Статті в журналах: "Z-disc proteins"

1

Knöll, Ralph, Byambajav Buyandelger, and Max Lab. "The Sarcomeric Z-Disc and Z-Discopathies." Journal of Biomedicine and Biotechnology 2011 (2011): 1–12. http://dx.doi.org/10.1155/2011/569628.

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The sarcomeric Z-disc defines the lateral borders of the sarcomere and has primarily been seen as a structure important for mechanical stability. This view has changed dramatically within the last one or two decades. A multitude of novel Z-disc proteins and their interacting partners have been identified, which has led to the identification of additional functions and which have now been assigned to this structure. This includes its importance for intracellular signalling, for mechanosensation and mechanotransduction in particular, an emerging importance for protein turnover and autophagy, as well as its molecular links to the t-tubular system and the sarcoplasmic reticulum. Moreover, the discovery of mutations in a wide variety of Z-disc proteins, which lead to perturbations of several of the above-mentioned systems, gives rise to a diverse group of diseases which can be termed Z-discopathies. This paper provides a brief overview of these novel aspects as well as points to future research directions.

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2

Wadmore, Kirsty, Amar J. Azad, and Katja Gehmlich. "The Role of Z-disc Proteins in Myopathy and Cardiomyopathy." International Journal of Molecular Sciences 22, no. 6 (March 17, 2021): 3058. http://dx.doi.org/10.3390/ijms22063058.

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The Z-disc acts as a protein-rich structure to tether thin filament in the contractile units, the sarcomeres, of striated muscle cells. Proteins found in the Z-disc are integral for maintaining the architecture of the sarcomere. They also enable it to function as a (bio-mechanical) signalling hub. Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle. This review will focus on six key Z-disc proteins: α-actinin 2, filamin C, myopalladin, myotilin, telethonin and Z-disc alternatively spliced PDZ-motif (ZASP), which have all been linked to myopathies and cardiomyopathies. We will summarise pathogenic variants identified in the six genes coding for these proteins and look at their involvement in myopathy and cardiomyopathy. Listing the Minor Allele Frequency (MAF) of these variants in the Genome Aggregation Database (GnomAD) version 3.1 will help to critically re-evaluate pathogenicity based on variant frequency in normal population cohorts.

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3

Takagi, Yasuharu, Dmitry Ushakov, Xuefei Ma, Kelsey Temprine, James R. Sellers, Hari Shroff, and Michelle Peckham. "3D Palm Shows Distinct Distributions of Z-Disc Proteins with the Z-Discs in Cardiomyocytes." Biophysical Journal 104, no. 2 (January 2013): 485a. http://dx.doi.org/10.1016/j.bpj.2012.11.2676.

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4

Bullard, Belinda, Gillian Sainsbury, and Nigel Miller. "Digestion of proteins associated with the Z-disc by calpain." Journal of Muscle Research and Cell Motility 11, no. 3 (June 1990): 271–79. http://dx.doi.org/10.1007/bf01843580.

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5

Waterman-Storer, C. M. "An immunoelectron microscopic examination of the intermediate filament protein, desmin, in exercise-damaged skeletal muscle." Proceedings, annual meeting, Electron Microscopy Society of America 49 (August 1991): 14–15. http://dx.doi.org/10.1017/s0424820100084375.

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Intense exercise has been shown to produce pathological changes in normal skeletal muscle ultrastructure. Eccentric exercise (muscle lengthening during active tension development) in particular has been shown to cause the most severe muscle damage, and studies of both human and animal tissue following eccentric exercise have documented disruption to the contractile apparatus. The disruption originates at the Z-disc, which appears broadened, smeared, or totally disrupted, with Z-discs of adjacent myofibrils out of register and running a “zig-zag” course transversely across the fiber. This condition is known as Z-line streaming. Several researchers have implicated the disruption of the intermediate filament system in the etiology of exercise-induced Z-line streaming, as these filaments are believed to link adjacent myofibrils at the level of the Z-disc. The intermediate filaments are composed predominantly of the proteins desmin and vimentin. This study utilized immunoelectron microscopic localization of desmin in order to elucidate the role of the intermediate filament system in Zline streaming of eccentrically-exercised skeletal muscle.

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6

Faulkner, Gerolamo Lanfranchi, Gior, Georgine. "Telethonin and Other New Proteins of the Z-Disc of Skeletal Muscle." IUBMB Life (International Union of Biochemistry and Molecular Biology: Life) 51, no. 5 (May 1, 2001): 275–82. http://dx.doi.org/10.1080/152165401317190761.

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7

Katzemich, Anja, Kuo-An Liao, and Frieder Schoeck. "Zasp PDZ Domain Proteins Cooperate in Z-Disc Formation and Myofibril Assembly." Biophysical Journal 104, no. 2 (January 2013): 447a. http://dx.doi.org/10.1016/j.bpj.2012.11.2481.

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8

Katzemich, Anja, Kuo An Liao, Stefan Czerniecki, and Frieder Schöck. "Alp/Enigma Family Proteins Cooperate in Z-Disc Formation and Myofibril Assembly." PLoS Genetics 9, no. 3 (March 7, 2013): e1003342. http://dx.doi.org/10.1371/journal.pgen.1003342.

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9

Bennett, Pauline M., Alison M. Maggs, Anthony J. Baines, and Jennifer C. Pinder. "The Transitional Junction: A New Functional Subcellular Domain at the Intercalated Disc." Molecular Biology of the Cell 17, no. 4 (April 2006): 2091–100. http://dx.doi.org/10.1091/mbc.e05-12-1109.

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We define here a previously unrecognized structural element close to the heart muscle plasma membrane at the intercalated disc where the myofibrils lead into the adherens junction. At this location, the plasma membrane is extensively folded. Immunofluorescence and immunogold electron microscopy reveal a spectrin-rich domain at the apex of the folds. These domains occur at the axial level of what would be the final Z-disc of the terminal sarcomere in the myofibril, although there is no Z-disc-like structure there. However, a sharp transitional boundary lies between the myofibrillar I-band and intercalated disc thin filaments, identifiable by the presence of Z-disc proteins, α-actinin, and N-terminal titin. This allows for the usual elastic positioning of the A-band in the final sarcomere, whereas the transduction of the contractile force normally associated with the Z-disc is transferred to the adherens junctions at the plasma membrane. The axial conjunction of the transitional junction with the spectrin-rich domains suggests a mechanism for direct communication between intercalated disc and contractile apparatus. In particular, it provides a means for sarcomeres to be added to the ends of the cells during growth. This is of particular relevance to understanding myocyte elongation in dilated cardiomyopathy.

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10

Kawano, Fuminori, Ryo Fujita, Naoya Nakai, Masahiro Terada, Takashi Ohira, and Yoshinobu Ohira. "HSP25 can modulate myofibrillar desmin cytoskeleton following the phosphorylation at Ser15 in rat soleus muscle." Journal of Applied Physiology 112, no. 1 (January 1, 2012): 176–86. http://dx.doi.org/10.1152/japplphysiol.00783.2011.

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The main purpose of the present study was to investigate the role(s) of 25-kDa heat shock protein (HSP25) in the regulation and integration of myofibrillar Z-disc structure during down- or upregulation of the size in rat soleus muscle fibers. Hindlimb unloading by tail suspension was performed in adult rats for 7 days, and reloading was allowed for 5 days after the termination of suspension. Interaction of HSP25 and Z-disc proteins, phosphorylation status, distribution, and complex formation of HSP25 were investigated. Non- and single-phosphorylated HSP25s were generally expressed in the cytoplasmic fraction of normal muscle. The level of total HSP25, as well as the phosphorylation ratio, did not change significantly in response to atrophy. Increased expressions of HSP25, phosphorylated at serine 15 (p-Ser15) and dual-phosphorylated form, were noted, when atrophied muscles were reloaded. Myofibrillar HSP25 was also noted in reloaded muscle. Histochemical analysis further indicated the localization of p-Ser15 in the regions with disorganization of Z-disc structure in reloaded muscle fibers. HSP25 formed a large molecular complex in the cytoplasmic fraction of normal muscle, whereas dissociation of free HSP25 with Ser15 phosphorylation was noted in reloaded muscle. The interaction of p-Ser15 with desmin and actinin was detected in Z-discs by proximity ligation assay. Strong interaction between p-Ser15 and desmin, but not actinin, was noted in the disorganized areas. These results indicated that HSP25 contributed to the desmin cytoskeletal organization following the phosphorylation at Ser15 during reloading and regrowing of soleus muscle.

