Synchrony of sarcomeric movement regulates left ventricular pump function in the in vivo beating mouse heart

Abstract

Sarcomeric contraction in cardiomyocytes serves as the basis for the heart’s pump functions. It has generally been considered that in cardiac muscle as well as in skeletal muscle, sarcomeres equally contribute to myofibrillar dynamics in myocytes at varying loads by producing similar levels of active and passive force. In the present study, we expressed α-actinin–AcGFP in Z-disks to analyze dynamic behaviors of sequentially connected individual sarcomeres along a myofibril in a left ventricular (LV) myocyte of the in vivo beating mouse heart. To quantify the magnitude of the contribution of individual sarcomeres to myofibrillar dynamics, we introduced the novel parameter “contribution index” (CI) to measure the synchrony in movements between a sarcomere and a myofibril (from −1 [complete asynchrony] to 1 [complete synchrony]). First, CI varied markedly between sarcomeres, with an average value of ∼0.3 during normal systole. Second, when the movements between adjacent sarcomeres were asynchronous (CI < 0), a sarcomere and the ones next to the adjacent sarcomeres and farther away moved in synchrony (CI > 0) along a myofibril. Third, when difference in LV pressure in diastole and systole (ΔLVP) was lowered to <10 mm Hg, diastolic sarcomere length increased. Under depressed conditions, the movements between adjacent sarcomeres were in marked asynchrony (CI, −0.3 to −0.4), and, as a result, average CI was linearly decreased in association with a decrease in ΔLVP. These findings suggest that in the left ventricle of the in vivo beating mouse heart, (1) sarcomeres heterogeneously contribute to myofibrillar dynamics due to an imbalance of active and passive force between neighboring sarcomeres, (2) the force imbalance is pronounced under depressed conditions coupled with a marked increase in passive force and the ensuing tug-of-war between sarcomeres, and (3) sarcomere synchrony via the distal intersarcomere interaction regulates the heart's pump function in coordination with myofibrillar contractility.

Contractile State Dependent Sarcomere Length Variability in Isolated Guinea-Pig Cardiomyocytes

“…Nanometer-scale changes in the length of a single sarcomere result in a large change in the contractile response ( Fukuda et al, 2001 ; Serizawa et al, 2011 ; Kobirumaki-Shimozawa et al, 2014 ; Rassier 2017 ). At present, the intracellular inhomogeneity in SL has been shown for isolated skinned and intact cardiomyocytes as well as in the in-vivo mouse heart ( Sarai et al, 2002 ; Herzog et al, 2010 ; Serizawa et al, 2011 ; Shintani et al, 2014 ; Kobirumaki-Shimozawa et al, 2016 ; Shimozawa et al, 2016 ; Kobirumaki-Shimozawa et al, 2021 ). This inhomogeneity increases upon the activation of the skeletal and cardiac myofibril ( Telley et al, 2006a ; Shimamoto et al, 2009 ; Moo et al, 2017 ; Rassier, 2017 ; Moo and Herzog, 2018 ) or upon an increase in intracellular Ca 2+ content ( Sarai et al, 2002 ).…”

“…end-diastole and end-systole). Highly precise evaluation of SL variability can be achieved using Z-disk specific fluorescent labeling, which has been implemented in skinned and cultured cardiomyocytes ( Serizawa et al, 2011 ; Shintani et al, 2014 ; Kolb et al, 2016 ) and recently in living mice in vivo ( Kobirumaki-Shimozawa et al, 2016 ; Kobirumaki-Shimozawa et al, 2018 ; Kobirumaki-Shimozawa et al, 2021 ). It should be noted that, the SL range obtained in our study was found to be similar to that obtained by Z-disk labeling and reported in ( Kobirumaki-Shimozawa et al, 2016 ).…”

“…According to the idea that the adjacent sarcomeres play a “tug of war” during activation of a myofibril ( Shimozawa et al, 2016 ), the systolic stiffening and pre-systolic heterogeneity of sarcomeres (i.e. co-existence of “compliant” and “stiff” sarcomeres) can greatly affect their mechanical communication leading to dynamic changes in SL variability during the contraction-relaxation process ( Shimamoto et al, 2009 ; Azeloglu and Costa, 2010 ; de Souza Leite and Rassier, 2020 ; Kobirumaki-Shimozawa et al, 2021 ). The mechanical communication between in-series sarcomeres is also affected by the passive properties of myofibrils and intracellular matrix ( de Souza Leite et al, 2017 ).…”

“…EPI layer ( Clark and Campbell 2019 ; Pitoulis et al, 2020 ; Clark et al, 2021 ). Recent studies have shown that SL non-uniformity in the ventricles exists not only at the tissue (macroscale) level, but also present at the level of single cardiomyocyte (microscale level) ( Sarai et al, 2002 ; Serizawa et al, 2011 ; Shintani et al, 2014 ; Kobirumaki-Shimozawa et al, 2016 ; de Souza Leite and Rassier 2020 ; Kobirumaki-Shimozawa et al, 2021 ). At the microscale level, the variability in SL may regulate force developed by a cardiomyocyte ( de Souza Leite and Rassier 2020 ; Kobirumaki-Shimozawa et al, 2021 ).…”

“…Recent studies have shown that SL non-uniformity in the ventricles exists not only at the tissue (macroscale) level, but also present at the level of single cardiomyocyte (microscale level) ( Sarai et al, 2002 ; Serizawa et al, 2011 ; Shintani et al, 2014 ; Kobirumaki-Shimozawa et al, 2016 ; de Souza Leite and Rassier 2020 ; Kobirumaki-Shimozawa et al, 2021 ). At the microscale level, the variability in SL may regulate force developed by a cardiomyocyte ( de Souza Leite and Rassier 2020 ; Kobirumaki-Shimozawa et al, 2021 ). Indeed, it was shown that subtle changes in SL (∼100 nm) result in noticeable changes in the developed tension ( Fukuda et al, 2001 ; Serizawa et al, 2011 ; Kobirumaki-Shimozawa et al, 2014 ).…”