Distinct contributions of the thin and thick filaments to length-dependent activation in heart muscle

Xuemeng Zhang,Ivanka Sevrieva,Ziqian Yan,Yin-Biao Sun,Malcolm Irving,Thomas Kampourakis

doi:10.7554/elife.24081

Abstract

The Frank-Starling relation is a fundamental auto-regulatory property of the heart that ensures the volume of blood ejected in each heartbeat is matched to the extent of venous filling. At the cellular level, heart muscle cells generate higher force when stretched, but despite intense efforts the underlying molecular mechanism remains unknown. We applied a fluorescence-based method, which reports structural changes separately in the thick and thin filaments of rat cardiac muscle, to elucidate that mechanism. The distinct structural changes of troponin C in the thin filaments and myosin regulatory light chain in the thick filaments allowed us to identify two aspects of the Frank-Starling relation. Our results show that the enhanced force observed when heart muscle cells are maximally activated by calcium is due to a change in thick filament structure, but the increase in calcium sensitivity at lower calcium levels is due to a change in thin filament structure.

Highlights

The Frank-Starling law of the heart describes the relationship between cardiac stroke volume and end-diastolic volume and operates on a beat-to-beat basis
Contraction of heart muscle is initiated by Ca2+ binding to the regulatory domain of troponin in the actin-containing thin filaments, that triggers a cascade of structural changes in the thin filament and leads to an azimuthal movement of tropomyosin around the filament that allow myosin to interact with actin and generate force (Tobacman, 1996; Gordon et al, 2000; Kobayashi and Solaro, 2005)
The IT arm of troponin, a rigid domain containing the C-terminal lobe of TnC and a coiledcoil formed by a-helices from troponin I (TnI) and troponin T (TnT), anchors the troponin complex to the thin filament

Summary

Introduction

The Frank-Starling law of the heart describes the relationship between cardiac stroke volume and end-diastolic volume and operates on a beat-to-beat basis. The Frank-Starling relationship implies that increasing cardiac sarcomere length results in enhanced performance of cardiac muscle cells during the subsequent contraction (Allen and Kentish, 1985; de Tombe et al, 2010). This myofilament length-dependent activation (LDA) is two-fold: with an increase in sarcomere length (SL), there are increases in (1) the maximum force developed by the myofilaments at high Ca2+ and (2) their sensitivity to Ca2+. Over the last forty years, the main focus has been on the myofilament Ca2+-sensitivity component of LDA

Methods

Results

Conclusion