A new article in Circulation Research shows how the contractile units of cardiac muscle cells function, and how they become dysfunctional during disease.
In the heart, contraction is accomplished by the coordinated shortening of muscle cells, called cardiomyocytes. These cells are composed of contractile units called sarcomeres, which are arranged end-to-end as in an accordion. It has long been believed that the contraction of cardiomyocytes, and thus the whole heart, is triggered by the simultaneous shortening of sarcomeres. In new work published in Circulation Research, Jia Li and collaborators have called this belief into question.
Figure 1. Recordings of the positions of individual sarcomeres revealed that, while most sarcomeres contract, a minority are stretched by their more forceful neighbours.
Working in the Louch Group at IEMR, with collaborators from Norway, France, Germany, and Sweden, Dr. Li employed new techniques to discern the movement of individual sarcomeres with high accuracy. The technique is illustrated in Figure 1, with the signal from each sarcomere visible as a bright vertical line (top panel), and the movement of the sarcomere signal detected in the panels below. From these measurements, Dr. Li inferred the change in length of each sarcomere (bottom panel). She observed that while most sarcomeres shortened when the cell was electrically activated, a significant fraction of the sarcomeres (about 15%) were lengthened instead. This surprising result suggests that sarcomeres don’t always shorten together as we’d assumed previously.
Figure 2. Recordings were made at resting length (left panels) and after a 20% increase in cell length (right panels). Very similar Ca2+ signals were observed in the two cases (top panels). However, while some sarcomeres were stretched at resting length (see orange trace, bottom panel), all sarcomeres were observed to contract after cell stretch.
In her next series of experiments, Dr. Li examined the effects of stretching the cell. In the whole heart, this type of stretching occurs when the ventricle is filled with more blood, leading to a strengthening of cardiac function to meet increasing demand – a phenomenon referred to as the Frank-Starling mechanism. Dr. Li observed that when she stretched the cell, progressively more sarcomeres were recruited to contract, without any changes in the Ca2+ signal that triggers contraction (Figure 2). With all sarcomeres eventually shortening, the contraction of the cell and the efficiency of its contraction were amplified. Thus, the progressive recruitment of shortening sarcomeres is a previously unrealized contributor to the Frank-Starling mechanism.
Finally, experiments were conducted to understand what causes a sarcomere to shorten or be stretched. Dr Li observed that the stretched sarcomeres were shorter and produced less force than their neighbours. She showed that titin, an elastic protein in the cell, importantly controls sarcomere length, and thus the likelihood that it contracts or is stretched. Importantly, lower titin expression, which can result from human mutations, was linked to more variability in sarcomere length, more sarcomeres being stretched, and reduced efficiency of contraction. These data support a critical role of titin in controlling sarcomere function, and show that this control is lost in diseases affecting titin’s expression. In ongoing work, Dr. Li aims to understand this derangement in greater detail, with the hope of developing novel treatments for cardiac patients with these mutations.
Circ Res, 133 (3), 255-270
PubMed 37401464 DOI 10.1161/CIRCRESAHA.123.322588
