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The Journal of Clinical Investigation May 2022Passive stiffness of the heart is determined largely by extracellular matrix and titin, which functions as a molecular spring within sarcomeres. Titin stiffening is...
Passive stiffness of the heart is determined largely by extracellular matrix and titin, which functions as a molecular spring within sarcomeres. Titin stiffening is associated with the development of diastolic dysfunction (DD), while augmented titin compliance appears to impair systolic performance in dilated cardiomyopathy. We found that myofibril stiffness was elevated in mice lacking histone deacetylase 6 (HDAC6). Cultured adult murine ventricular myocytes treated with a selective HDAC6 inhibitor also exhibited increased myofibril stiffness. Conversely, HDAC6 overexpression in cardiomyocytes led to decreased myofibril stiffness, as did ex vivo treatment of mouse, rat, and human myofibrils with recombinant HDAC6. Modulation of myofibril stiffness by HDAC6 was dependent on 282 amino acids encompassing a portion of the PEVK element of titin. HDAC6 colocalized with Z-disks, and proteomics analysis suggested that HDAC6 functions as a sarcomeric protein deacetylase. Finally, increased myofibril stiffness in HDAC6-deficient mice was associated with exacerbated DD in response to hypertension or aging. These findings define a role for a deacetylase in the control of myofibril function and myocardial passive stiffness, suggest that reversible acetylation alters titin compliance, and reveal the potential of targeting HDAC6 to manipulate the elastic properties of the heart to treat cardiac diseases.
Topics: Animals; Connectin; Histone Deacetylase 6; Humans; Mice; Myocardium; Myocytes, Cardiac; Myofibrils; Rats; Sarcomeres
PubMed: 35575093
DOI: 10.1172/JCI148333 -
Cells & Development Dec 2021Muscles generate forces for animal locomotion. The contractile apparatus of muscles is the sarcomere, a highly regular array of large actin and myosin filaments linked... (Review)
Review
Muscles generate forces for animal locomotion. The contractile apparatus of muscles is the sarcomere, a highly regular array of large actin and myosin filaments linked by gigantic titin springs. During muscle development many sarcomeres assemble in series into long periodic myofibrils that mechanically connect the attached skeleton elements. Thus, ATP-driven myosin forces can power movement of the skeleton. Here we review muscle and myofibril morphogenesis, with a particular focus on their mechanobiology. We describe recent progress on the molecular structure of sarcomeres and their mechanical connections to the skeleton. We discuss current models predicting how tension coordinates the assembly of key sarcomeric components to periodic myofibrils that then further mature during development. This requires transcriptional feedback mechanisms that may help to coordinate myofibril assembly and maturation states with the transcriptional program. To fuel the varying energy demands of muscles we also discuss the close mechanical interactions of myofibrils with mitochondria and nuclei to optimally support powerful or enduring muscle fibers.
Topics: Animals; Biophysics; Morphogenesis; Myofibrils; Myosins; Sarcomeres
PubMed: 34863916
DOI: 10.1016/j.cdev.2021.203760 -
Mechanisms of Development Apr 2017Muscles are the major force producing tissue in the human body. While certain muscle types specialize in producing maximum forces, others are very enduring. An extreme... (Review)
Review
Muscles are the major force producing tissue in the human body. While certain muscle types specialize in producing maximum forces, others are very enduring. An extreme example is the heart, which continuously beats for the entire life. Despite being specialized, all body muscles share similar contractile mini-machines called sarcomeres that are organized into regular higher order structures called myofibrils. The major sarcomeric components and their organizational principles are conserved throughout most of the animal kingdom. In this review, we discuss recent progress in the understanding of myofibril and sarcomere development largely obtained from in vivo models. We focus on the role of mechanical forces during muscle and myofibril development and propose a tension driven self-organization mechanism for myofibril formation. We discuss recent technological advances that allow quantification of forces across tissues or molecules in vitro and in vivo. Although their application towards muscle development is still in its infancy, these technologies are likely to provide fundamental new insights into the mechanobiology of muscle and myofibril development in the near future.
