Impact of myocyte strain on cardiac myofilament activation

Abstract

When cardiac myocytes are stretched by a longitudinal strain, they develop proportionally more active force at a given sub-maximal Ca(2+) concentration than they did at the shorter length. This is known as length-dependent activation. It is one of the most important contributors to the Frank-Starling relationship, a critical part of normal cardiovascular function. Despite intense research efforts, the mechanistic basis of the Frank-Starling relationship remains unclear. Potential mechanisms involving myofibrillar lattice spacing, titin-based effects, and cooperative activation have all been proposed. This review summarizes some of these mechanisms and discusses two additional potential theories that reflect the effects of localized strains that occur within and between half-sarcomeres. The main conclusion is that the Frank-Starling relationship is probably the integrated result of many interacting molecular mechanisms. Multiscale computational modeling may therefore provide the best way of determining the key processes that underlie length-dependent activation and their relative strengths.

Fig. 1

Ca²⁺–force curves for chemically skinned rat ventricular muscle. Reproduced from Fig. 4, Hibberd and Jewell [28] with permission. The top panel shows pooled force data from seven preparations normalized to the maximal force generated by each muscle sample at the longer length. The bottom panel shows the same data normalized to the maximal force generated by the preparation at each length. The Ca²⁺ concentration required to produce half the maximal amount of force is lower at the longer sarcomere length

Fig. 2

Passive and restoring force generation by titin molecules. Reproduced with permission from Granzier and Labeit [24]. At short half-sarcomere lengths (a), part of the titin molecule is bent backward producing a recoil force that can help lengthen the half-sarcomere. As the half-sarcomeres length progressively (b, c, d) titin molecules are straightened and eventually stretched by progressive extension of the PEVK and N2B regions

Fig. 3

Schematic diagram of a half-sarcomere composed of two filaments. Reproduced with permission from Campbell [5]. a The spacing of myosin heads along the thick filament is a non-integer multiple of the spacing of binding sites on the thin filament. There are therefore positions (e.g., myosin 10) where a myosin head is aligned close to a binding site on actin and places (e.g., myosin 14) where the myosin head may be positioned too far from a binding site to attach. b If the filaments extend slightly when a myosin head generates force, additional myosin heads may be pulled close enough to actin sites that they can interact with them

Fig. 4

Simulated force and half-sarcomere length traces for single and multi-half-sarcomere frameworks. Reproduced with permission from Campbell [6]. Note that in the pCa 4.5 condition, force rises more quickly with muscle strain during the latter half of the stretch in the simulation of the multi-half-sarcomere system than it does for a single half-sarcomere. This is an emergent property of the contractile system. The black line is an experimental data record obtained using a chemically permeabilized rabbit psoas fiber [8]. n_m is the number of parallel myofibrils in the simulation. n_hs is the number of half-sarcomeres in series in each myofibril. The two simulations therefore correspond to networks of 1 half-sarcomere (n_m=1, n_hs=1, blue) and 300 half-sarcomeres (n_m=6, n_hs=50, red), respectively