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11

Stachowski-Doll, Marisa J., Maria Papadaki, Thomas G. Martin, Weikang Ma, Henry M. Gong, Stephanie Shao, Shi Shen та ін. "GSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation". Circulation Research 130, № 6 (18 березня 2022): 871–86. http://dx.doi.org/10.1161/circresaha.121.319491.

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Background: Altered kinase localization is gaining appreciation as a mechanism of cardiovascular disease. Previous work suggests GSK-3β (glycogen synthase kinase 3β) localizes to and regulates contractile function of the myofilament. We aimed to discover GSK-3β’s in vivo role in regulating myofilament function, the mechanisms involved, and the translational relevance. Methods: Inducible cardiomyocyte-specific GSK-3β knockout mice and left ventricular myocardium from nonfailing and failing human hearts were studied. Results: Skinned cardiomyocytes from knockout mice failed to exhibit calcium sensitization with stretch indicating a loss of length-dependent activation (LDA), the mechanism underlying the Frank-Starling Law. Titin acts as a length sensor for LDA, and knockout mice had decreased titin stiffness compared with control mice, explaining the lack of LDA. Knockout mice exhibited no changes in titin isoforms, titin phosphorylation, or other thin filament phosphorylation sites known to affect passive tension or LDA. Mass spectrometry identified several z-disc proteins as myofilament phospho-substrates of GSK-3β. Agreeing with the localization of its targets, GSK-3β that is phosphorylated at Y216 binds to the z-disc. We showed pY216 was necessary and sufficient for z-disc binding using adenoviruses for wild-type, Y216F, and Y216E GSK-3β in neonatal rat ventricular cardiomyocytes. One of GSK-3β’s z-disc targets, abLIM-1 (actin-binding LIM protein 1), binds to the z-disc domains of titin that are important for maintaining passive tension. Genetic knockdown of abLIM-1 via siRNA in human engineered heart tissues resulted in enhancement of LDA, indicating abLIM-1 may act as a negative regulator that is modulated by GSK-3β. Last, GSK-3β myofilament localization was reduced in left ventricular myocardium from failing human hearts, which correlated with depressed LDA. Conclusions: We identified a novel mechanism by which GSK-3β localizes to the myofilament to modulate LDA. Importantly, z-disc GSK-3β levels were reduced in patients with heart failure, indicating z-disc localized GSK-3β is a possible therapeutic target to restore the Frank-Starling mechanism in patients with heart failure.

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12

Thornell, L. E., E. Carlsson, E. Kugelberg, and B. K. Grove. "Myofibrillar M-band structure and composition of physiologically defined rat motor units." American Journal of Physiology-Cell Physiology 253, no. 3 (September 1, 1987): C456—C468. http://dx.doi.org/10.1152/ajpcell.1987.253.3.c456.

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The isometric contraction time of 19 fast and slow rat motor units in the soleus and the anterior tibial muscles were recorded. The motor unit fibers, subsequently distinguished by glycogen depletion, were histochemically differentiated into fiber types and analyzed immunohistochemically for high molecular weight M-band proteins, as well as ultrastructurally for M-band fine structure, Z-disc width, and volume density of mitochondria. All fibers belonging to slow-twitch motor units in both the anterior tibialis and soleus muscles were histochemically classed as type 1. They lacked the Mr 165,000 M-protein, showed ultrastructurally a four-line M-band pattern, and had broad Z-discs, whereas the volume density of the mitochondria varied considerably. Muscle fibers belonging to the fast-twitch motor units were histochemically classed as types 2A and 2B in anterior tibialis and type 2A in soleus. They contained a three- or a five-line M-band pattern and medium-to-thin Z-discs in the anterior tibialis and a five-line M-band pattern and broad Z-discs in the soleus. Furthermore, the volume density of mitochondria showed considerable variation within and in between soleus and anterior tibialis type 2 fibers. As the differences in M-band composition and structure between fiber types overrode the intragroup variability in contraction times of slow and fast units within and between the two muscles, it is concluded that the M-band composition and structure is fundamentally related to whether the fiber is innervated by a slow or fast motor neuron, whereas other parameters such as contraction time, Z-disc width, and mitochondrial content of fibers of fast and slow units are relative and vary between muscles. Thus the M-band appearance can be used as a reliable marker to distinguish between fibers of slow- and fast-twitch motor units in rat leg muscles.

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13

Mao, Zhenfeng, and Fumihiko Nakamura. "Structure and Function of Filamin C in the Muscle Z-Disc." International Journal of Molecular Sciences 21, no. 8 (April 13, 2020): 2696. http://dx.doi.org/10.3390/ijms21082696.

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Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding partners. FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2). The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit. FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres. Since phosphorylation of FLNC by PKC diminishes the calpain sensitivity, assembly, and disassembly of the Z-disc may be regulated by phosphorylation of FLNC. Mutations of FLNC result in cardiomyopathy and muscle weakness. Although this review will focus on the current understanding of FLNC structure and functions in muscle, we will also discuss other filamins because they share high sequence similarity and are better characterized. We will also discuss a possible role of FLNC as a mechanosensor during muscle contraction.

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14

Mavroidis, Manolis, and Yassemie Capetanaki. "Desmin is required for correct z-disc localization of small heat shock proteins in cardiac tissue." Journal of Molecular and Cellular Cardiology 33, no. 6 (June 2001): A75. http://dx.doi.org/10.1016/s0022-2828(01)90297-4.

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15

Gregorich, Zachery R., Jitandrakumar R. Patel, Wenxuan Cai, Ziqing Lin, Rachel Heurer, Daniel P. Fitzsimons, Richard L. Moss, and Ying Ge. "Deletion of Enigma Homologue from the Z-disc slows tension development kinetics in mouse myocardium." Journal of General Physiology 151, no. 5 (January 14, 2019): 670–79. http://dx.doi.org/10.1085/jgp.201812214.

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Enigma Homologue (ENH) is a component of the Z-disc, a structure that anchors actin filaments in the contractile unit of muscle, the sarcomere. Cardiac-specific ablation of ENH protein expression causes contractile dysfunction that ultimately culminates in dilated cardiomyopathy. However, whether ENH is involved in the regulation of myocardial contractility is unknown. To determine if ENH is required for the mechanical activity of cardiac muscle, we analyze muscle mechanics of isolated trabeculae from the hearts of ENH+/+ and ENH−/− mice. We detected no differences in steady-state mechanical properties but show that when muscle fibers are allowed to relax and then are restretched, the rate at which tension redevelops is depressed in ENH−/− mouse myocardium relative to that in ENH+/+ myocardium. SDS-PAGE analysis demonstrated that the expression of β-myosin heavy chain is increased in ENH−/− mouse myocardium, which could partially, but not completely, account for the depression in tension redevelopment kinetics. Using top-down proteomics analysis, we found that the expression of other thin/thick filament regulatory proteins is unaltered, although the phosphorylation of a cardiac troponin T isoform, cardiac troponin I, and myosin regulatory light chain is decreased in ENH−/− mouse myocardium. Nevertheless, these alterations are very small and thus insufficient to explain slowed tension redevelopment kinetics in ENH−/− mouse myocardium. These data suggest that the ENH protein influences tension redevelopment kinetics in mouse myocardium, possibly by affecting cross-bridge cycling kinetics. Previous studies also indicate that ablation of specific Z-disc proteins in myocardium slows contraction kinetics, which could also be a contributing factor in this study.

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16

von Nandelstadh, Pernilla, Mohamed Ismail, Chiara Gardin, Heli Suila, Ivano Zara, Anna Belgrano, Giorgio Valle, Olli Carpen, and Georgine Faulkner. "A Class III PDZ Binding Motif in the Myotilin and FATZ Families Binds Enigma Family Proteins: a Common Link for Z-Disc Myopathies." Molecular and Cellular Biology 29, no. 3 (December 1, 2008): 822–34. http://dx.doi.org/10.1128/mcb.01454-08.