Topics: Actins; Animals; Biomechanical Phenomena; Connectin; Drosophila melanogaster; Gene Expression Regulation, Developmental; Humans; Integrins; Muscle Development; Muscle Tonus; Myofibrils; Signal Transduction; Tendons
PubMed: 27913119
DOI: 10.1016/j.mod.2016.11.003 -
The FEBS Journal May 2022Desmin is the primary intermediate filament (IF) of cardiac, skeletal, and smooth muscle. By linking the contractile myofibrils to the sarcolemma and cellular... (Review)
Review
Desmin is the primary intermediate filament (IF) of cardiac, skeletal, and smooth muscle. By linking the contractile myofibrils to the sarcolemma and cellular organelles, desmin IF contributes to muscle structural and cellular integrity, force transmission, and mitochondrial homeostasis. Mutations in desmin cause myofibril misalignment, mitochondrial dysfunction, and impaired mechanical integrity leading to cardiac and skeletal myopathies in humans, often characterized by the accumulation of protein aggregates. Recent evidence indicates that desmin filaments also regulate proteostasis and cell size. In skeletal muscle, changes in desmin filament dynamics can facilitate catabolic events as an adaptive response to a changing environment. In addition, post-translational modifications of desmin and its misfolding in the heart have emerged as key determinants of homeostasis and disease. In this review, we provide an overview of the structural and cellular roles of desmin and propose new models for its novel functions in preserving the homeostasis of striated muscles.
Topics: Desmin; Homeostasis; Humans; Muscle, Skeletal; Muscular Diseases; Myofibrils
PubMed: 33825342
DOI: 10.1111/febs.15864 -
Archives of Biochemistry and Biophysics May 2019
Topics: Animals; Humans; Muscle Contraction; Muscle Proteins; Myofibrils
PubMed: 31051122
DOI: 10.1016/j.abb.2019.04.011 -
Biomolecules Jan 2021Protein degradation maintains cellular integrity by regulating virtually all biological processes, whereas impaired proteolysis perturbs protein quality control, and... (Review)
Review
Protein degradation maintains cellular integrity by regulating virtually all biological processes, whereas impaired proteolysis perturbs protein quality control, and often leads to human disease. Two major proteolytic systems are responsible for protein breakdown in all cells: autophagy, which facilitates the loss of organelles, protein aggregates, and cell surface proteins; and the ubiquitin-proteasome system (UPS), which promotes degradation of mainly soluble proteins. Recent findings indicate that more complex protein structures, such as filamentous assemblies, which are not accessible to the catalytic core of the proteasome in vitro, can be efficiently degraded by this proteolytic machinery in systemic catabolic states in vivo. Mechanisms that loosen the filamentous structure seem to be activated first, hence increasing the accessibility of protein constituents to the UPS. In this review, we will discuss the mechanisms underlying the disassembly and loss of the intricate insoluble filamentous myofibrils, which are responsible for muscle contraction, and whose degradation by the UPS causes weakness and disability in aging and disease. Several lines of evidence indicate that myofibril breakdown occurs in a strictly ordered and controlled manner, and the function of AAA-ATPases is crucial for their disassembly and loss.
Topics: Animals; Humans; Muscle Proteins; Myofibrils; Proteasome Endopeptidase Complex; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 33467597
DOI: 10.3390/biom11010110 -
Nature Communications Apr 2021Complex animals build specialised muscles to match specific biomechanical and energetic needs. Hence, composition and architecture of sarcomeres and mitochondria are...
Complex animals build specialised muscles to match specific biomechanical and energetic needs. Hence, composition and architecture of sarcomeres and mitochondria are muscle type specific. However, mechanisms coordinating mitochondria with sarcomere morphogenesis are elusive. Here we use Drosophila muscles to demonstrate that myofibril and mitochondria morphogenesis are intimately linked. In flight muscles, the muscle selector spalt instructs mitochondria to intercalate between myofibrils, which in turn mechanically constrain mitochondria into elongated shapes. Conversely in cross-striated leg muscles, mitochondria networks surround myofibril bundles, contacting myofibrils only with thin extensions. To investigate the mechanism causing these differences, we manipulated mitochondrial dynamics and found that increased mitochondrial fusion during myofibril assembly prevents mitochondrial intercalation in flight muscles. Strikingly, this causes the expression of cross-striated muscle specific sarcomeric proteins. Consequently, flight muscle myofibrils convert towards a partially cross-striated architecture. Together, these data suggest a biomechanical feedback mechanism downstream of spalt synchronizing mitochondria with myofibril morphogenesis.
