scholarly journals Cardiac sarcomere mechanics in health and disease

2021 ◽  
Author(s):  
Claudia Crocini ◽  
Michael Gotthardt
Keyword(s):  
Striated Muscle ◽  
Cardiac Contraction ◽  
Structural Basis ◽  
Passive Tension ◽  
Sarcomeric Proteins ◽  
Cardiac Sarcomere ◽  
Health And Disease ◽  
Composition Structure ◽  
Contractile Forces ◽  
Active Force Generation

AbstractThe sarcomere is the fundamental structural and functional unit of striated muscle and is directly responsible for most of its mechanical properties. The sarcomere generates active or contractile forces and determines the passive or elastic properties of striated muscle. In the heart, mutations in sarcomeric proteins are responsible for the majority of genetically inherited cardiomyopathies. Here, we review the major determinants of cardiac sarcomere mechanics including the key structural components that contribute to active and passive tension. We dissect the molecular and structural basis of active force generation, including sarcomere composition, structure, activation, and relaxation. We then explore the giant sarcomere-resident protein titin, the major contributor to cardiac passive tension. We discuss sarcomere dynamics exemplified by the regulation of titin-based stiffness and the titin life cycle. Finally, we provide an overview of therapeutic strategies that target the sarcomere to improve cardiac contraction and filling.

scholarly journals The panniculus carnosus muscle: A novel model of striated muscle regeneration that exhibits sex differences in the mdx mouse

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ola A. Bahri ◽  
Neia Naldaiz-Gastesi ◽  
Donna C. Kennedy ◽  
Antony M. Wheatley ◽  
Ander Izeta ◽  
...  
Keyword(s):  
Muscle Regeneration ◽  
Striated Muscle ◽  
Fold Increase ◽  
Wide Distribution ◽  
Calcium Handling ◽  
Mdx Mouse ◽  
Wild Type ◽  
Health And Disease ◽  
Fast Twitch ◽  
Shivering Thermogenesis

Abstract The dermal striated muscle panniculus carnosus (PC), prevalent in lower mammals with remnants in humans, is highly regenerative, and whose function is purported to be linked to defence and shivering thermogenesis. Given the heterogeneity of responses of different muscles to disease, we set out to characterize the PC in wild-type and muscular dystrophic mdx mice. The mouse PC contained mainly fast-twitch type IIB myofibers showing body wide distribution. The PC exemplified heterogeneity in myofiber sizes and a prevalence of central nucleated fibres (CNFs), hallmarks of regeneration, in wild-type and mdx muscles, which increased with age. PC myofibers were hypertrophic in mdx compared to wild-type mice. Sexual dimorphism was apparent with a two-fold increase in CNFs in PC from male versus female mdx mice. To evaluate myogenic potential, PC muscle progenitors were isolated from 8-week old wild-type and mdx mice, grown and differentiated for 7-days. Myogenic profiling of PC-derived myocytes suggested that male mdx satellite cells (SCs) were more myogenic than female counterparts, independent of SC density in PC muscles. Muscle regenerative differences in the PC were associated with alterations in expression of calcium handling regulatory proteins. These studies highlight unique aspects of the PC muscle and its potential as a model to study mechanisms of striated muscle regeneration in health and disease.

scholarly journals A comprehensive guide to the ROMK potassium channel: form and function in health and disease

2009 ◽  
Vol 297 (4) ◽  
pp. F849-F863 ◽  
Author(s):  
Paul A. Welling ◽  
Kevin Ho
Keyword(s):  
Potassium Channel ◽  
Molecular Mechanisms ◽  
Atomic Level ◽  
Structural Basis ◽  
Potassium Homeostasis ◽  
Form And Function ◽  
Founding Member ◽  
Channel Form ◽  
Health And Disease ◽  
And Function

The discovery of the renal outer medullary K+channel (ROMK, Kir1.1), the founding member of the inward-rectifying K+channel (Kir) family, by Ho and Hebert in 1993 revolutionized our understanding of potassium channel biology and renal potassium handling. Because of the central role that ROMK plays in the regulation of salt and potassium homeostasis, considerable efforts have been invested in understanding the underlying molecular mechanisms. Here we provide a comprehensive guide to ROMK, spanning from the physiology in the kidney to the organization and regulation by intracellular factors to the structural basis of its function at the atomic level.

scholarly journals Tubulin acetylation increases cytoskeletal stiffness to regulate mechanotransduction in striated muscle

