Impact of titin strain on the cardiac slow force response

Abstract

Stretch of myocardium, such as occurs upon increased filling of the cardiac chamber, induces two distinct responses: an immediate increase in twitch force followed by a slower increase in twitch force that develops over the course of several minutes. The immediate response is due, in part, to modulation of myofilament Ca2+ sensitivity by sarcomere length (SL). The slowly developing force response, termed the Slow Force Response (SFR), is caused by a slowly developing increase in intracellular Ca2+ upon sustained stretch. A blunted immediate force response was recently reported for myocardium isolated from homozygous giant titin mutant rats (HM) compared to muscle from wild-type littermates (WT). Here, we examined the impact of titin isoform on the SFR. Right ventricular trabeculae were isolated and mounted in an experimental chamber. SL was measured by laser diffraction. The SFR was recorded in response to a 0.2 μm SL stretch in the presence of [Ca2+]o=0.4 mM, a bathing concentration reflecting ~50% of maximum twitch force development at 25 °C. Presence of the giant titin isoform (HM) was associated with a significant reduction in diastolic passive force upon stretch, and ~50% reduction of the magnitude of the SFR; the rate of SFR development was unaffected. The sustained SL stretch was identical in both muscle groups. Therefore, our data suggest that cytoskeletal strain may underlie directly the cellular mechanisms that lead to the increased intracellular [Ca2+]i that causes the SFR, possibly by involving cardiac myocyte integrin signaling pathways.

Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes

“…It is likely that the decreased passive stiffness would have an effect when the heart muscle is shortening under load that would not be apparent in the isometric contraction 31 . Such changes could be related to disruption of the dynamics of myosin head activation by stretch leading to reduced contractility 32 or alteration of the “slow force response” by modulating of mechanosensitive signalling pathways that affect [Ca 2+ ]i homeostasis and promote apoptosis and fibrosis as observed in our samples 33 . In concert such processes could impair contractility and potentially trigger a DCM phenotype.…”

The slow force response to stretch: Controversy and contradictions

“…31 Recent evidence has suggested that titin may also operate as a stretch-sensitive modifier of active force generation. 33 As an aside, the observation that passive force decreases over the time course of the SFR has recently been attributed to increased titin phosphorylation via the cGMP-PKG activity in response to NO production. 33 As an aside, the observation that passive force decreases over the time course of the SFR has recently been attributed to increased titin phosphorylation via the cGMP-PKG activity in response to NO production.…”

“…32 This suggestion is supported by studies showing a direct correlation between the active magnitude of the SFR and titin strain. 33 As an aside, the observation that passive force decreases over the time course of the SFR has recently been attributed to increased titin phosphorylation via the cGMP-PKG activity in response to NO production. 34 Titin kinase (A-band) 35 and N2B/N2A (I-band) 36,37 are examples of mechanosensitive regions of titin.…”

Extensive eccentric contractions in intact cardiac trabeculae: revealing compelling differences in contractile behaviour compared to skeletal muscles

“…B 286: 20190719 mediates these phenomena in cardiac muscle. However, the underlying molecular mechanisms, in particular during long eccentric contractions of myocardium, remain(s) unknown [39,40].…”