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ABSTRACT Interactions between Z-disc proteins regulate muscle functions and disruption of these interactions results in muscle disorders. Mutations in Z-disc components myotilin, ZASP/Cypher, and FATZ-2 (calsarcin-1/myozenin-2) are associated with myopathies. We report here that the myotilin and the FATZ (calsarcin/myozenin) families share high homology at their final C-terminal five amino acids. This C-terminal E[ST][DE][DE]L motif is present almost exclusively in these families and is evolutionary conserved. We show by in vitro and in vivo studies that proteins from the myotilin and FATZ (calsarcin/myozenin) families interact via this novel type of class III PDZ binding motif with the PDZ domains of ZASP/Cypher and other Enigma family members: ALP, CLP-36, and RIL. We show that the interactions can be modulated by phosphorylation. Calmodulin-dependent kinase II phosphorylates the C terminus of FATZ-3 (calsarcin-3/myozenin-3) and myotilin, whereas PKA phosphorylates that of FATZ-1 (calsarcin-2/myozenin-1) and FATZ-2 (calsarcin-1/myozenin-1). This is the first report of a binding motif common to both the myotilin and the FATZ (calsarcin/myozenin) families that is specific for interactions with Enigma family members.

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17

Won, Jong-Heon, Kyung-Sook Chung, Eun-Young Park, Jeong-Hun Lee, Jung-Hye Choi, Leon Tapondjou, Hee-Juhn Park, Masaaki Nomura, Ahmed Hassan, and Kyung-Tae Lee. "23-Hydroxyursolic Acid Isolated from the Stem Bark of Cussonia bancoensis Induces Apoptosis through Fas/Caspase-8-Dependent Pathway in HL-60 Human Promyelocytic Leukemia Cells." Molecules 23, no. 12 (December 13, 2018): 3306. http://dx.doi.org/10.3390/molecules23123306.

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The natural product 23-hydroxyursolic acid (23-HUA) is a derivative of ursolic acid, which is known to induce cancer cell apoptosis. However, apoptotic effects and mechanisms of 23-HUA have not been well characterized yet. Herein, we investigated the molecular mechanisms of 23-HUA-induced apoptosis in HL-60 human promyelocytic leukemia cells. 23-HUA-treated HL-60 cells showed apoptotic features including internucleosomal DNA condensation and fragmentation as well as externalization of phosphatidylserine residues. 23-HUA induced a series of mitochondrial events including disruption of mitochondrial membrane potential (ΔΨm), cytochrome c and Smac/DIABLO release and loss of balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins in HL-60 cells. In addition, 23-HUA activated caspase-8, caspase-9 and caspase-3. Pretreatment with a broad caspase inhibitor (z-VAD-fmk), a caspase-3 inhibitor (z-DEVD-fmk), and a caspase-8 inhibitor (z-IETD-fmk) significantly attenuated 23-HUA-induced DNA fragmentation. After 23-HUA-induced apoptosis, proteins expression levels of FasL, Fas and FADD constituting the death-inducing signaling complex (DISC) were upregulated in HL-60 cells. Moreover, transfection with Fas or FADD siRNA significantly blocked 23-HUA-induced DNA fragmentation and caspases activation. Taken together, these findings indicate that 23-HUA induces apoptosis in HL-60 human promyelocytic leukemia cells through formation of DISC and caspase-8 activation leading to loss of ΔΨm and caspase-3 activation.

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18

Lin, X., L. Brubaker, I. Bajraktari, R. Ohman, R. Griggs, K. Fischbeck, and A. Mankodi. "P.15.3 Effects of ZASP mutations on Z-disc proteins associated with myofibrillar myopathy in skeletal muscle." Neuromuscular Disorders 23, no. 9-10 (October 2013): 819. http://dx.doi.org/10.1016/j.nmd.2013.06.628.

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19

Agarwal, Radhika, Joao A. Paulo, Christopher N. Toepfer, Jourdan K. Ewoldt, Subramanian Sundaram, Anant Chopra, Qi Zhang, et al. "Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation." Circulation Research 129, no. 7 (September 17, 2021): 751–66. http://dx.doi.org/10.1161/circresaha.120.317076.

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Rationale: Dominant heterozygous variants in filamin C ( FLNC ) cause diverse cardiomyopathies, although the underlying molecular mechanisms remain poorly understood. Objective: We aimed to define the molecular mechanisms by which FLNC variants altered human cardiomyocyte gene and protein expression, sarcomere structure, and contractile performance. Methods and Results: Using CRISPR/Cas9, we introduced FLNC variants into human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). We compared isogenic hiPSC-CMs with normal (wild-type), ablated expression ( FLNC −/− ), or haploinsufficiency ( FLNC +/− ) that causes dilated cardiomyopathy. We also studied a heterozygous in-frame deletion ( FLNC +/Δ7aa ) which did not affect FLNC expression but caused aggregate formation, similar to FLNC variants associated with hypertrophic cardiomyopathy. FLNC −/− hiPSC-CMs demonstrated profound sarcomere misassembly and reduced contractility. Although sarcomere formation and function were unaffected in FLNC +/ − and FLNC +/Δ7aa hiPSC-CMs, these heterozygous variants caused increases in lysosome content, enhancement of autophagic flux, and accumulation of FLNC-binding partners and Z-disc proteins. Conclusions: FLNC expression is required for sarcomere organization and physiological function. Variants that produce misfolded FLNC proteins cause the accumulation of FLNC and FLNC-binding partners which leads to increased lysosome expression and activation of autophagic pathways. Surprisingly, similar pathways were activated in FLNC haploinsufficient hiPSC-CMs, likely initiated by the loss of stoichiometric FLNC protein interactions and impaired turnover of proteins at the Z-disc. These results indicate that both FLNC haploinsufficient variants and variants that produce misfolded FLNC protein cause disease by similar proteotoxic mechanisms and indicate the therapeutic potential for augmenting protein degradative pathways to treat a wide range of FLNC -related cardiomyopathies.

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20

Ferguson, C., A. Lakey, A. Hutchings, G. W. Butcher, K. R. Leonard, and B. Bullard. "Cytoskeletal proteins of insect muscle: location of zeelins in Lethocerus flight and leg muscle." Journal of Cell Science 107, no. 5 (May 1, 1994): 1115–29. http://dx.doi.org/10.1242/jcs.107.5.1115.

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Asynchronous insect flight muscles produce oscillatory contractions and can contract at high frequency because they are activated by stretch as well as by Ca2+. Stretch activation depends on the high stiffness of the fibres and the regular structure of the filament lattice. Cytoskeletal proteins may be important in stabilising the lattice. Two proteins, zeelin 1 (35 kDa) and zeelin 2 (23 kDa), have been isolated from the cytoskeletal fraction of Lethocerus flight muscle. Both zeelins have multiple isoforms of the same molecular mass and different charge. Zeelin 1 forms micelles and zeelin 2 forms filaments when renatured in low ionic strength solutions. Filaments of zeelin 2 are ribbons 10 nm wide and 3 nm thick. The position of zeelins in fibres from Lethocerus flight and leg muscle was determined by immunofluorescence and immunoelectron microscopy. Zeelin 1 is found in flight and leg fibres and zeelin 2 only in flight fibres. In flight myofibrils, both zeelins are in discrete regions of the A-band in each half sarcomere. Zeelin 1 is across the whole A-band in leg myofibrils. Zeelins are not in the Z-disc, as was thought previously, but migrate to the Z-disc in glycerinated fibres. Zeelins are associated with thick filaments and analysis of oblique sections showed that zeelin 1 is closer to the filament shaft than zeelin 2. The antibody labelling pattern is consistent with zeelin molecules associated with myosin near the end of the rod region. Alternatively, the position of zeelins may be determined by other A-band proteins. There are about 2.0 to 2.5 moles of myosin per mole of each zeelin. The function of these cytoskeletal proteins may be to maintain the ordered structure of the thick filament.

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21

Frey, Norbert, and Eric N. Olson. "Calsarcin-3, a Novel Skeletal Muscle-specific Member of the Calsarcin Family, Interacts with Multiple Z-disc Proteins." Journal of Biological Chemistry 277, no. 16 (February 12, 2002): 13998–4004. http://dx.doi.org/10.1074/jbc.m200712200.

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22

HOSHIJIMA, M., M. PASHMFOROUSH, R. KNOLL, and K. R. CHIEN. "The MLP Family of Cytoskeletal Z Disc Proteins and Dilated Cardiomyopathy: A Stress Pathway Model for Heart Failure Progression." Cold Spring Harbor Symposia on Quantitative Biology 67 (January 1, 2002): 399–408. http://dx.doi.org/10.1101/sqb.2002.67.399.

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23

van der Ven, P. F., J. W. Bartsch, M. Gautel, H. Jockusch, and D. O. Furst. "A functional knock-out of titin results in defective myofibril assembly." Journal of Cell Science 113, no. 8 (April 15, 2000): 1405–14. http://dx.doi.org/10.1242/jcs.113.8.1405.

