Sarcomeric Auto-Oscillations in Single Myofibrils From the Heart of Patients With Dilated Cardiomyopathy

Abstract

Background: Left ventricular wall motion is depressed in patients with dilated cardiomyopathy (DCM). However, whether or not the depressed left ventricular wall motion is caused by impairment of sarcomere dynamics remains to be fully clarified. Methods and Results: We analyzed the mechanical properties of single sarcomere dynamics during sarcomeric auto-oscillations (calcium spontaneous oscillatory contractions [Ca-SPOC]) that occurred at partial activation under the isometric condition in myofibrils from donor hearts and from patients with severe DCM (New York Heart Association classification III-IV). Ca-SPOC reproducibly occurred in the presence of 1 μmol/L free Ca 2+ in both nonfailing and DCM myofibrils, and sarcomeres exhibited a saw-tooth waveform along single myofibrils composed of quick lengthening and slow shortening. The period of Ca-SPOC was longer in DCM myofibrils than in nonfailing myofibrils, in association with prolonged shortening time. Lengthening time was similar in both groups. Then, we performed Tn (troponin) exchange in myofibrils with a DCM-causing homozygous mutation (K36Q) in cTnI (cardiac TnI). On exchange with the Tn complex from healthy porcine ventricles, period, shortening time, and shortening velocity in cTnI-K36Q myofibrils became similar to those in Tn-reconstituted nonfailing myofibrils. Protein kinase A abbreviated period in both Tn-reconstituted nonfailing and cTnI-K36Q myofibrils, demonstrating acceleration of cross-bridge kinetics. Conclusions: Sarcomere dynamics was found to be depressed under loaded conditions in DCM myofibrils because of impairment of thick-thin filament sliding. Thus, microscopic analysis of Ca-SPOC in human cardiac myofibrils is beneficial to systematically unveil the kinetic properties of single sarcomeres in various types of heart disease.

Nanoscopic changes in the lattice structure of striated muscle sarcomeres involved in the mechanism of spontaneous oscillatory contraction (SPOC)

“…The correlation can be found in both ADP-SPOC 13 and Ca-SPOC 4 . Our recent studies further showed that myofibrils prepared from human myocardium can exhibit Ca-SPOC, with an oscillation period that matches the resting heart rate of humans 12,14 .…”

“…The correlation can be found in both ADP-SPOC 13 and Ca-SPOC 4 . Our recent studies further showed that myofibrils prepared from human myocardium can exhibit Ca-SPOC, with an oscillation period that matches the resting heart rate of humans 12 , 14 . Despite the yet-to-be-determined causality, these correlations infer a physiological role of SPOC in the heartbeat mechanism.…”

“…SPOC occurs at a range of average SL from ~ 2.2 to 3.0 µm, which changes depending on the amount of load applied to the myofibril. To examine whether the Aw oscillation can be observed at varying average SLs in SPOC, we held the ends of a single myofibril by a pair of microneedles using a previously established method 5,14,29,47,54 and stretched the myofibril by altering the distance between the two microneedles. A pair of microbeads was attached to the lateral sides of a sarcomere's A-band prior to the measurement.…”

Thermal Activation of Thin Filaments in Striated Muscle

“…Unlike in skeletal muscle, cardiac myofilaments are not fully activated under physiological conditions because [Ca 2+ ] i is maintained relatively low (∼10 −6 M), even at the peak of systole (Bers, 2002). Because of this partial activation nature, cardiac myofilaments exhibit non-linear properties, such as lengthdependent activation (Kobirumaki-Shimozawa et al, 2014) and spontaneous sarcomeric auto-oscillations (SPOC) (see Ishiwata et al, 2011;Kagemoto et al, 2018). In both skeletal and cardiac muscles, lowering [Ca 2+ ] i dissociates Ca 2+ from TnC, resulting in dissociation of myosin from thin filaments, i.e., relaxation.…”

Session 1SBP: ASB-BSJ Joint Symposium—current challenges in biophysics centering on biomolecular interactions and the underlying forces

“…This was followed by Prof Norio Fukuda from Jikei University, Tokyo, who revealed cutting edge imaging results of cardiac tissue as well as cardiac cells that revealed novel insights into force generation in the heart (Shimozawa et al 2017). His data detailed remarkable movement patterns in the sarcomeres, thus providing new mechanisms to describe force generation in cardiac tissues (Kagemoto et al 2018). The focus on the biophysics of the cardiac system was continued by Prof Cris dos Remedios from the University of Sydney, who shared the story of his establishment of a cardiac tissue bank (Dos Remedios et al 2017), which has now developed into a remarkable resource for scientists worldwide to access high-quality cardiac tissue samples for research.…”