2020 ◽  
Author(s):  
Andrew K. Coleman ◽  
Humberto C. Joca ◽  
Guoli Shi ◽  
W. Jonathan Lederer ◽  
Christopher W. Ward
Keyword(s):  
Nadph Oxidase ◽  
Striated Muscle ◽  
Isolated Cardiomyocytes ◽  
Tubulin Acetylation ◽  
Health And Disease ◽  
Nadph Oxidase 2 ◽  
Contraction And Relaxation

AbstractMicrotubules tune cytoskeletal stiffness to regulate the mechanics and mechanotransduction of striated muscle. While recent evidence suggests that microtubules enriched in detyrosinated α-tubulin are responsible for these effects in healthy muscle, and for their excess in disease, the possible contribution from several other α-tubulin modifications has not been investigated. Here we used genetic or pharmacologic strategies in isolated cardiomyocytes or skeletal myofibers to increase the level of acetylated α-tubulin without altering the level of detyrosinated α-tubulin. We show that microtubules enriched in acetylated α-tubulin contribute to the cytoskeletal stiffness and viscoelastic resistance, showing slowed rates of contraction and relaxation during unloaded contraction, and increased activation of NADPH Oxidase 2 (Nox2) by mechanotransduction. Together these findings add to growing evidence that microtubules contribute to the mechanobiology of striated muscle in health and disease.

scholarly journals The desmin mutation R349P increases contractility and fragility of stem cell-generated muscle micro-tissues

2021 ◽  
Author(s):  
Marina Spoerrer ◽  
Delf Kah ◽  
Richard C Gerum ◽  
Barbara Reischl ◽  
Danyil Huraskin ◽  
...  
Keyword(s):  
Striated Muscle ◽  
Contractile Function ◽  
Three Dimensional ◽  
Mechanical Damage ◽  
Underlying Mechanism ◽  
Intermediate Filament Protein ◽  
Wild Type ◽  
Age Related ◽  
Contractile Forces

Desminopathies comprise hereditary myopathies and cardiomyopathies caused by mutations in the intermediate filament protein desmin that lead to severe and often lethal degeneration of striated muscle tissue. Animal and single cell studies hinted that this degeneration process is associated with massive ultrastructural defects correlating with increased susceptibility of the muscle to acute mechanical stress. The underlying mechanism of mechanical susceptibility, and how muscle degeneration develops over time, however, has remained elusive. Here, we investigated the effect of a desmin mutation on the formation, differentiation, and contractile function of in vitro-engineered three-dimensional micro-tissues grown from muscle stem cells (satellite cells) isolated from heterozygous R349P desmin knock-in mice. Micro-tissues grown from desmin-mutated cells exhibited spontaneous unsynchronized contractions, higher contractile forces in response to electrical stimulation, and faster force recovery compared to tissues grown from wild-type cells. Within one week of culture, the majority of R349P desmin-mutated tissues disintegrated, whereas wild-type tissues remained intact over at least three weeks. Moreover, under tetanic stimulation lasting less than five seconds, desmin-mutated tissues partially or completely ruptured, whereas wild-type tissues did not display signs of damage. Our results demonstrate that the progressive degeneration of desmin-mutated micro-tissues is closely linked to extracellular matrix fiber breakage associated with increased contractile forces and unevenly distributed tensile stress. This suggests that the age-related degeneration of skeletal and cardiac muscle in patients suffering from desminopathies may be similarly exacerbated by mechanical damage from high-intensity muscle contractions. We conclude that micro-tissues may provide a valuable tool for studying the organization of myocytes and the pathogenic mechanisms of myopathies.

scholarly journals Investigations of the Contribution of a Putative Glycine Hinge to Ryanodine Receptor Channel Gating

2013 ◽  
Vol 288 (23) ◽  
pp. 16671-16679 ◽  
Author(s):  
Joanne Euden ◽  
Sammy A. Mason ◽  
Cedric Viero ◽  
N. Lowri Thomas ◽  
Alan J. Williams
Keyword(s):  
Ryanodine Receptor ◽  
Striated Muscle ◽  
Transmembrane Helix ◽  
Channel Gating ◽  
Disease Process ◽  
Structural Data ◽  
Structural Basis ◽  
Detailed Knowledge ◽  
Ion Translocation ◽  
Channel Opening