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Titin, also called connectin, is a giant muscle protein that spans the distance from the sarcomeric Z-disc to the M-band. Titin is thought to direct the assembly of sarcomeres and to maintain sarcomeric integrity by interacting with numerous sarcomeric proteins and providing a mechanical linkage. Since severe defects of such an important molecule are likely to result in embryonic lethality, a cell culture model should offer the best practicable tool to probe the cellular functions of titin. The myofibroblast cell line BHK-21/C13 was described to assemble myofibrils in culture. We have now characterized the sub-line BHK-21-Bi, which bears a small deletion within the titin gene. RNA analysis revealed that in this mutant cell line only a small internal portion of the titin mRNA is deleted. However, western blots, immunofluorescence microscopy and immunoprecipitation experiments showed that only the N-terminal, approx. 100 kDa central Z-disc portion of the 3 MDa titin protein is expressed, due to the homozygous deletion in the gene. Most importantly, in BHK-21-Bi cells the formation of thick myosin filaments and the assembly of myofibrils are impaired, although sarcomeric proteins are expressed. Lack of thick filament formation and of ordered actin-myosin arrays was confirmed by electron microscopy. Myogenisation induced by transfection with MyoD yielded myofibrils only in myotubes formed from wild type and not from mutant cells, ruling out that a principal failure in myogenic commitment of the BHK-21-Bi cells might cause the observed effects. These experiments provide the first direct evidence for the crucial role of titin in both thick filament formation as a molecular ruler and in the coordination of myofibrillogenesis.

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24

Solís, Christopher, Elisabeth DiNello, Chad M. Warren, Kyle Dittloff, and R. John Solaro. "Whole-cell mechanical loading and unloading triggers more post-translational modifications in Z-disc proteins than myosin activators and inhibitors." Biophysical Journal 121, no. 3 (February 2022): 434a. http://dx.doi.org/10.1016/j.bpj.2021.11.597.

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25

Knyazeva, A. A., N. A. Smolina, I. Y. Kasherininov, S. L. Verbilo, and A. A. Kostareva. "EXPRESSION OF GENES ENCODING Z-DISC PROTEINS IN CARDIAC HYPERTROPHY CAUSED BY RENOVASCULAR HYPERTENSION IN «2 KIDNEY, 1 CLIP» MODEL." Translational Medicine 4, no. 5 (January 1, 2017): 61–68. http://dx.doi.org/10.18705/2311-4495-2017-4-5-61-68.

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Kao, Shao-Yen, Elena Nikonova, Sabrina Chaabane, Albiona Sabani, Alexandra Martitz, Anja Wittner, Jakob Heemken, Tobias Straub, and Maria L. Spletter. "A Candidate RNAi Screen Reveals Diverse RNA-Binding Protein Phenotypes in Drosophila Flight Muscle." Cells 10, no. 10 (September 22, 2021): 2505. http://dx.doi.org/10.3390/cells10102505.

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The proper regulation of RNA processing is critical for muscle development and the fine-tuning of contractile ability among muscle fiber-types. RNA binding proteins (RBPs) regulate the diverse steps in RNA processing, including alternative splicing, which generates fiber-type specific isoforms of structural proteins that confer contractile sarcomeres with distinct biomechanical properties. Alternative splicing is disrupted in muscle diseases such as myotonic dystrophy and dilated cardiomyopathy and is altered after intense exercise as well as with aging. It is therefore important to understand splicing and RBP function, but currently, only a small fraction of the hundreds of annotated RBPs expressed in muscle have been characterized. Here, we demonstrate the utility of Drosophila as a genetic model system to investigate basic developmental mechanisms of RBP function in myogenesis. We find that RBPs exhibit dynamic temporal and fiber-type specific expression patterns in mRNA-Seq data and display muscle-specific phenotypes. We performed knockdown with 105 RNAi hairpins targeting 35 RBPs and report associated lethality, flight, myofiber and sarcomere defects, including flight muscle phenotypes for Doa, Rm62, mub, mbl, sbr, and clu. Knockdown phenotypes of spliceosome components, as highlighted by phenotypes for A-complex components SF1 and Hrb87F (hnRNPA1), revealed level- and temporal-dependent myofibril defects. We further show that splicing mediated by SF1 and Hrb87F is necessary for Z-disc stability and proper myofibril development, and strong knockdown of either gene results in impaired localization of kettin to the Z-disc. Our results expand the number of RBPs with a described phenotype in muscle and underscore the diversity in myofibril and transcriptomic phenotypes associated with splicing defects. Drosophila is thus a powerful model to gain disease-relevant insight into cellular and molecular phenotypes observed when expression levels of splicing factors, spliceosome components and splicing dynamics are altered.

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Yang, Fenghua, David L. Aiello та W. Glen Pyle. "Cardiac myofilament regulation by protein phosphatase type 1α and CapZ". Biochemistry and Cell Biology 86, № 1 (лютий 2008): 70–78. http://dx.doi.org/10.1139/o07-150.

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Myofilament regulation by protein kinases is well characterized, but relatively little is known about protein phosphatase control of myofilaments. Increased protein phosphatase type 1 (PP1) activity observed in failing hearts underscores the need for investigation of this intracellular signal, including the elements that regulate its activity. The Z-disc protein CapZ controls protein kinase C (PKC) regulation of cardiac myofilaments, but whether this effect is specific to PKC, or CapZ plays a general role in intracellular signalling, is not known. We sought to determine how the α isoform of PP1 (PP1α) regulates murine cardiac myofilaments and whether CapZ influences PP1α-dependent regulation of cardiac myofilaments. Immunoblot analysis showed PP1α binding to cardiac myofilaments. Exogenous PP1α increased myofilament Ca2+ sensitivity and maximal actomyosin Mg2+-ATPase activity while dephosphorylating myosin binding protein C, troponin T, troponin I, and myosin light chain 2. Extraction of CapZ decreased myofilament-associated PP1α and attenuated the effects of PP1α on myofilament activation. PP1α-dependent dephosphorylation of myofilament proteins was reduced with CapZ extraction, except for troponin I. Extracting CapZ after PP1α treatment allowed most of the PP1α-dependent effects on myofilament activation to remain, indicating that CapZ removal modestly desensitizes cardiac myofilaments to dephosphorylation. Our results demonstrate myofilament regulation by PP1α and support the concept that cardiac Z-discs are vital components in intracellular signalling.

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Henry, Marisa L., Deborah Velez-Irizarry, Joe D. Pagan, Lorraine Sordillo, Jeff Gandy, and Stephanie J. Valberg. "The Impact of N-Acetyl Cysteine and Coenzyme Q10 Supplementation on Skeletal Muscle Antioxidants and Proteome in Fit Thoroughbred Horses." Antioxidants 10, no. 11 (October 30, 2021): 1739. http://dx.doi.org/10.3390/antiox10111739.

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Horses have one of the highest skeletal muscle oxidative capacities amongst mammals, which, combined with a high glycolytic capacity, could perturb redox status during maximal exercise. We determined the effect of 30 d of oral coenzyme Q10 and N-acetyl-cysteine supplementation (NACQ) on muscle glutathione (GSH), cysteine, ROS, and coenzyme Q10 concentrations, and the muscle proteome, in seven maximally exercising Thoroughbred horses using a placebo and randomized cross-over design. Gluteal muscle biopsies were obtained the day before and 1 h after maximal exercise. Concentrations of GSH, cysteine, coenzyme Q10, and ROS were measured, and citrate synthase, glutathione peroxidase, and superoxide dismutase activities analyzed. GSH increased significantly 1 h post-exercise in the NACQ group (p = 0.022), whereas other antioxidant concentrations/activities were unchanged. TMT proteomic analysis revealed 40 differentially expressed proteins with NACQ out of 387 identified, including upregulation of 13 mitochondrial proteins (TCA cycle and NADPH production), 4 Z-disc proteins, and down regulation of 9 glycolytic proteins. NACQ supplementation significantly impacted muscle redox capacity after intense exercise by enhancing muscle glutathione concentrations and increasing expression of proteins involved in the uptake of glutathione into mitochondria and the NAPDH-associated reduction of oxidized glutathione, without any evident detrimental effects on performance.

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29

Riaz, Muhammad, Jinkyu Park, Lorenzo R. Sewanan, Yongming Ren, Jonas Schwan, Subhash K. Das, Pawel T. Pomianowski, et al. "Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy." Circulation 145, no. 16 (April 19, 2022): 1238–53. http://dx.doi.org/10.1161/circulationaha.121.056265.

