Mechano-chemo-transduction in cardiac myocytes

Abstract

The heart has the ability to adjust to changing mechanical loads. The Frank-Starling law and the Anrep effect describe exquisite intrinsic mechanisms the heart has for autoregulating the force of contraction to maintain cardiac output under changes of preload and afterload. Although these mechanisms have been known for more than a century, their cellular and molecular underpinnings are still debated. How does the cardiac myocyte sense changes in preload or afterload? How does the myocyte adjust its response to compensate for such changes? In cardiac myocytes Ca²⁺ is a crucial regulator of contractile force and in this review we compare and contrast recent studies from different labs that address these two important questions. The 'dimensionality' of the mechanical milieu under which experiments are carried out provide important clues to the location of the mechanosensors and the kinds of mechanical forces they can sense and respond to. As a first approximation, sensors inside the myocyte appear to modulate reactive oxygen species while sensors on the cell surface appear to also modulate nitric oxide signalling; both signalling pathways affect Ca²⁺ handling. Undoubtedly, further studies will add layers to this simplified picture. Clarifying the intimate links from cellular mechanics to reactive oxygen species and nitric oxide signalling and to Ca²⁺ handling will deepen our understanding of the Frank-Starling law and the Anrep effect, and also provide a unified view on how arrhythmias may arise in seemingly disparate diseases that have in common altered myocyte mechanics.

Keywords: calcium signalling; cardiac arrhythmia; cardiac myocytes; heart disease; mechanotransduction; muscle mechanics; nitric oxide synthase; reactive oxygen species.

Figure 1. Location of mechanosensors and how they change during contraction

Internal mechanosensors S₁ and S₂ respond to orthogonal strains. Surface sensor S₃ lies on the neutral plane. ε_m is the myocyte strain (fractional shortening) and ε_s is the sensor strain. Left panel depicts a myocyte embedded in‐gel at resting state. Right panel depicts a myocyte in‐gel at contracted state when the internal and surface mechanosensors are under mechanical loading.

Figure 2. How different experimental systems distinguish between surface and internal mechanosensors

Surface (yellow) and internal (red and green) mechanosensors are depicted as springs. As the myocyte is stretched (left column) or contracts (right column) surface mechanosensors experience different strains (change in length divided by original length) depending on experimental system. The ellipticity of the mechanosensor represents the degree of strain. A perfect circle indicates zero strain. In the 1‐D system, the blue cylinders at the cell edges are the glass rods or carbon fibres. In the 2‐D system the blue sheet represents the stretchable membrane. In the 3‐D system, the blue cylinder represents the hydrogel.