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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 -
Handbook of Experimental Pharmacology 2017In this chapter, we present the current knowledge on de novo assembly, growth, and dynamics of striated myofibrils, the functional architectural elements developed in... (Review)
Review
In this chapter, we present the current knowledge on de novo assembly, growth, and dynamics of striated myofibrils, the functional architectural elements developed in skeletal and cardiac muscle. The data were obtained in studies of myofibrils formed in cultures of mouse skeletal and quail myotubes, in the somites of living zebrafish embryos, and in mouse neonatal and quail embryonic cardiac cells. The comparative view obtained revealed that the assembly of striated myofibrils is a three-step process progressing from premyofibrils to nascent myofibrils to mature myofibrils. This process is specified by the addition of new structural proteins, the arrangement of myofibrillar components like actin and myosin filaments with their companions into so-called sarcomeres, and in their precise alignment. Accompanying the formation of mature myofibrils is a decrease in the dynamic behavior of the assembling proteins. Proteins are most dynamic in the premyofibrils during the early phase and least dynamic in mature myofibrils in the final stage of myofibrillogenesis. This is probably due to increased interactions between proteins during the maturation process. The dynamic properties of myofibrillar proteins provide a mechanism for the exchange of older proteins or a change in isoforms to take place without disassembling the structural integrity needed for myofibril function. An important aspect of myofibril assembly is the role of actin-nucleating proteins in the formation, maintenance, and sarcomeric arrangement of the myofibrillar actin filaments. This is a very active field of research. We also report on several actin mutations that result in human muscle diseases.
Topics: Actins; Animals; Humans; Mice; Muscle Development; Muscle, Striated; Myofibrils; Myosins; Polymerization; Sarcomeres; Zebrafish
PubMed: 27832381
DOI: 10.1007/164_2016_53 -
Circulation. Cardiovascular Genetics Oct 2017
Topics: Myocardial Contraction; Myocytes, Cardiac; Myofibrils; Transcriptome
PubMed: 29030406
DOI: 10.1161/CIRCGENETICS.117.001950 -
Circulation Journal : Official Journal... 2015The members of the nebulin protein family, including nebulin, nebulette, LASP-1, LASP-2, and N-RAP, contain various numbers of nebulin repeats and bind to actin, but are... (Review)
Review
The members of the nebulin protein family, including nebulin, nebulette, LASP-1, LASP-2, and N-RAP, contain various numbers of nebulin repeats and bind to actin, but are otherwise heterogeneous with regard to size, expression pattern, and function. This review focuses on the roles of nebulin family members in the heart. Nebulin is the largest member predominantly expressed in skeletal muscle, where it stretches along the thin filament. In heart, nebulin is detectable only at low levels and its absence has no apparent effects. Nebulette is similar in structure to the nebulin C-terminal Z-line region and specifically expressed in heart. Nebulette gene mutations have been identified in dilated cardiomyopathy patients and transgenic mice overexpressing nebulette mutants partially recapitulate the human pathology. In contrast, nebulette knockout mice show no functional phenotype, but exhibit Z-line widening. LASP-2 is an isoform of nebulette expressed in multiple tissues, including the heart. It is present in the Z-line and intercalated disc and able to bind and cross-link filamentous actin. LASP-1 is similar in structure to LASP-2, but expressed only in non-muscle tissue. N-RAP is present in myofibril precursors during myofibrillogenesis and thought to be involved in myofibril assembly, while it is localized at the intercalated disc in adult heart. Additional in vivo models are required to provide further insights into the functions of nebulin family members in the heart.