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Background: Familial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics. Methods: Our discovery was based on insights from a severe phenotype of an individual with HCM and a second genetic alteration in a sarcomeric mechanosensing protein. We derived cardiomyocytes from patient-specific induced pluripotent stem cells and developed robust engineered heart tissues by seeding induced pluripotent stem cell–derived cardiomyocytes into a laser-cut scaffold possessing native cardiac fiber alignment to study human cardiac mechanobiology at both the cellular and tissue levels. Coupled with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions, we have identified a new mechanotransduction pathway in HCM, shown to be essential in modulating the phenotypic expression of HCM in 5 families bearing distinct sarcomeric mutations. Results: Enhanced actomyosin crossbridge formation caused by sarcomeric mutations in cardiac myosin heavy chain ( MYH7 ) led to increased force generation, which, when coupled with slower twitch relaxation, destabilized the MLP (muscle LIM protein) stretch-sensing complex at the Z-disc. Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin–nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy. We demonstrate that the common muscle LIM protein–W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation. By mitigating enhanced actomyosin crossbridge formation through either genetic or pharmacological means, we alleviated stress at the Z-disc, preventing the development of hypertrophy associated with sarcomeric mutations. Conclusions: Our studies have uncovered a novel biomechanical mechanism through which dysregulated sarcomeric force production is sensed and leads to pathological signaling, remodeling, and hypertrophic responses. Together, these establish the foundation for developing innovative mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex.

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Gontier, Y. "The Z-disc proteins myotilin and FATZ-1 interact with each other and are connected to the sarcolemma via muscle-specific filamins." Journal of Cell Science 118, no. 16 (August 15, 2005): 3739–49. http://dx.doi.org/10.1242/jcs.02484.

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Yang, Jiacheng, Judith A. Drazba, Donald G. Ferguson, and Meredith Bond. "A-kinase Anchoring Protein 100 (AKAP100) is Localized in Multiple Subcellular Compartments in the Adult Rat Heart." Journal of Cell Biology 142, no. 2 (July 27, 1998): 511–22. http://dx.doi.org/10.1083/jcb.142.2.511.

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Stimulation of β-adrenergic receptors activates type I and II cyclic AMP–dependent protein kinase A, resulting in phosphorylation of various proteins in the heart. It has been proposed that PKA II compartmentalization by A-kinase–anchoring proteins (AKAPs) regulates cyclic AMP–dependent signaling in the cell. We investigated the expression and localization of AKAP100 in adult hearts. By immunoblotting, we identified AKAP100 in adult rat and human hearts, and showed that type I and II regulatory (RI and II) subunits of PKA are present in the rat heart. By immunofluorescence and confocal microscopy of rat cardiac myocytes and cryostat sections of rat left ventricle papillary muscles, we localized AKAP100 to the nucleus, sarcolemma, intercalated disc, and at the level of the Z-line. After double immunostaining of transverse cross-sections of the papillary muscles with AKAP100 plus α-actinin–specific antibodies or AKAP100 plus ryanodine receptor–specific antibodies, confocal images showed AKAP100 localization at the region of the transverse tubule/junctional sarcoplasmic reticulum. RI is distributed differently from RII in the myocytes. RII, but not RI, was colocalized with AKAP100 in the rat heart. Our studies suggest that AKAP100 tethers PKA II to multiple subcellular compartments for phosphorylation of different pools of substrate proteins in the heart.

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Berger, Joachim, Silke Berger, Yu Shan G. Mok, Mei Li, Hakan Tarakci та Peter D. Currie. "Genetic dissection of novel myopathy models reveals a role of CapZα and Leiomodin 3 during myofibril elongation". PLOS Genetics 18, № 2 (11 лютого 2022): e1010066. http://dx.doi.org/10.1371/journal.pgen.1010066.

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Myofibrils within skeletal muscle are composed of sarcomeres that generate force by contraction when their myosin-rich thick filaments slide past actin-based thin filaments. Although mutations in components of the sarcomere are a major cause of human disease, the highly complex process of sarcomere assembly is not fully understood. Current models of thin filament assembly highlight a central role for filament capping proteins, which can be divided into three protein families, each ascribed with separate roles in thin filament assembly. CapZ proteins have been shown to bind the Z-disc protein α-actinin to form an anchoring complex for thin filaments and actin polymerisation. Subsequent thin filaments extension dynamics are thought to be facilitated by Leiomodins (Lmods) and thin filament assembly is concluded by Tropomodulins (Tmods) that specifically cap the pointed end of thin filaments. To study thin filament assembly in vivo, single and compound loss-of-function zebrafish mutants within distinct classes of capping proteins were analysed. The generated lmod3- and capza1b-deficient zebrafish exhibited aspects of the pathology caused by variations in their human orthologs. Although loss of the analysed main capping proteins of the skeletal muscle, capza1b, capza1a, lmod3 and tmod4, resulted in sarcomere defects, residual organised sarcomeres were formed within the assessed mutants, indicating that these proteins are not essential for the initial myofibril assembly. Furthermore, detected similarity and location of myofibril defects, apparent at the peripheral ends of myofibres of both Lmod3- and CapZα-deficient mutants, suggest a function in longitudinal myofibril growth for both proteins, which is molecularly distinct to the function of Tmod4.

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Atomi, Yoriko, Eri Fujita-Ohto, Tetsuo Yamaguchi, Takashi Sakurai, and Yoshinobu Fujita. "1P148 Analysis of dynamic interaction of aB-crystallin with Z-disc protein in beating cardiac myocyte(Muscle-muscle proteins and contraction,Oral Presentations)." Seibutsu Butsuri 47, supplement (2007): S60. http://dx.doi.org/10.2142/biophys.47.s60_3.

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34

Lehti, T. Maarit, Mika Silvennoinen, Riikka Kivelä, Heikki Kainulainen, and Jyrki Komulainen. "Effects of streptozotocin-induced diabetes and physical training on gene expression of titin-based stretch-sensing complexes in mouse striated muscle." American Journal of Physiology-Endocrinology and Metabolism 292, no. 2 (February 2007): E533—E542. http://dx.doi.org/10.1152/ajpendo.00229.2006.

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In striated muscle, a sarcomeric noncontractile protein, titin, is proposed to form the backbone of the stress- and strain-sensing structures. We investigated the effects of diabetes, physical training, and their combination on the gene expression of proteins of putative titin stretch-sensing complexes in skeletal and cardiac muscle. Mice were divided into control (C), training (T), streptozotocin-induced diabetic (D), and diabetic training (DT) groups. Training groups performed for 1, 3, or 5 wk of endurance training on a motor-driven treadmill. Muscle samples from T and DT groups together with respective controls were collected 24 h after the last training session. Gene expression of calf muscles (soleus, gastrocnemius, and plantaris) and cardiac muscle were analyzed using microarray and quantitative PCR. Diabetes induced changes in mRNA expression of the proteins of titin stretch-sensing complexes in Z-disc (MLP, myostatin), I-band (CARP, Ankrd2), and M-line (titin kinase signaling). Training alleviated diabetes-induced changes in most affected mRNA levels in skeletal muscle but only one change in cardiac muscle. In conclusion, we showed diabetes-induced changes in mRNA levels of several fiber-type-biased proteins (MLP, myostatin, Ankrd2) in skeletal muscle. These results are consistent with previous observations of diabetes-induced atrophy leading to slower fiber type composition. The ability of exercise to alleviate diabetes-induced changes may indicate slower transition of fiber type.

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Chun, M., and S. Falkenthal. "Ifm(2)2 is a myosin heavy chain allele that disrupts myofibrillar assembly only in the indirect flight muscle of Drosophila melanogaster." Journal of Cell Biology 107, no. 6 (December 1, 1988): 2613–21. http://dx.doi.org/10.1083/jcb.107.6.2613.

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Using a combination of molecular and genetic techniques we demonstrate that Ifm(2)2 is an allele of the single-copy sarcomeric myosin heavy chain gene. Flies homozygous for this allele accumulate wild-type levels of mRNA and protein in tubular muscle of adults, but fail to accumulate detectable amounts of myosin heavy chain mRNA or protein in the indirect flight muscle. We propose that the mutation interferes with either transcription of the gene or splicing of the primary transcript in the indirect flight muscle and not in other muscle tissues. Biochemical and electron microscopic analysis of flies homozygous for this mutation has revealed that thick filament assembly is abolished in the indirect flight muscle resulting in the instability of wild-type thick filament proteins. In contrast, thin filament and Z disc assembly are marginally affected. We discuss a working hypothesis for sarcomere assembly and define and experimental approach to test the predictions of this proposed pathway for sarcomere assembly.