Ryanodine receptor channels (RyR) are key components of striated muscle excitation-contraction coupling, and alterations in their function underlie both inherited and acquired disease. A full understanding of the disease process will require a detailed knowledge of the mechanisms and structures involved in RyR function. Unfortunately, high-resolution structural data, such as exist for K+-selective channels, are not available for RyR. In the absence of these data, we have used modeling to identify similarities in the structural elements of K+ channel pore-forming regions and postulated equivalent regions of RyR. This has identified a sequence of residues in the cytosolic cavity-lining transmembrane helix of RyR (G4864LIIDA4869 in RyR2) analogous to the glycine hinge motif present in many K+ channels. Gating in these K+ channels can be disrupted by substitution of residues for the hinge glycine. We investigated the involvement of glycine 4864 in RyR2 gating by monitoring properties of recombinant human RyR2 channels in which this glycine is replaced by residues that alter gating in K+ channels. Our data demonstrate that introducing alanine at position 4864 produces no significant change in RyR2 function. In contrast, function is altered when glycine 4864 is replaced by either valine or proline, the former preventing channel opening and the latter modifying both ion translocation and gating. Our studies reveal novel information on the structural basis of RyR gating, identifying both similarities with, and differences from, K+ channels. Glycine 4864 is not absolutely required for channel gating, but some flexibility at this point in the cavity-lining transmembrane helix is necessary for normal RyR function.

scholarly journals Downsizing the molecular spring of the giant protein titin reveals that skeletal muscle titin determines passive stiffness and drives longitudinal hypertrophy

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ambjorn Brynnel ◽  
Yaeren Hernandez ◽  
Balazs Kiss ◽  
Johan Lindqvist ◽  
Maya Adler ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mouse Model ◽  
Striated Muscle ◽  
Super Resolution ◽  
Editorial Note ◽  
Passive Stiffness ◽  
Thin Filaments ◽  
In Series ◽  
Active Force Generation

Titin, the largest protein known, forms an elastic myofilament in the striated muscle sarcomere. To establish titin’s contribution to skeletal muscle passive stiffness, relative to that of the extracellular matrix, a mouse model was created in which titin’s molecular spring region was shortened by deleting 47 exons, the TtnΔ112-158 model. RNA sequencing and super-resolution microscopy predicts a much stiffer titin molecule. Mechanical studies with this novel mouse model support that titin is the main determinant of skeletal muscle passive stiffness. Unexpectedly, the in vivo sarcomere length working range was shifted to shorter lengths in TtnΔ112-158 mice, due to a ~ 30% increase in the number of sarcomeres in series (longitudinal hypertrophy). The expected effect of this shift on active force generation was minimized through a shortening of thin filaments that was discovered in TtnΔ112-158 mice. Thus, skeletal muscle titin is the dominant determinant of physiological passive stiffness and drives longitudinal hypertrophy.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

scholarly journals Structural changes induced in Ca2+-regulated myosin filaments by Ca2+ and ATP.

1989 ◽  
Vol 109 (2) ◽  
pp. 529-538 ◽  
Author(s):  
L L Frado ◽  
R Craig
Keyword(s):  
Structural Changes ◽  
Striated Muscle ◽  
Structural Basis ◽  
Ordered Structure ◽  
Compact Structure ◽  
Crude Homogenate ◽  
Myosin Filaments ◽  
The Cross ◽  
Cross Bridges ◽  
Muscle Myosin

We have used electron microscopy and proteolytic susceptibility to study the structural basis of myosin-linked regulation in synthetic filaments of scallop striated muscle myosin. Using papain as a probe of the structure of the head-rod junction, we find that this region of myosin is approximately five times more susceptible to proteolytic attack under activating (ATP/high Ca2+) or rigor (no ATP) conditions than under relaxing conditions (ATP/low Ca2+). A similar result was obtained with native myosin filaments in a crude homogenate of scallop muscle. Proteolytic susceptibility under conditions in which ADP or adenosine 5'-(beta, gamma-imidotriphosphate) (AMPPNP) replaced ATP was similar to that in the absence of nucleotide. Synthetic myosin filaments negatively stained under relaxing conditions showed a compact structure, in which the myosin cross-bridges were close to the filament backbone and well ordered, with a clear 14.5-nm axial repeat. Under activating or rigor conditions, the cross-bridges became clumped and disordered and frequently projected further from the filament backbone, as has been found with native filaments; when ADP or AMPPNP replaced ATP, the cross-bridges were also disordered. We conclude (a) that Ca2+ and ATP affect the affinity of the myosin cross-bridges for the filament backbone or for each other; (b) that the changes observed in the myosin filaments reflect a property of the myosin molecules alone, and are unlikely to be an artifact of negative staining; and (c) that the ordered structure occurs only in the relaxed state, requiring both the presence of hydrolyzed ATP on the myosin heads and the absence of Ca2+.

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