Abnormalities of diastolic function are common to virtually all forms of cardiac failure. However, their underlying mechanisms, precise role in the generation and phenotypic expression of heart failure, and value as specific therapeutic targets remain poorly understood. A growing proportion of heart failure patients, particularly among the elderly, have apparently preserved systolic function, and this is fueling interest for better understanding and treating diastolic abnormalities. Much of the attention in clinical and experimental studies has focused on relaxation and filling abnormalities of the heart, whereas chamber stiffness has been less well studied, particularly in humans. Nonetheless, new insights from basic and clinical research are helping define the regulators of diastolic dysfunction and illuminate novel targets for treatment. This review puts these developments into perspective with the major aim of highlighting current knowledge gaps and controversies.

What Mechanisms Underlie Diastolic Dysfunction in Heart Failure

Post-activation potentiation (PAP) is a well-described phenomenon with a short half-life (~28 s) that enhances muscle force production at submaximal levels of calcium saturation (i.e., submaximal levels of muscle activation). It has been largely explained by an increased myosin light chain phosphorylation occurring in type II muscle fibers, and its effects have been quantified in humans by measuring muscle twitch force responses to a bout of muscular activity. However, enhancements in (sometimes maximal) voluntary force production detected several minutes after high-intensity muscle contractions are also observed, which are also most prominent in muscles with a high proportion of type II fibers. This effect has been considered to reflect PAP. Nonetheless, the time course of myosin light chain phosphorylation (underpinning "classic" PAP) rarely matches that of voluntary force enhancement and, unlike PAP, changes in muscle temperature, muscle/cellular water content, and muscle activation may at least partly underpin voluntary force enhancement; this enhancement has thus recently been called post-activation performance enhancement (PAPE) to distinguish it from "classical" PAP. In fact, since PAPE is often undetectable at time points where PAP is maximal (or substantial), some researchers have questioned whether PAP contributes to PAPE under most conditions in vivo in humans. Equally, minimal evidence has been presented that PAP is of significant practical importance in cases where multiple physiological processes have already been upregulated by a preceding, comprehensive, active muscle warm-up. Given that confusion exists with respect to the mechanisms leading to acute enhancement of both electrically evoked (twitch force; PAP) and voluntary (PAPE) muscle function in humans after acute muscle activity, the first purpose of the present narrative review is to recount the history of PAP/PAPE research to locate definitions and determine whether they are the same phenomena. To further investigate the possibility of these phenomena being distinct as well as to better understand their potential functional benefits, possible mechanisms underpinning their effects will be examined in detail. Finally, research design issues will be addressed which might contribute to confusion relating to PAP/PAPE effects, before the contexts in which these phenomena may (or may not) benefit voluntary muscle function are considered.

/pdf/post-activation-potentiation-versus-post-activation-8klieqawrd.pdf

Post-activation Potentiation Versus Post-activation Performance Enhancement in Humans: Historical Perspective, Underlying Mechanisms, and Current Issues.

The muscles that power vertebrate locomotion are associated with springy tissues, both within muscle and in connective tissue elements such as tendons. These springs share in common the same simple action: they stretch and store elastic strain energy when force is applied to them and recoil to release energy when force decays. Although this elastic action is simple, it serves a diverse set of functions, including metabolic energy conservation, amplification of muscle power output, attenuation of muscle power input, and rapid mechanical feedback that may aid in stability. In recent years, our understanding of the mechanisms and importance of biological springs in locomotion has advanced significantly, and it has been demonstrated that elastic mechanisms are essential for the effective function of the muscle motors that power movement. Here, we review some recent advances in our understanding of elastic mechanisms, with an emphasis on two proposed organizing principles. First, we review the evidence that the various functions of biological springs allow the locomotor system to operate beyond the bounds of intrinsic muscle properties, including metabolic and mechanical characteristics, as well as motor control processes. Second, we propose that an energy-based framework is useful for interpreting the diverse functions of series-elastic springs. In this framework, the direction and timing of the flow of energy between the body, the elastic element and the contracting muscle determine the function served by the elastic mechanism (e.g. energy conservation vs power amplification). We also review recent work demonstrating that structures such as tendons remodel more actively and behave more dynamically than previously assumed.

