The relation between sarcomere energetics and the rate of isometric tension relaxation in healthy and diseased cardiac muscle

Abstract

Full muscle relaxation happens when [Ca 2+ ] falls below the threshold for force activation. Several experimental models, from whole muscle organs and intact muscle down to skinned fibers, have been used to explore the cascade of kinetic events leading to mechanical relaxation. The use of single myofibrils together with fast solution switching techniques, has provided new information about the role of cross-bridge (CB) dissociation in the time course of isometric force decay. Myofibril's relaxation is biphasic starting with a slow seemingly linear phase, with a rate constant, slow k REL , followed by a fast monoexponential phase. Sarcomeres remain isometric during the slow force decay that reflects CB detachment under isometric conditions while the final fast relaxation phase begins with a sudden give of few sarcomeres and is then dominated by intersarcomere dynamics. Based on a simple two-state model of the CB cycle, myofibril slow k REL represents the apparent forward rate with which CBs leave force generating states (g app) under isometric conditions and correlates with the energy cost of tension generation (ATPase/tension ratio); in short slow k REL ~ g app ~ tension cost. The validation of this relationship is obtained by simultaneously measuring maximal isometric force and ATP consumption in skinned myocardial strips that provide an unambiguous determination of the relation between contractile and energetic properties of the sarcomere. Thus, combining kinetic experiments in isolated myofibrils and mechanical and energetic measurements in multicellular cardiac strips, we are able to provide direct evidence for a positive linear correlation between myofibril isometric relaxation kinetics (slow k REL) and the energy cost of force production both measured in preparations from the same cardiac sample. This correlation remains true among different types of muscles with different ATPase activities and also when CB kinetics are altered by cardiomyopathy-related mutations. Sarcomeric mutations associated to hypertrophic cardiomyopathy (HCM), a primary cardiac disorder caused by mutations in genes encoding sarcomeric proteins, have been often found to accelerate CB turnover rate and increase the energy cost of myocardial contraction. Here we review data showing that faster CB detachment results in a proportional increase in the energetic cost of tension generation in heart samples from both HCM patients and mouse models of the disease.

Mavacamten has a differential impact on force generation in myofibrils from rabbit psoas and human cardiac muscle

“…This suggests no major effect of the drug on the apparent rate of cross-bridge detachment (g app ) in rabbit psoas myofibrils. This conclusion is in keeping with previous findings showing slow k REL (which reflects g app ;Huxley, 1957;Poggesi et al, 2005;Vitale et al, 2021) to be independent of N a also in the case of Ca 2+ modulation and at the same time to be very sensitive to [P i ] (Tesi et al, 2002b;Poggesi et al, 2005).…”

“…In the last 10 yr, a lot of experimental evidence has supported the hypothesis that HCM could mainly result from an increase in the availability of myosin heads for entering the actomyosin chemomechanical cycle (Spudich, 2014;Garfinkel et al, 2018;Trivedi et al, 2018;Spudich, 2019) associated with a shift from the so-called autoinhibited or super-relaxed (SRX) state (Stewart et al, 2010;Hooijman et al, 2011;Alamo et al, 2017) to a disordered-relaxed (DRX) state (McNamara et al, 2015). The increase in DRX over SRX state proportion would contribute to the observed increase in the energy cost of contraction, triggering a complex signaling cascade leading to overt hypertrophic remodeling and a number of functional modifications (Ashrafian et al, 2003;Vitale et al, 2021).…”

Making waves: A proposed new role for myosin-binding protein C in regulating oscillatory contractions in vertebrate striated muscle

“…Therefore, cMyBP-C haploinsufficiency in HCM patients or in response to cardiac stress could result in increased SPOCs and dysregulation of myofilament relaxation similar to that seen in Spy-C myocytes following TEVp treatment. Chronic dysregulation of SPOC activity could then alter contractile kinetics, energetics, excitationcontraction coupling, or Ca 2+ homeostasis (Lehman et al, 2019;Solaro, 2008;Yotti et al, 2019;Vitale et al, 2019;Toepfer et al, 2020). Allelic and cell-to-cell imbalances in cMyBP-C expression in myocytes of HCM patients (Kraft et al, 2016) could further exacerbate dysregulation, leading to changes in source-sink dynamics between neighboring cells that create ectopic or reentry foci for arrhythmia (Viner et al, 2019;Nitsan et al, 2016).…”

Novel insights into sarcomere regulatory systems control of cardiac thin filament activation

“…Studies with bundles of myofibrils developing force in an environment in which rapid solution switching instantaneously adds and removes Ca 2+ with little diffusional barriers provide a novel view of the role of sarcomeres in the kinetics of the isometric twitch ( Colomo et al, 1997 ). Vitale et al (2019) provided an excellent summary of the advantages of the use of myofibril-sized preparations over other techniques. This approach avoids the use of photolysis, which may lead to artifacts associated with conditions required to release caged compounds.…”