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Handbook of Clinical Neurology 2013Myofibrillar myopathies (MFMs) are rare, inherited or sporadic, progressive neuromuscular disorders with considerable clinical and genetic heterogeneity. MFMs are... (Review)
Review
Myofibrillar myopathies (MFMs) are rare, inherited or sporadic, progressive neuromuscular disorders with considerable clinical and genetic heterogeneity. MFMs are defined morphologically by foci of myofibril dissolution that begins at the Z-disk, accumulation of myofibrillar degradation products, and ectopic expression of a large number of proteins including desmin. To date, mutations in six genes are known to cause MFMs, accounting for approximately half of the MFM patients identified. The causative genes encode mainly sarcomeric Z-disk(-related) proteins: desmin, αB-crystallin, myotilin, Z-band alternatively spliced PDZ motif containing protein (ZASP), filamin C and the antiapoptotic BCL2-associated athanogene 3 (Bag3). Although in most MFM patients the disease presents in adulthood and evolves slowly, some patients with desminopathy, αB-crystallinopathy or Bag3opathies have an infantile or juvenile disease onset. Cardiac involvement is very common in desminopathies and can sometimes be the initial or only symptom of the disease. Respiratory symptoms are noted during childhood in αB-crystallinopathies. Early severe cardiac and respiratory involvement is seen in Bag3opathies. Optical microscopic and immunohistochemical features are similar in MFMs; however, ultrastructural findings can be useful to differentiate between the distinct MFM subtypes. No curative treatment for MFMs is currently available. Careful follow-up, especially of cardiac and respiratory function, is important.
Topics: Child; Desmin; Humans; Muscle, Skeletal; Myofibrils; Myopathies, Structural, Congenital
PubMed: 23622358
DOI: 10.1016/B978-0-444-59565-2.00005-8 -
Biomechanics and Modeling in... Dec 2018Sarcomeres are building blocks of skeletal muscles. Given force-length relations of sarcomeres serially connected in a myofibril, the myofibril force-length relation can...
Sarcomeres are building blocks of skeletal muscles. Given force-length relations of sarcomeres serially connected in a myofibril, the myofibril force-length relation can be uniquely determined. Necessary and sufficient conditions are derived for capability of fully lengthening or completely shortening a myofibril under isometric, eccentric or concentric contraction, and for the myofibril force-length relation to be a continuous single-valued function. Intriguing phenomena such as sarcomere force-length hysteresis and myofibril regularity are investigated and their important roles in determining myofibril force-length relations are explored. The theoretical analysis leads to experimentally verifiable predictions on myofibril force-length relations. For illustration, simulated force-length relations of a myofibril portion consisting of a sarcomere pair are presented.
Topics: Animals; Biomechanical Phenomena; Humans; Isometric Contraction; Muscle Contraction; Muscle, Skeletal; Myofibrils; Sarcomeres; Stress, Mechanical
PubMed: 30047021
DOI: 10.1007/s10237-018-1057-0 -
Cytoskeleton (Hoboken, N.J.) Sep 2020The coordinated generation of mechanical forces by cardiac myocytes is required for proper heart function. Myofibrils are the functional contractile units of force...
The coordinated generation of mechanical forces by cardiac myocytes is required for proper heart function. Myofibrils are the functional contractile units of force production within individual cardiac myocytes. At the molecular level, myosin motors form cross-bridges with actin filaments and use ATP to convert chemical energy into mechanical forces. The energetic efficiency of the cross-bridge cycle is influenced by the viscous damping of myofibril contraction. The viscoelastic response of myofibrils is an emergent property of their individual mechanical components. Previous studies have implicated titin-actin interactions, cell-ECM adhesion, and microtubules as regulators of the viscoelastic response of myofibrils. Here we probed the viscoelastic response of myofibrils using laser-assisted dissection. As a proof-of-concept, we found actomyosin contractility was required to endow myofibrils with their viscoelastic response, with blebbistatin treatment resulting in decreased myofibril tension and viscous damping. Focal adhesion kinase (FAK) is a key regulator of cell-ECM adhesion, microtubule stability, and myofibril assembly. We found inhibition of FAK signaling altered the viscoelastic properties of myofibrils. Specifically, inhibition of FAK resulted in increased viscous damping of myofibril retraction following laser ablation. This damping was not associated with acute changes in the electrophysiological properties of cardiac myocytes. These results implicate FAK as a regulator of mechanical properties of myofibrils.