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Beall, C. J., and E. Fyrberg. "Muscle abnormalities in Drosophila melanogaster heldup mutants are caused by missing or aberrant troponin-I isoforms." Journal of Cell Biology 114, no. 5 (September 1, 1991): 941–51. http://dx.doi.org/10.1083/jcb.114.5.941.

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We have investigated the molecular bases of muscle abnormalities in four Drosophila melanogaster heldup mutants. We find that the heldup gene encodes troponin-I, one of the principal regulatory proteins associated with skeletal muscle thin filaments. heldup3, heldup4, and heldup5 mutants, all of which have grossly abnormal flight muscle myofibrils, lack mRNAs encoding one or more troponin-I isoforms. In contrast, heldup2, an especially interesting mutant wherein flight muscles are atrophic, synthesizes the complete mRNA complement. By sequencing mutant troponin-I cDNAs we demonstrate that the molecular basis for muscle degeneration in heldup2 is conversion of an invariant alanine residue to valine. We finally show that degeneration of heldup2 thin filament/Z-disc networks can be prevented by eliminating thick filaments from flight muscles using a null allele of the sarcomeric myosin heavy chain gene. This latter observation suggests that actomyosin interactions exacerbate the structural or functional defect resulting from the troponin-I mutation.

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Francis, G. R., and R. H. Waterston. "Muscle organization in Caenorhabditis elegans: localization of proteins implicated in thin filament attachment and I-band organization." Journal of Cell Biology 101, no. 4 (October 1, 1985): 1532–49. http://dx.doi.org/10.1083/jcb.101.4.1532.

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The body wall muscle cells of Caenorhabditis elegans contain an obliquely striated myofibrillar lattice that is associated with the cell membrane through two structures: an M-line analogue in the A-band and a Z-disc analogue, or dense-body, in the I-band. By using a fraction enriched in these structures as an immunogen for hybridoma production, we prepared monoclonal antibodies that identify four components of the I-band as determined by immunofluorescence and Western transfer analysis. A major constituent of the dense-body is a 107,000-D polypeptide that shares determinants with vertebrate alpha-actinin. A second dense-body constituent is a more basic and antigenically distinct 107,000-D polypeptide that is localized to a narrow domain of the dense-body at or subjacent to the plasma membrane. This basic dense-body polypeptide is also found at certain cell boundaries where thin filaments in half-bands terminate at membrane-associated structures termed attachment plaques. A third, unidentified antigen is also found closely apposed to the cell membrane in regions of not only the dense-body and attachment plaque, but also the M-line analogue. Finally, a fourth high molecular weight antigen, composed of two polypeptides of approximately 400,000-D, is localized to the I-band regions surrounding the dense-body. The attachment of the dense-body to the cell surface and the differential localization of the dense-body-associated antigens suggest a model for their organization in which the unidentified antigen is a cell surface component, and the two 107,000-D polypeptides define different cytoplasmic domains of the dense-body.

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Ye, Maosen, Fei Ye, Liutao He, Yiping Liu, Xiaoling Zhao, Huadong Yin, Diyan Li, Hengyong Xu, Qing Zhu, and Yan Wang. "Molecular Cloning, Expression Profiling, and Marker Validation of the Chicken Myoz3 Gene." BioMed Research International 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/5930918.

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Myozenin3 (Myoz3) has been reported to bind multiple Z-disc proteins and hence play a key role in signal transduction and muscle fiber type differentiation. The purpose of current study is to better understand the basic characteristics of Myoz3. Firstly, we cloned the ORF (open reading frame) of the Myoz3 gene. AA (amino acid) sequence analysis revealed that the Myoz3 gene encodes a 26 kDa protein which have 97% identities with that of turkey. Expression profiling showed that Myoz3 mRNA is mainly expressed in leg muscle and breast muscle. Furthermore, we investigated Myoz3 gene polymorphisms in two broiler breeds, the Yellow Bantam (YB) and the Avian. Five SNPs (single nucleotide polymorphisms) were identified in the YB breed and 3 were identified in the Avian breed. Genotypes and haplotype were constructed and their associations with carcass traits were analyzed. In the YB breed, c.516 C>T had a strong effect on both shank bone length and the L⁎ value of breast muscle, and the H1H3 diplotype had the highest FC compared to other diplotypes. The markers identified in this study may serve as useful targets for the marker-assisted selection (MAS) of growth and meat quality traits in chickens.

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Kulke, Michael, Ciprian Neagoe, Bernhard Kolmerer, Ave Minajeva, Horst Hinssen, Belinda Bullard, and Wolfgang A. Linke. "Kettin, a major source of myofibrillar stiffness in Drosophila indirect flight muscle." Journal of Cell Biology 154, no. 5 (September 3, 2001): 1045–58. http://dx.doi.org/10.1083/jcb.200104016.

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Kettin is a high molecular mass protein of insect muscle that in the sarcomeres binds to actin and α-actinin. To investigate kettin's functional role, we combined immunolabeling experiments with mechanical and biochemical studies on indirect flight muscle (IFM) myofibrils of Drosophila melanogaster. Micrographs of stretched IFM sarcomeres labeled with kettin antibodies revealed staining of the Z-disc periphery. After extraction of the kettin-associated actin, the A-band edges were also stained. In contrast, the staining pattern of projectin, another IFM–I-band protein, was not altered by actin removal. Force measurements were performed on single IFM myofibrils to establish the passive length-tension relationship and record passive stiffness. Stiffness decreased within seconds during gelsolin incubation and to a similar degree upon kettin digestion with μ-calpain. Immunoblotting demonstrated the presence of kettin isoforms in normal Drosophila IFM myofibrils and in myofibrils from an actin-null mutant. Dotblot analysis revealed binding of COOH-terminal kettin domains to myosin. We conclude that kettin is attached not only to actin but also to the end of the thick filament. Kettin along with projectin may constitute the elastic filament system of insect IFM and determine the muscle's high stiffness necessary for stretch activation. Possibly, the two proteins modulate myofibrillar stiffness by expressing different size isoforms.

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Candasamy, Alexandra J., Robert S. Haworth, Friederike Cuello, Michael Ibrahim, Sriram Aravamudhan, Marcus Krüger, Mark R. Holt, et al. "Phosphoregulation of the Titin-cap Protein Telethonin in Cardiac Myocytes." Journal of Biological Chemistry 289, no. 3 (November 26, 2013): 1282–93. http://dx.doi.org/10.1074/jbc.m113.479030.

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Telethonin (also known as titin-cap or t-cap) is a muscle-specific protein whose mutation is associated with cardiac and skeletal myopathies through unknown mechanisms. Our previous work identified cardiac telethonin as an interaction partner for the protein kinase D catalytic domain. In this study, kinase assays used in conjunction with MS and site-directed mutagenesis confirmed telethonin as a substrate for protein kinase D and Ca2+/calmodulin-dependent kinase II in vitro and identified Ser-157 and Ser-161 as the phosphorylation sites. Phosphate affinity electrophoresis and MS revealed endogenous telethonin to exist in a constitutively bis-phosphorylated form in isolated adult rat ventricular myocytes and in mouse and rat ventricular myocardium. Following heterologous expression in myocytes by adenoviral gene transfer, wild-type telethonin became bis-phosphorylated, whereas S157A/S161A telethonin remained non-phosphorylated. Nevertheless, both proteins localized predominantly to the sarcomeric Z-disc, where they partially replaced endogenous telethonin. Such partial replacement with S157A/S161A telethonin disrupted transverse tubule organization and prolonged the time to peak of the intracellular Ca2+ transient and increased its variance. These data reveal, for the first time, that cardiac telethonin is constitutively bis-phosphorylated and suggest that such phosphorylation is critical for normal telethonin function, which may include maintenance of transverse tubule organization and intracellular Ca2+ transients.

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Sponga, Antonio, Joan L. Arolas, Thomas C. Schwarz, Cy M. Jeffries, Ariadna Rodriguez Chamorro, Julius Kostan, Andrea Ghisleni та ін. "Order from disorder in the sarcomere: FATZ forms a fuzzy but tight complex and phase-separated condensates with α-actinin". Science Advances 7, № 22 (травень 2021): eabg7653. http://dx.doi.org/10.1126/sciadv.abg7653.

