Damped elastic recoil of the titin spring in myofibrils of human myocardium

Abstract

The giant protein titin functions as a molecular spring in muscle and is responsible for most of the passive tension of myocardium. Because the titin spring is extended during diastolic stretch, it will recoil elastically during systole and potentially may influence the overall shortening behavior of cardiac muscle. Here, titin elastic recoil was quantified in single human heart myofibrils by using a high-speed charge-coupled device-line camera and a nanonewtonrange force sensor. Application of a slack-test protocol revealed that the passive shortening velocity (Vp) of nonactivated cardiomyofibrils depends on: (i) initial sarcomere length, (ii) release-step amplitude, and (iii) temperature. Selective digestion of titin, with low doses of trypsin, decelerated myofibrillar passive recoil and eventually stopped it. Selective extraction of actin filaments with a Ca 2؉ -independent gelsolin fragment greatly reduced the dependency of Vp on release-step size and temperature. These results are explained by the presence of viscous forces opposing myofibrillar passive recoil that are caused mainly by weak actin-titin interactions. Thus, Vp is determined by two distinct factors: titin elastic recoil and internal viscous drag forces. The recoil could be modeled as that of a damped entropic spring consisting of independent worm-like chains. The functional importance of myofibrillar elastic recoil was addressed by comparing instantaneous Vp to unloaded shortening velocity, which was measured in demembranated, fully Ca 2؉ -activated, human cardiac fibers. Titin-driven passive recoil was much faster than active unloaded shortening velocity in early phases of isotonic contraction. Damped myofibrillar elastic recoil could help accelerate active contraction speed of human myocardium during early systolic shortening. T itin, the largest protein known to date (3-3.7 MDa), has recently attracted the attention of researchers in fields as diverse as muscle mechanics, single-molecule biophysics, or protein (un)folding. Titin is a modular polypeptide consisting of up to 300 domains of the Ig-like or fibronectin-like type, which are interspersed with unique sequences (1). Titin molecules span half of a sarcomere, the structural unit of skeletal and cardiac muscle, but only part of the molecule in the so-called I-band is extensible; the remainder is firmly bound to other sarcomeric proteins and is functionally inextensible (Fig. 1A). The extensible segment of titin functions as a molecular spring, contributing in various ways to the mechanical characteristics of muscle. In human heart (HH), titin exists in different length isoforms: the shorter N2B isoform is coexpressed with the longer N2BA isoform in the I-band of the same half-sarcomere (1). The normal N2BA to N2B ratio is Ϸ30:70 (2).Titin's mechanical properties have been extensively studied over the past years by diverse approaches, such as (sub)cellular mechanics (3, 4), electron microscopy (5), steered molecular dynamics simulations (6), and force measurements employing optical twee...

Differential actin binding along the PEVK domain of skeletal muscle titin

“…It has been shown earlier that the unloaded shortening of striated muscle is influenced by viscous and viscoelastic forces (de Tombe and ter Keurs, 1990;de Tombe and ter Keurs, 1991;de Tombe and ter Keurs, 1992). It has even been suggested that titin might play a role in influencing unloaded shortening velocity (Kulke et al, 2001;Opitz et al, 2003). We suggest a possible mechanism of how titin might inhibit unloaded sarcomere shortening (Fig.…”

Quantification of left and right ventricular kinetic energy using four-dimensional intracardiac magnetic resonance imaging flow measurements

“…The driving force for LV filling is primarily the elastic recoil caused by the "springs" available in the form of the protein titin (13) in the contracting actin-myosin complex and elastic structures in the extracellular matrix (12,30). The LV has a higher muscle mass compared with the RV and thereby contains more titin and a larger possibility for elastic recoil.…”

The origin of passive force enhancement in skeletal muscle

“…Different titin isoforms have also been used to explain differences in passive stiffness between psoas and soleus rabbit fibers (10,22). Furthermore, degradation or extraction of titin from myofibrils leads to a rapid drop in passive force (12,26,35) in cardiac and skeletal myofibrils.…”