Topics: Focal Adhesions; Humans; Myocytes, Cardiac; Myofibrils; Viscosity
PubMed: 32885903
DOI: 10.1002/cm.21632 -
The Journal of Clinical Investigation Jan 1998Loss of myofibril organization is a common feature of chronic dilated and progressive cardiomyopathy. To study how the heart compensates for myofibril degeneration,...
Loss of myofibril organization is a common feature of chronic dilated and progressive cardiomyopathy. To study how the heart compensates for myofibril degeneration, transgenic mice were created that undergo progressive loss of myofibrils after birth. Myofibril degeneration was induced by overexpression of tropomodulin, a component of the thin filament complex which determines and maintains sarcomeric actin filament length. The tropomodulin cDNA was placed under control of the alpha-myosin heavy chain gene promoter to overexpress tropomodulin specifically in the myocardium. Offspring with the most severe phenotype showed cardiomyopathic changes between 2 and 4 wk after birth. Hearts from these mice present characteristics consistent with dilated cardiomyopathy and a failed hypertrophic response. Histological analysis showed widespread loss of myofibril organization. Confocal microscopy of isolated cardiomyocytes revealed intense tropomodulin immunoreactivity in transgenic mice together with abnormal coincidence of tropomodulin and alpha-actinin reactivity at Z discs. Contractile function was compromised severely as determined by echocardiographic analyses and isolated Langendorff heart preparations. This novel experimentally induced cardiomyopathy will be useful for understanding dilated cardiomyopathy and the effect of thin filament-based myofibril degeneration upon cardiac structure and function.
Topics: Animals; Antimetabolites; Cardiomyopathy, Dilated; Carrier Proteins; Disease Models, Animal; Gene Expression; Hemodynamics; Mice; Mice, Transgenic; Microfilament Proteins; Myocardial Contraction; Myofibrils; Propylthiouracil; Tropomodulin
PubMed: 9421465
DOI: 10.1172/JCI1167 -
Experimental Cell Research Jul 2009N-RAP is a striated muscle-specific scaffolding protein that organizes alpha-actinin and actin into symmetrical I-Z-I structures in developing myofibrils. Here we...
N-RAP is a striated muscle-specific scaffolding protein that organizes alpha-actinin and actin into symmetrical I-Z-I structures in developing myofibrils. Here we determined the order of events during myofibril assembly through time-lapse confocal microscopy of cultured embryonic chick cardiomyocytes coexpressing fluorescently tagged N-RAP and either alpha-actinin or actin. During de novo myofibril assembly, N-RAP assembled in fibrillar structures within the cell, with dots of alpha-actinin subsequently organizing along these structures. The initial fibrillar structures were reminiscent of actin fibrils, and coassembly of N-RAP and actin into newly formed fibrils supported this. The alpha-actinin dots subsequently broadened to Z-lines that were wider than the underlying N-RAP fibril, and N-RAP fluorescence intensity decreased. FRAP experiments showed that most of the alpha-actinin dynamically exchanged during all stages of myofibril assembly. In contrast, less than 20% of the N-RAP in premyofibrils was exchanged during 10-20 min after photobleaching, but this value increased to 70% during myofibril maturation. The results show that N-RAP assembles into an actin containing scaffold before alpha-actinin recruitment; that the N-RAP scaffold is much more stable than the assembling structural components; that N-RAP dynamics increase as assembly progresses; and that N-RAP leaves the structure after assembly is complete.
Topics: Actinin; Actins; Animals; Cells, Cultured; Chick Embryo; Humans; Muscle Proteins; Myocytes, Cardiac; Myofibrils; Protein Binding
PubMed: 19233165
DOI: 10.1016/j.yexcr.2009.02.006 -
Advances in Experimental Medicine and... 2000Sarcomeres of cardiac muscle are comprised of numerous proteins organized in an elegantly precise order. The exact mechanism of how these proteins are assembled into... (Review)
Review
Sarcomeres of cardiac muscle are comprised of numerous proteins organized in an elegantly precise order. The exact mechanism of how these proteins are assembled into myofibrils during heart development is not yet understood, although existing in vitro and in vivo model systems have provided great insight into this complex process. It has been proposed by several groups that the giant elastic protein titin acts as a "molecular template" to orchestrate sarcomeric organization during myofibrillogenesis. Titin's highly modular structure, composed of both repeating and unique domains that interact with a wide spectrum of contractile and regulatory ligands, supports this hypothesis. Recent functional studies have provided clues to the physiological significance of the interaction of titin with several titin-binding proteins in the context of live cardiac cells. Improved models of cardiac myofibril assembly, along with the application of powerful functional studies in live cells, as well as the characterization of additional titin ligands, is likely to reveal surprising new functions for the titin third filament system.