Topics: Adaptor Proteins, Signal Transducing; Adult; Animals; Cardiomyopathy, Dilated; Carrier Proteins; Cytoskeletal Proteins; Homeodomain Proteins; Humans; LIM Domain Proteins; Mice; Mice, Transgenic; Muscle Proteins; Mutation; Myocardium; Myofibrils
PubMed: 26321576
DOI: 10.1253/circj.CJ-15-0854 -
International Journal of Molecular... Jun 2018In muscle, but not in single-molecule mechanics studies, actin, myosin and accessory proteins are incorporated into a highly ordered myofilament lattice. In view of this... (Review)
Review
In muscle, but not in single-molecule mechanics studies, actin, myosin and accessory proteins are incorporated into a highly ordered myofilament lattice. In view of this difference we compare results from single-molecule studies and muscle mechanics and analyze to what degree data from the two types of studies agree with each other. There is reasonable correspondence in estimates of the cross-bridge power-stroke distance (7⁻13 nm), cross-bridge stiffness (~2 pN/nm) and average isometric force per cross-bridge (6⁻9 pN). Furthermore, models defined on the basis of single-molecule mechanics and solution biochemistry give good fits to experimental data from muscle. This suggests that the ordered myofilament lattice, accessory proteins and emergent effects of the sarcomere organization have only minor modulatory roles. However, such factors may be of greater importance under e.g., disease conditions. We also identify areas where single-molecule and muscle data are conflicting: (1) whether force generation is an Eyring or Kramers process with just one major power-stroke or several sub-strokes; (2) whether the myofilaments and the cross-bridges have Hookean or non-linear elasticity; (3) if individual myosin heads slip between actin sites under certain conditions, e.g., in lengthening; or (4) if the two heads of myosin cooperate.
Topics: Actin Cytoskeleton; Actins; Actomyosin; Animals; Isometric Contraction; Muscle Contraction; Muscle Fibers, Skeletal; Myofibrils; Myosins
PubMed: 29941816
DOI: 10.3390/ijms19071863 -
The Journal of General Physiology Jan 2019Regulation of muscle contraction has been viewed as principally involving Ca binding to regulatory proteins on the thin filament, but while this is an important element...
Regulation of muscle contraction has been viewed as principally involving Ca binding to regulatory proteins on the thin filament, but while this is an important element of regulation, the mechanism does not explain the precise matching of muscle performance to the load it must lift or move. Now, it is increasingly evident that mechanisms instrinsic to the thick filament activate myosin cross-bridges as the force or load on a muscle increases. Both thick and thin filament regulatory mechanisms are featured in this special issue of the .
Topics: Animals; Calcium; Muscle Proteins; Muscles; Myofibrils
PubMed: 30578329
DOI: 10.1085/jgp.201812288 -
Archives of Biochemistry and Biophysics Mar 2019Movement of the myocardium can modify organ-level cardiac function and its molecular (crossbridge) mechanisms. This motion, which is defined by myocardial strain and... (Review)
Review
Movement of the myocardium can modify organ-level cardiac function and its molecular (crossbridge) mechanisms. This motion, which is defined by myocardial strain and strain rate (muscle shortening, lengthening, and the speed of these movements), occurs throughout the cardiac cycle, including during isovolumic periods. This review highlights how the left ventricular myocardium moves throughout the cardiac cycle, how muscle mechanics experiments provide insight into the regulation of forces used to move blood in and out of the left ventricle, and its impact on (and regulation by) crossbridge and sarcomere kinetics. We specifically highlight how muscle mechanics experiments explain how myocardial relaxation is accelerated by lengthening (strain rate) during late systole and isovolumic relaxation, a lengthening which has been measured in human hearts. Advancing and refining both in vivo measurement and ex vivo protocols with physiologic strain and strain rates could reveal important insights into molecular (crossbridge) kinetics. These advances could provide an improvement in both diagnosis and precise treatment of cardiac dysfunction.
