Sarcomere length-dependent Ca2+ activation in skinned rabbit psoas muscle fibers: coordinated regulation of thin filament cooperative activation and passive force

Abstract

In skeletal muscle, active force production varies as a function of sarcomere length (SL). It has been considered that this SL dependence results simply from a change in the overlap length between the thick and thin filaments. The purpose of this study was to provide a systematic understanding of the SL-dependent increase in Ca2+ sensitivity in skeletal muscle, by investigating how thin filament “on–off” switching and passive force are involved in the regulation. Rabbit psoas muscles were skinned, and active force measurements were taken at various Ca2+ concentrations with single fibers, in the short (2.0 and 2.4 μm) and long (2.4 and 2.8 μm) SL ranges. Despite the same magnitude of SL elongation, the SL-dependent increase in Ca2+ sensitivity was more pronounced in the long SL range. MgADP (3 mM) increased the rate of rise of active force and attenuated SL-dependent Ca2+ activation in both SL ranges. Conversely, inorganic phosphate (Pi, 20 mM) decreased the rate of rise of active force and enhanced SL-dependent Ca2+ activation in both SL ranges. Our analyses revealed that, in the absence and presence of MgADP or Pi, the magnitude of SL-dependent Ca2+ activation was (1) inversely correlated with the rate of rise of active force, and (2) in proportion to passive force. These findings suggest that the SL dependence of active force in skeletal muscle is regulated via thin filament “on–off” switching and titin (connectin)-based interfilament lattice spacing modulation in a coordinated fashion, in addition to the regulation via the filament overlap.Electronic supplementary materialThe online version of this article (doi:10.1007/s12576-011-0173-8) contains supplementary material, which is available to authorized users.

Optimal length, calcium sensitivity, and twitch characteristics of skeletal muscles from mdm mice with a deletion in N2A titin

“…Increasing filament strain is thought to increase thick filament cooperativity (Fusi et al, 2016;Linari et al, 2015). Additionally, tropomyosin activation may be facilitated by neighboring troponin complexes that are already active, the so-called 'thin filament cooperativity' (Fukuda et al, 2011;Terui et al, 2008), which increases with increasing sarcomere length (Fukuda et al, 2011;Terui et al, 2008). We found no difference in length dependence of calcium sensitivity between wild-type and mdm muscles, suggesting no effect of the mdm mutation regardless of the mechanisms involved.…”

“…Current theories have focused instead on length-dependent thick and/or thin filament cooperativity (Fukuda et al, 2011;Terui et al, 2010). Cross-bridge attachment to the thin filaments may be facilitated by neighboring cross-bridges that are already attached, the so-called 'thick filament cooperativity' (Fusi et al, 2016;Linari et al, 2015;Reconditi et al, 2014).…”

“…Although it is well documented that changes in titin-based force affect Ca 2+ sensitivity at specific sarcomere lengths (Fukuda et al, 2011;Mateja et al, 2013;Ottenheijm et al, 2012), the mechanism is elusive. It has been argued that titin force regulates Ca 2+ sensitivity by mechanisms associated with a decrease in actin-myosin lattice spacing, and/or length-dependent strain of the thick filaments, which theoretically increase the number of cross-bridges and cross-bridge force in active muscle (Fukuda et al, 2011;Fusi et al, 2016;Konhilas et al, 2002b). However, Ma et al (2018) recently demonstrated that thick filament rearrangement is similar during active and passive stretch, suggesting that thick filament strain in contracting muscle is simply an effect of stretch and is not associated with increased crossbridge force.…”

Functional significance of C-terminal mobile domain of cardiac troponin I

“…However, the underlying mechanism of LDA is still unknown. Different characteristics of the myofilaments contribute to LDA, such as the inter-filament lattice spacing [24–26], the distinctive structural changes in thick and thin filaments [27, 28], the orientation and number of cross-bridges [29–31], titin-based passive tension [32–37], and the increase in positive feedback on myocardial contractile regulation [38–40]. Our previous studies have shown that Ca 2+ -induced opening of the N-domain of cTnC [40], and Ca 2+ -induced movement of C-terminus of cTnI [41] are both SL- and cross-bridge-dependent.…”

Titin stiffness modifies the force-generating region of muscle sarcomeres

“…Among the proteins suggested to contribute to LDA, titin seems to be a particularly strong candidate 2 10 11 12 13 14 . The stiffness of titin could modulate LDA by adding to lattice compression via a radial force component ( F R ) that arises out of stretching the titin springs in the sarcomere ( Fig.…”