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Анотація:

In sarcomeres, α-actinin cross-links actin filaments and anchors them to the Z-disk. FATZ (filamin-, α-actinin-, and telethonin-binding protein of the Z-disk) proteins interact with α-actinin and other core Z-disk proteins, contributing to myofibril assembly and maintenance. Here, we report the first structure and its cellular validation of α-actinin-2 in complex with a Z-disk partner, FATZ-1, which is best described as a conformational ensemble. We show that FATZ-1 forms a tight fuzzy complex with α-actinin-2 and propose an interaction mechanism via main molecular recognition elements and secondary binding sites. The obtained integrative model reveals a polar architecture of the complex which, in combination with FATZ-1 multivalent scaffold function, might organize interaction partners and stabilize α-actinin-2 preferential orientation in Z-disk. Last, we uncover FATZ-1 ability to phase-separate and form biomolecular condensates with α-actinin-2, raising the question whether FATZ proteins can create an interaction hub for Z-disk proteins through membraneless compartmentalization during myofibrillogenesis.

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Fowler, V. M., M. A. Sussmann, P. G. Miller, B. E. Flucher, and M. P. Daniels. "Tropomodulin is associated with the free (pointed) ends of the thin filaments in rat skeletal muscle." Journal of Cell Biology 120, no. 2 (January 15, 1993): 411–20. http://dx.doi.org/10.1083/jcb.120.2.411.

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The length and spatial organization of thin filaments in skeletal muscle sarcomeres are precisely maintained and are essential for efficient muscle contraction. While the major structural components of skeletal muscle sarcomeres have been well characterized, the mechanisms that regulate thin filament length and spatial organization are not well understood. Tropomodulin is a new, 40.6-kD tropomyosin-binding protein from the human erythrocyte membrane skeleton that binds to one end of erythrocyte tropomyosin and blocks head-to-tail association of tropomyosin molecules along actin filaments. Here we show that rat psoas skeletal muscle contains tropomodulin based on immunoreactivity, identical apparent mobility on SDS gels, and ability to bind muscle tropomyosin. Results from immunofluorescence labeling of isolated myofibrils at resting and stretched lengths using anti-erythrocyte tropomodulin antibodies indicate that tropomodulin is localized at or near the free (pointed) ends of the thin filaments; this localization is not dependent on the presence of myosin thick filaments. Immunoblotting of supernatants and pellets obtained after extraction of myosin from myofibrils also indicates that tropomodulin remains associated with the thin filaments. 1.2-1.6 copies of muscle tropomodulin are present per thin filament in myofibrils, supporting the possibility that one or two tropomodulin molecules may be associated with the two terminal tropomyosin molecules at the pointed end of each thin filament. Although a number of proteins are associated with the barbed ends of the thin filaments at the Z disc, tropomodulin is the first protein to be specifically located at or near the pointed ends of the thin filaments. We propose that tropomodulin may cap the tropomyosin polymers at the pointed end of the thin filament and play a role in regulating thin filament length.

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Koh, Timothy J., and Joel Escobedo. "Cytoskeletal disruption and small heat shock protein translocation immediately after lengthening contractions." American Journal of Physiology-Cell Physiology 286, no. 3 (March 2004): C713—C722. http://dx.doi.org/10.1152/ajpcell.00341.2003.

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The purposes of this study were to determine whether, immediately after lengthening contractions, 1) levels of specific force-transmitting cytoskeletal elements are reduced in skeletal muscle cells and 2) cytosolic small heat shock proteins (HSPs) translocate to structures prone to disruption. Western blot analysis demonstrated decreased concentrations of z-disk proteins α-actinin and plectin and membrane scaffolding proteins dystrophin and β-spectrin in muscle exposed to lengthening contractions compared with contralateral control muscle. Lengthening contractions also resulted in immediate translocation of constitutively expressed HSP25 and αB-crystallin from the soluble to the insoluble fraction of muscle homogenates, and cryosections showed translocation from a diffuse, cytosolic localization to striations that corresponded to z-disks. Lengthening contraction-induced translocation of HSP25 and αB-crystallin was associated with phosphorylation of these small HSPs, which may trigger their protective activity. In summary, these findings demonstrate loss of z-disk and membrane scaffolding proteins immediately after lengthening contractions, and concomitant translocation of HSP25 and αB-crystallin to the z-disk, which may help to stabilize or repair cytoskeletal elements at this site.

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Mykkänen, Olli-Matti, Mikaela Grönholm, Mikko Rönty, Maciej Lalowski, Paula Salmikangas, Heli Suila, and Olli Carpén. "Characterization of Human Palladin, a Microfilament-associated Protein." Molecular Biology of the Cell 12, no. 10 (October 2001): 3060–73. http://dx.doi.org/10.1091/mbc.12.10.3060.

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Анотація:

Actin-containing microfilaments control cell shape, adhesion, and contraction. In striated muscle, α-actinin and other Z-disk proteins coordinate the organization and functions of actin filaments. In smooth muscle and nonmuscle cells, periodic structures termed dense bodies and dense regions, respectively, are thought to serve functions analogous to Z-discs. We describe here identification and characterization of human palladin, a protein expressed mainly in smooth muscle and nonmuscle and distributed along microfilaments in a periodic manner consistent with dense regions/bodies. Palladin contains three Ig-domains most homologous to the sarcomeric Z-disk protein myotilin. The N terminus includes an FPPPP motif recognized by the Ena-Vasp homology domain 1 domain in Ena/vasodilatator-stimulated phosphoprotein (VASP)/Wiscott-Aldrich syndrome protein (WASP) protein family. Cytoskeletal proteins with FPPPP motif target Ena/VASP/WASP proteins to sites of actin modulation. We identified palladin in a yeast two-hybrid search as an ezrin-associated protein. An interaction between palladin and ezrin was further verified by affinity precipitation and blot overlay assays. The interaction was mediated by the α-helical domain of ezrin and by Ig-domains 2–3 of palladin. Ezrin is typically a component of the cortical cytoskeleton, but in smooth muscle cells it is localized along microfilaments. These cells express palladin abundantly and thus palladin may be involved in the microfilament localization of ezrin. Palladin expression was up-regulated in differentiating dendritic cells (DCs), coinciding with major cytoskeletal and morphological alterations. In immature DCs, palladin localized in actin-containing podosomes and in mature DCs along actin filaments. The regulated expression and localization suggest a role for palladin in the assembly of DC cytoskeleton.

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Kollár, Veronika, Dávid Szatmári, László Grama, and Miklós S. Z. Kellermayer. "Dynamic Strength of Titin's Z-Disk End." Journal of Biomedicine and Biotechnology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/838530.

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Titin is a giant filamentous protein traversing the half sarcomere of striated muscle with putative functions as diverse as providing structural template, generating elastic response, and sensing and relaying mechanical information. The Z-disk region of titin, which corresponds to the N-terminal end of the molecule, has been thought to be a hot spot for mechanosensing while also serving as anchorage for its sarcomeric attachment. Understanding the mechanics of titin's Z-disk region, particularly under the effect of binding proteins, is of great interest. Here we briefly review recent findings on the structure, molecular associations, and mechanics of titin's Z-disk region. In addition, we report experimental results on the dynamic strength of titin's Z1Z2 domains measured by nanomechanical manipulation of the chemical dimer of a recombinant protein fragment.

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46

Zhao, Bing, Tingjun Dai, Dandan Zhao, Xiaotian Ma, Cuiping Zhao, Ling Li, Yuan Sun, et al. "Clinicopathologic Profiles of Sporadic Late-Onset Nemaline Myopathy." Neurology - Neuroimmunology Neuroinflammation 9, no. 4 (May 17, 2022): e1184. http://dx.doi.org/10.1212/nxi.0000000000001184.