Topics: Animals; Heart; Humans; Movement; Myofibrils; Stress, Mechanical
PubMed: 30710504
DOI: 10.1016/j.abb.2019.01.034 -
Proteomics. Clinical Applications Aug 2014Global cardiac myofilament protein phosphorylation levels, and their site-specific stoichiometry, are physiologically and clinically relevant for heart function. Unlike... (Review)
Review
Global cardiac myofilament protein phosphorylation levels, and their site-specific stoichiometry, are physiologically and clinically relevant for heart function. Unlike myofilament phosphorylation, other PTMs such as O-GlcNAcylation are just beginning to gain attention due to their potential physiological and clinical implications. This review will focus on what is currently known about cardiac troponin I phosphorylation, and on the potential physiological and clinical impact of targeted proteomics including new findings on cardiac troponin I sites and stoichiometry. We will then discuss the increasing recognition of other myofilament PTMs functional relevance and the potential of targeted MS approaches, particularly MRM, for accelerating their systematic characterization. In addition, we will broadly discuss the development and application of MRM to quantitatively assess site-specific PTMs. Finally, we will give an overview of expert's consensus on MRM methods design/validation and best practices to develop MRM assays intended to reach clinical application. The unique ability of MRM and similar methods to identify and quantify cardiac myofilament PTMs is likely to become central in answering important biological questions in the field of cardiac integrative physiology.
Topics: Animals; Heart; Humans; Myofibrils; Phosphorylation; Protein Processing, Post-Translational; Proteomics; Translational Research, Biomedical
PubMed: 24976615
DOI: 10.1002/prca.201400034 -
JCI Insight Sep 2023Pediatric cardiomyopathy (CM) represents a group of rare, severe disorders that affect the myocardium. To date, the etiology and mechanisms underlying pediatric CM are...
Pediatric cardiomyopathy (CM) represents a group of rare, severe disorders that affect the myocardium. To date, the etiology and mechanisms underlying pediatric CM are incompletely understood, hampering accurate diagnosis and individualized therapy development. Here, we identified biallelic variants in the highly conserved flightless-I (FLII) gene in 3 families with idiopathic, early-onset dilated CM. We demonstrated that patient-specific FLII variants, when brought into the zebrafish genome using CRISPR/Cas9 genome editing, resulted in the manifestation of key aspects of morphological and functional abnormalities of the heart, as observed in our patients. Importantly, using these genetic animal models, complemented with in-depth loss-of-function studies, we provided insights into the function of Flii during ventricular chamber morphogenesis in vivo, including myofibril organization and cardiomyocyte cell adhesion, as well as trabeculation. In addition, we identified Flii function to be important for the regulation of Notch and Hippo signaling, crucial pathways associated with cardiac morphogenesis and function. Taken together, our data provide experimental evidence for a role for FLII in the pathogenesis of pediatric CM and report biallelic variants as a genetic cause of pediatric CM.
Topics: Animals; Cell Adhesion; Microfilament Proteins; Myocytes, Cardiac; Myofibrils; Zebrafish; Trans-Activators; Cardiomyopathies
PubMed: 37561591
DOI: 10.1172/jci.insight.168247 -
Biochimica Et Biophysica Acta.... Oct 2020Muscle atrophy is an inevitable sequel of fasting, denervation, aging, exposure to microgravity, and many human diseases including, cancer, type-2 diabetes, and renal... (Review)
Review
Muscle atrophy is an inevitable sequel of fasting, denervation, aging, exposure to microgravity, and many human diseases including, cancer, type-2 diabetes, and renal failure. During atrophy the destruction of the muscle's fundamental contractile machinery, the myofibrils, is accelerated leading to a reduction in muscle mass, weakness, frailty, and physical disability. Recent findings indicate that atrophy can be a major cause of death in affected individuals, and inhibition of muscle wasting is likely to prolong survival. Major advances in our understanding of the mechanisms for myofibril breakdown in atrophy include the discovery of biological pathways and key components that play prominent roles. On fasting or denervation, degradation of myofibrillar proteins requires an initial dissociation of the desmin cytoskeleton, whose integrity is critical for myofibril stability. This loss of desmin filaments involves phosphorylation, ubiquitination, and subsequent depolymerization by calpain-1, and appears to reduce myofibrils integrity and facilitate their destruction. Consequently, depolymerization of desmin filament in atrophy seems to be an early key event for overall proteolysis. A focus of this review is to discuss these new insights and the specific role of calpain-1 in promoting desmin filaments loss, and to highlight important key questions that merit further study.
Topics: Animals; Calpain; Desmin; Humans; Muscular Atrophy; Myofibrils; Polymerization; Ubiquitination
PubMed: 32603758
DOI: 10.1016/j.bbamcr.2020.118788