Topics: Animals; Connectin; Heart; Humans; Ligands; Membrane Proteins; Muscle Proteins; Myocardium; Myofibrils; Protein Kinases; Sarcomeres
PubMed: 10987067
DOI: 10.1007/978-1-4615-4267-4_5 -
Fa Yi Xue Za Zhi Dec 2017To study the relationship between myofibril fragmentation index (MFI) of human skeletal muscle and postmortem interval (PMI).
OBJECTIVES
To study the relationship between myofibril fragmentation index (MFI) of human skeletal muscle and postmortem interval (PMI).
METHODS
The protein concentrations of human right biceps brachii muscle and right quadriceps femoris muscle were obtained at different PMI, and detected at room temperature by biuret method. The MFI of skeletal muscle at 540 nm was measured by ultraviolet spectrophotometer. Regression analysis was performed with time of death as independent variable () and MFI as dependent variable ().
RESULTS
In early PMI, the MFI of human skeletal muscle increased obviously according to the prolongation of PMI, and peaking by 12 h and then tended to steady. Within 12 h after death, the regression equations of right biceps brachii muscle and right quadriceps femoris muscle were =32.660+3.227 (=0.987 9) and =32.380+3.495 (=0.983 9), respectively.
CONCLUSIONS
There's high correlation between MFI and PMI. Combining with forensic practice, MFI can be used for the estimation of early PMI (especially in 12 h).
Topics: Autopsy; Death; Forensic Pathology; Humans; Muscle, Skeletal; Myofibrils; Postmortem Changes; Proteins; Regression Analysis; Spectrophotometry
PubMed: 29441764
DOI: 10.3969/j.issn.1004-5619.2017.06.004 -
Journal of Molecular and Cellular... Aug 2018
Topics: Heart; Humans; Myocardial Contraction; Myofibrils; Sarcomeres
PubMed: 29908919
DOI: 10.1016/j.yjmcc.2018.06.003 -
PLoS Genetics Jun 2022Myofibrils of the skeletal muscle are comprised of sarcomeres that generate force by contraction when myosin-rich thick filaments slide past actin-based thin filaments....
Myofibrils of the skeletal muscle are comprised of sarcomeres that generate force by contraction when myosin-rich thick filaments slide past actin-based thin filaments. Surprisingly little is known about the molecular processes that guide sarcomere assembly in vivo, despite deficits within this process being a major cause of human disease. To overcome this knowledge gap, we undertook a forward genetic screen coupled with reverse genetics to identify genes required for vertebrate sarcomere assembly. In this screen, we identified a zebrafish mutant with a nonsense mutation in mob4. In Drosophila, mob4 has been reported to play a role in spindle focusing as well as neurite branching and in planarians mob4 was implemented in body size regulation. In contrast, zebrafish mob4geh mutants are characterised by an impaired actin biogenesis resulting in sarcomere defects. Whereas loss of mob4 leads to a reduction in the amount of myofibril, transgenic expression of mob4 triggers an increase. Further genetic analysis revealed the interaction of Mob4 with the actin-folding chaperonin TRiC, suggesting that Mob4 impacts on TRiC to control actin biogenesis and thus myofibril growth. Additionally, mob4geh features a defective microtubule network, which is in-line with tubulin being the second main folding substrate of TRiC. We also detected similar characteristics for strn3-deficient mutants, which confirmed Mob4 as a core component of STRIPAK and surprisingly implicates a role of the STRIPAK complex in sarcomerogenesis.
Topics: Actins; Animals; Chaperonins; Microtubules; Myofibrils; Sarcomeres; Zebrafish
PubMed: 35737712
DOI: 10.1371/journal.pgen.1010287 -
Acta Histochemica 1978A modification of the histochemical method for myosin ATPase was used to determine the myofibril complement, mean myofibril size and myofibrillar packing of defined...
A modification of the histochemical method for myosin ATPase was used to determine the myofibril complement, mean myofibril size and myofibrillar packing of defined muscle fibre types in rat skeletal muscle. Fast muscle fibres (Types IIA and IIB) were found to have smaller myofibrils and a lower packing density than slower (Type I) fibres. These findings were discussed with respect to their relevance in estimations of muscle strength from histological and histochemical preparations of muscle cross-sections.
Topics: Animals; Histocytochemistry; Male; Muscles; Myofibrils; Rats
PubMed: 107701
DOI: 10.1016/S0065-1281(78)80023-3