/pdf/flexible-mechanisms-the-diverse-roles-of-biological-springs-4ak3a7zear.pdf

Flexible mechanisms: the diverse roles of biological springs in vertebrate movement

Mechanical stress signals transmitted through the heart walls during hemodynamic loading are sensed by the myocytes, which respond with changes in contractile performance and gene expression. External forces play an important role in physiological heart development and hypertrophy, but disruption of the well-balanced stress-sensing machinery causes mechanical dysregulation, cardiac remodelling, and heart failure. Nodal points of mechanosensing in the cardiomyocytes may reside in the Z-disk, I-band, and M-band regions of the sarcomeres. Longitudinal linkage of these regions is provided by the titin filament, and several 'hot spots' along this giant protein, in complex with some of its >20 ligands, may be pivotal to the myofibrillar stress or stretch response. This review outlines the known interaction partners of titin, highlights the putative stress/stretch-sensor complexes at titin's NH(2) and COOH termini and their role in myopathies, and summarizes the known disease-associated mutations in those titin regions. Another focus is the elastic I-band titin section, which interacts with a diverse number of proteins and whose main function is as a determinant of diastolic distensibility and passive stiffness. The discussion centers on recent insights into the plasticity, mechanical role, and regulation of the elastic titin springs during cardiac development and in human heart disease. Titin and titin-based protein complexes are now recognized as integral parts of the mechanosensitive protein network and as critical components in cardiomyocyte stress/stretch signalling.

/pdf/sense-and-stretchability-the-role-of-titin-and-titin-zbzsfup1e5.pdf

Sense and stretchability: The role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction†

Rationale: Protein kinase C (PKC) regulates contractility of cardiac muscle cells by phosphorylating thin- and thick- filament-based proteins. Myocardial sarcomeres also contain a third myofilament, titin, and it is unknown whether titin can be phosphorylated by PKC and whether it affects passive tension. Objective: The purpose of this study was to examine the effect of PKC on titin phosphorylation and titin-based passive tension. Methods and Results: Phosphorylation assays with PKCα revealed that titin is phosphorylated in skinned myocardial tissues; this effect is exacerbated by pretreating with protein phosphatase 1. In vitro phosphorylation of recombinant protein representing titin’s spring elements showed that PKCα targets the proline – glutamate – valine – lysine (PEVK) spring element. Furthermore, mass spectrometry in combination with site-directed mutagenesis identified 2 highly conserved sites in the PEVK region that are phosphorylated by PKCα (S11878 and S12022); when these 2 sites are mutated t...

PKC Phosphorylation of Titin's PEVK Element. A Novel and Conserved Pathway for Modulating Myocardial Stiffness

Titin (also known as connectin) is a giant protein with a wide range of cellular functions, including providing muscle cells with elasticity. Its physiological extension is largely derived from the PEVK segment, rich in proline (P), glutamate (E), valine (V), and lysine (K) residues. We studied recombinant PEVK molecules containing the two conserved elements: ≈28-residue PEVK repeats and E-rich motifs. Single molecule experiments revealed that calcium-induced conformational changes reduce the bending rigidity of the PEVK fragments, and site-directed mutagenesis identified four glutamate residues in the E-rich motif that was studied (exon 129), as critical for this process. Experiments with muscle fibers showed that titin-based tension is calcium responsive. We propose that the PEVK segment contains E-rich motifs that render titin a calcium-dependent molecular spring that adapts to the physiological state of the cell.

https://www.pnas.org/content/pnas/100/23/13716.full.pdf

Calcium-dependent molecular spring elements in the giant protein titin

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Calcium-dependent molecular spring elements in the giant protein titin