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Background and ObjectivesSporadic late-onset nemaline myopathy (SLONM) is a treatable or otherwise fatal myopathy. Diagnosis of SLONM is still challenging, and no therapeutic consensus has been achieved. Here, we reported the clinicopathologic features and long-term follow-up data of SLONM in a Chinese cohort.MethodsWe performed a retrospective evaluation of clinical, pathologic, and treatment outcomes of 17 patients with SLONM diagnosed between March 1986 and April 2021 at our neuromuscular center. Immunohistochemistry (IHC) with antibodies against 5 Z-disc–associated proteins was performed in the muscle biopsies of SLONM to identify a potential pathologic marker in aid of diagnosis. In comparison, we also performed muscle IHC in patients with selective type II fiber atrophy (n = 22), neurogenic atrophy (n = 22), mitochondrial myopathy (n = 5), immune-mediated necrotizing myopathy (n = 5), and normal controls (n = 5).ResultsMost of the patients exhibited asymmetric limb muscles weakness (71%, 12/17) and neck extensor weakness (53%, 9/17). Immunofixation electrophoresis was performed in 11 patients, and 4 of them were identified with monoclonal gammopathy of undetermined significance (MGUS). EMG from 16 patients demonstrated a myopathic pattern with spontaneous activities in 69% (11/16) of them. Muscle MRI showed preferential involvement of paraspinal, gluteus minimus and medius, semimembranosus, and soleus muscles. Suspected nemaline bodies on modified Gomori trichrome were confirmed by IHC using anti–α-actinin antibody (100%, 17/17), anti-myotilin antibody (94%, 16/17), anti-desmin antibody (94%, 16/17), anti–α-B crystallin antibody (65%, 11/17), and anti-telethonin antibody (18%, 3/17) with various positive rates. Notably, anti–α-actinin IHC showed the highest percentage of strongly positive staining (77%, 13/17), being the only one without negative results. Moderate improvement following autologous stem cell transplantation (ASCT) was noted in 3/4 patients with MGUS; favorable outcomes were also achieved in 6/7 patients without MGUS, including 3 patients with complete recovery who were given a combined treatment of prednisone and another immunosuppressant.DiscussionSLONM is a treatable myopathy with ASCT or traditional immunotherapy, especially when combined with steroids and immunosuppressants. Anti–α-actinin immunostaining is the most reliable pathologic marker to identify rod-bearing fibers, and it should be performed routinely in adult patients with undiagnosed nonnecrotic myopathies.

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Hoshijima, Masahiko. "Mechanical stress-strain sensors embedded in cardiac cytoskeleton: Z disk, titin, and associated structures." American Journal of Physiology-Heart and Circulatory Physiology 290, no. 4 (April 2006): H1313—H1325. http://dx.doi.org/10.1152/ajpheart.00816.2005.

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Cardiac muscle is equipped with intricate intrinsic mechanisms to regulate adaptive remodeling. Recent and extensive experimental findings powered by novel strategies for screening protein-protein interactions, improved imaging technologies, and versatile transgenic mouse methodologies reveal that Z disks and titin filaments possess unexpectedly complicated sensory and modulatory mechanisms for signal reception and transduction. These mechanisms employ molecules such as muscle-enriched LIM domain proteins, PDZ-LIM domain proteins, myozenin gene family members, titin-associated ankyrin repeat family proteins, and muscle-specific ring finger proteins, which have been identified as potential molecular sensor components. Moreover, classic transmembrane signaling processes, including mitogen-activated kinase, protein kinase C, and calcium signaling, also involve novel interactions with the Z disk/titin network. This compartmentalization of signaling complexes permits alteration of receptor-dependent transcriptional regulation by direct sensing of intrinsic stress. Newly identified mechanical stress sensors are not limited to Z-disk region and to I-band and M-band regions of titin but are also embedded in muscle-specific membrane systems such as the costamere, intercalated disks, and caveolae-like microdomains. This review summarizes current knowledge of this rapidly developing area with focus on how the heart adjusts physiological remodeling process to meet with mechanical demands and how this process fails in cardiac pathologies.

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Reverter, Antonio, Nicholas J. Hudson, Yonghong Wang, Siok-Hwee Tan, Wes Barris, Keren A. Byrne, Sean M. McWilliam, et al. "A gene coexpression network for bovine skeletal muscle inferred from microarray data." Physiological Genomics 28, no. 1 (December 2006): 76–83. http://dx.doi.org/10.1152/physiolgenomics.00105.2006.

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We present the application of large-scale multivariate mixed-model equations to the joint analysis of nine gene expression experiments in beef cattle muscle and fat tissues with a total of 147 hybridizations, and we explore 47 experimental conditions or treatments. Using a correlation-based method, we constructed a gene network for 822 genes. Modules of muscle structural proteins and enzymes, extracellular matrix, fat metabolism, and protein synthesis were clearly evident. Detailed analysis of the network identified groupings of proteins on the basis of physical association. For example, expression of three components of the z-disk, MYOZ1, TCAP, and PDLIM3, was significantly correlated. In contrast, expression of these z-disk proteins was not highly correlated with the expression of a cluster of thick (myosins) and thin (actin and tropomyosins) filament proteins or of titin, the third major filament system. However, expression of titin was itself not significantly correlated with the cluster of thick and thin filament proteins and enzymes. Correlation in expression of many fast-twitch muscle structural proteins and enzymes was observed, but slow-twitch-specific proteins were not correlated with the fast-twitch proteins or with each other. In addition, a number of significant associations between genes and transcription factors were also identified. Our results not only recapitulate the known biology of muscle but have also started to reveal some of the underlying associations between and within the structural components of skeletal muscle.

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Abdul-Ghani, Safa, Kate J. Heesom, Gianni D. Angelini, and M.-Saadeh Suleiman. "Cardiac Phosphoproteomics during Remote Ischemic Preconditioning: A Role for the Sarcomeric Z-Disk Proteins." BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/767812.

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Remote ischemic preconditioning (RIPC) induced by brief ischemia/reperfusion cycles of remote organ (e.g., limb) is cardioprotective. The myocardial cellular changes during RIPC responsible for this phenomenon are not currently known. The aim of this work was to identify the activation by phosphorylation of cardiac proteins following RIPC. To achieve our aim we used isobaric tandem mass tagging (TMT) and reverse phase nanoliquid chromatography tandem spectrometry using a Linear Trap Quadropole (LTQ) Orbitrap Velos mass spectrometer. Male C57/Bl6 mice were anesthetized by an intraperitoneal injection of Tribromoethanol. A cuff was placed around the hind limb and inflated at 200 mmHg to prevent blood flow as confirmed by Laser Doppler Flowmetry. RIPC was induced by 4 cycles of 5 min of limb ischemia followed by 5 min of reperfusion. Hearts were extracted for phosphoproteomics. We identified approximately 30 phosphoproteins that were differentially expressed in response to RIPC protocol. The levels of several phosphoproteins in the Z-disk of the sarcomere including phospho-myozenin-2 were significantly higher than control. This study describes and validates a novel approach to monitor the changes in the cardiac phosphoproteome following the cardioprotective intervention of RIPC and prior to index ischemia. The increased level of phosphorylated sarcomeric proteins suggests they may have a role in cardiac signaling during RIPC.

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Saide, J. D., S. Chin-Bow, J. Hogan-Sheldon, L. Busquets-Turner, J. O. Vigoreaux, K. Valgeirsdottir, and M. L. Pardue. "Characterization of components of Z-bands in the fibrillar flight muscle of Drosophila melanogaster." Journal of Cell Biology 109, no. 5 (November 1, 1989): 2157–67. http://dx.doi.org/10.1083/jcb.109.5.2157.

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Twelve monoclonal antibodies have been raised against proteins in preparations of Z-disks isolated from Drosophila melanogaster flight muscle. The monoclonal antibodies that recognized Z-band components were identified by immunofluorescence microscopy of flight muscle myofibrils. These antibodies have identified three Z-disk antigens on immunoblots of myofibrillar proteins. Monoclonal antibodies alpha:1-4 recognize a 90-100-kD protein which we identify as alpha-actinin on the basis of cross-reactivity with antibodies raised against honeybee and vertebrate alpha-actinins. Monoclonal antibodies P:1-4 bind to the high molecular mass protein, projectin, a component of connecting filaments that link the ends of thick filaments to the Z-band in insect asynchronous flight muscles. The anti-projectin antibodies also stain synchronous muscle, but, surprisingly, the epitopes here are within the A-bands, not between the A- and Z-bands, as in flight muscle. Monoclonal antibodies Z(210):1-4 recognize a 210-kD protein that has not been previously shown to be a Z-band structural component. A fourth antigen, resolved as a doublet (approximately 400/600 kD) on immunoblots of Drosophila fibrillar proteins, is detected by a cross reacting antibody, Z(400):2, raised against a protein in isolated honeybee Z-disks. On Lowicryl sections of asynchronous flight muscle, indirect immunogold staining has localized alpha-actinin and the 210-kD protein throughout the matrix of the Z-band, projectin between the Z- and A-bands, and the 400/600-kD components at the I-band/Z-band junction. Drosophila alpha-actinin, projectin, and the 400/600-kD components share some antigenic determinants with corresponding honeybee proteins, but no honeybee protein interacts with any of the Z(210) antibodies.

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