Topics: Animals; Biomechanical Phenomena; Drosophila; Drosophila Proteins; Drosophila melanogaster; Feedback; Flight, Animal; Male; Mechanical Phenomena; Mitochondria; Morphogenesis; Muscle Development; Muscle, Skeletal; Myofibrils; Myogenic Regulatory Factors; Sarcomeres; Transcription Factors
PubMed: 33828099
DOI: 10.1038/s41467-021-22058-7 -
Animal Science Journal = Nihon Chikusan... Jul 2019Skeletal muscle consists of bundles of myofibers containing millions of myofibrils, each of which is formed of longitudinally aligned sarcomere structures. Sarcomeres... (Review)
Review
Skeletal muscle consists of bundles of myofibers containing millions of myofibrils, each of which is formed of longitudinally aligned sarcomere structures. Sarcomeres are the minimum contractile unit, which mainly consists of four components: Z-bands, thin filaments, thick filaments, and connectin/titin. The size and shape of the sarcomere component is strictly controlled. Surprisingly, skeletal muscle cells not only synthesize a series of myofibrillar proteins but also regulate the assembly of those proteins into the sarcomere structures. However, authentic sarcomere structures cannot be reconstituted by combining purified myofibrillar proteins in vitro, therefore there must be an elaborate mechanism ensuring the correct formation of myofibril structure in skeletal muscle cells. This review discusses the role of myosin, a main component of the thick filament, in thick filament formation and the dynamics of myosin in skeletal muscle cells. Changes in the number of myofibrils in myofibers can cause muscle hypertrophy or atrophy. Therefore, it is important to understand the fundamental mechanisms by which myofibers control myofibril formation at the molecular level to develop approaches that effectively enhance muscle growth in animals.
Topics: Animals; Atrophy; Cytoskeleton; Hypertrophy; Muscle, Skeletal; Myofibrils; Myosins; Sarcomeres
PubMed: 31134719
DOI: 10.1111/asj.13226 -
Biophysical Journal Dec 2020The smallest contractile unit in striated muscles is the sarcomere. Although some of the classic features of contraction assume a uniform behavior of sarcomeres within... (Review)
Review
The smallest contractile unit in striated muscles is the sarcomere. Although some of the classic features of contraction assume a uniform behavior of sarcomeres within myofibrils, the occurrence of sarcomere length nonuniformities has been well recognized for years, but it is yet not well understood. In the past years, there has been a great advance in experiments using isolated myofibrils and sarcomeres that has allowed scientists to directly evaluate sarcomere length nonuniformity. This review will focus on studies conducted with these preparations to develop the hypotheses that 1) force production in myofibrils is largely altered and regulated by intersarcomere dynamics and that 2) the mechanical work of one sarcomere in a myofibril is transmitted to other sarcomeres in series. We evaluated studies looking into myofibril activation, relaxation, and force changes produced during activation. We conclude that force production in myofibrils is largely regulated by intersarcomere dynamics, which arises from the cooperative work of the contractile and elastic elements within a myofibril.
Topics: Mechanical Phenomena; Muscle Contraction; Muscle, Skeletal; Myofibrils; Sarcomeres
PubMed: 33217382
DOI: 10.1016/j.bpj.2020.11.005 -
ELife Aug 2022Human muscle is a hierarchically organised tissue with its contractile cells called myofibers packed into large myofiber bundles. Each myofiber contains periodic...
Human muscle is a hierarchically organised tissue with its contractile cells called myofibers packed into large myofiber bundles. Each myofiber contains periodic myofibrils built by hundreds of contractile sarcomeres that generate large mechanical forces. To better understand the mechanisms that coordinate human muscle morphogenesis from tissue to molecular scales, we adopted a simple in vitro system using induced pluripotent stem cell-derived human myogenic precursors. When grown on an unrestricted two-dimensional substrate, developing myofibers spontaneously align and self-organise into higher-order myofiber bundles, which grow and consolidate to stable sizes. Following a transcriptional boost of sarcomeric components, myofibrils assemble into chains of periodic sarcomeres that emerge across the entire myofiber. More efficient myofiber bundling accelerates the speed of sarcomerogenesis suggesting that tension generated by bundling promotes sarcomerogenesis. We tested this hypothesis by directly probing tension and found that tension build-up precedes sarcomere assembly and increases within each assembling myofibril. Furthermore, we found that myofiber ends stably attach to other myofibers using integrin-based attachments and thus myofiber bundling coincides with stable myofiber bundle attachment in vitro. A failure in stable myofiber attachment results in a collapse of the myofibrils. Overall, our results strongly suggest that mechanical tension across sarcomeric components as well as between differentiating myofibers is key to coordinate the multi-scale self-organisation of muscle morphogenesis.
Topics: Humans; Induced Pluripotent Stem Cells; Muscle Development; Muscle Fibers, Skeletal; Myofibrils; Sarcomeres
PubMed: 35920628
DOI: 10.7554/eLife.76649