TS; ERK1/2 phosphorylation (at residues T203/Y205 and T183/Y185 in ERK 1 and 2, respectively) is increased in both directions. PKCε and protein synthesis are implicated in longitudinal remodeling but have not been assessed for TS [31].

Figure 2. Lengthwise strain of mechanosensory apparatus at the costameres with hypothetical effect on filament addition at the Z-disc

Lengthwise strain is detected by the costameric focal adhesion complex at the membrane containing many proteins, shown here are integrins, paxillin, vinculin, PYK2, FAK and Rho. Longitudinal strain is detected by differential phosphorylation of some of these proteins, and then signaled via PIP2 and PKCε to the Z-disc for thin filament addition via CapZ regulation.

Figure 3. CapZ β-GFP binding dynamics alter with hypertrophy

(A) Actin polymerization in muscle is partly regulated by the dynamics of CapZαβ dimer binding at barbed ends of the thin filament. The α- and β-tentacles bind the CapZαβ dimer tightly to actin in normal myocytes (69, 70). (B). With hypertrophic stimuli, the CapZ αβ complex binding is more dynamic perhaps by loosening of the β-tentacle so that CapZβ-GFP has a higher off rate (96). This more dynamic state may permit greater actin remodeling and sarcomeric growth.