Myofibrillogenesis in Skeletal Muscle Cells

Sanger, Joseph W.; Chowrashi, Prokash K.; Shaner, Nathan C.; Spalthoff, Simon; Wang, Jushuo; Freeman, Nancy L.; Sanger, Jean M.

doi:10.1097/00003086-200210001-00018

Cited by 115 publications

(102 citation statements)

References 33 publications

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“…Obscurins within the sarcomere Involvement of obscurins in the formation of the sarcomere Myofibrillogenesis is the complex process of assembling sarcomeric proteins into complete and functional sarcomeres (Sanger et al 2002). Obscurin proteins serve multiple roles during myofibrillogenesis, including providing overall structural integrity and myofibril stabilization and, more specifically, providing proper spatial positioning of other contractile proteins, such as myosin (Borisov et al 2006;KontrogianniKonstantopoulos et al 2009).…”

Section: Obscurins In Skeletal Musclementioning

confidence: 99%

Obscure functions: the location–function relationship of obscurins

2017

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The obscurin family of polypeptides is essential for normal striated muscle function and contributes to the pathogenesis of fatal diseases, including cardiomyopathies and cancers. The single mammalian obscurin gene, OBSCN, gives rise to giant (∼800 kDa) and smaller (∼40-500 kDa) proteins that are composed of tandem adhesion and signaling motifs. Mammalian obscurin proteins are expressed in a variety of cell types, including striated muscles, and localize to distinct subcellular compartments where they contribute to diverse cellular processes. Obscurin homologs in Caenorhabditis elegans and Drosophila possess a similar domain architecture and are also expressed in striated muscles. The long sought after question, "what does obscurin do?" is complex and cannot be addressed without taking into consideration the subcellular distribution of these proteins and local isoform concentration. Herein, we present an overview of the functions of obscurins and begin to define the intricate relationship between their subcellular distributions and functions in striated muscles.

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Section: Obscurins In Skeletal Musclementioning

confidence: 99%

Obscure functions: the location–function relationship of obscurins

2017

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“…Although this work was performed using recombinant mouse N-RAP fragments in chick cardiomyocytes, it appears that the N-RAP protein (Mohiddin et al, 2003) and key features of myofibril assembly (Sanger et al, 2002) are well conserved among vertebrate species. Important general questions that remain to be answered include the identity of the integral membrane proteins and linker molecules that tether the I-Z-I complex to the membrane, how the initial periodicity of the Z-bodies near the membrane is determined, and how the Z-body spacing is increased during maturation.…”

Section: N-rap Scaffolding Of I-z-i Assemblymentioning

confidence: 99%

N-RAP scaffolds I-Z-I assembly during myofibrillogenesis in cultured chick cardiomyocytes

Carroll

Herrera

et al. 2004

Journal of Cell Science

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N-RAP is a muscle-specific protein with an N-terminal LIM domain (LIM), C-terminal actin-binding super repeats homologous to nebulin (SR) and nebulin-related simple repeats (IB) in between the two. Based on biochemical data, immunofluorescence analysis of cultured embryonic chick cardiomyocytes and the targeting and phenotypic effects of these individual GFP-tagged regions of N-RAP, we proposed a novel model for the initiation of myofibril assembly in which N-RAP organizes α-actinin and actin into the premyofibril I-Z-I complexes. We tested the proposed model by expressing deletion mutants of N-RAP (i.e. constructs containing two of the three regions of N-RAP) in chick cardiomyocytes and observing the effects on α-actinin and actin organization into mature sarcomeres. Although individually expressing either the LIM, IB, or SR regions of N-RAP inhibited α-actinin assembly into Z-lines, expression of either the LIM-IB fusion or the IB-SR fusion permitted normal α-actinin organization. In contrast, the LIM-SR fusion (LIM-SR) inhibited α-actinin organization into Z-lines, indicating that the IB region is critical for Z-line assembly. While permitting normal Z-line assembly, LIM-IB and IB-SR decreased sarcomeric actin staining intensity; however, the effects of LIM-IB on actin assembly were significantly more severe, as estimated both by morphological assessment and by quantitative measurement of actin staining intensity. In addition, LIM-IB was consistently retained in mature Z-lines, while mature Z-lines without significant IB-SR incorporation were often observed. We conclude that the N-RAP super repeats are essential for organizing actin filaments during myofibril assembly in cultured embryonic chick cardiomyocytes, and that they also play an important role in removal of the N-RAP scaffold from the completed myofibrillar structure. This work strongly supports the N-RAP scaffolding model of premyofibril assembly.

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“…In addition to the early determination and differentiation of heart primordium, zebrafish mutations are also expected to contribute to the clarification of a molecular mechanism that governs myofibrillogenesis and morphogenesis of the heart. The unidirectional alignment of myofibrils is essential for proper functioning of striated muscle such as skeletal and heart muscles (18). Despite a well characterized morphology, the molecular mechanisms of myofibril formation are poorly understood (19).…”

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confidence: 99%

Zebrafish early cardiac connexin, Cx36.7/Ecx, regulates myofibril orientation and heart morphogenesis by establishing Nkx2.5 expression

Sultana¹,

Nag²,

Hoshijima³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Heart development is a precisely coordinated process of cellular proliferation, migration, differentiation, and integrated morphogenetic interactions, and therefore it is highly susceptible to developmental anomalies such as the congenital heart disease (CHD). One of the major causes of CHD has been shown to be the mutations in key cardiac transcription factors, including nkx2.5. Here, we report the analysis of zebrafish mutant ftk that showed a progressive heart malformation in the later stages of heart morphogenesis. Our analyses revealed that the cardiac muscle maturation and heart morphogenesis in ftk mutants were impaired because of the disorganization of myofibrils. Notably, we found that the expression of nkx2.5 was down-regulated in the ftk heart despite the normal expression of gata4 and tbx5, suggesting a common mechanism for the occurrence of ftk phenotype and CHD. We identified ftk to be a loss-of-function mutation in a connexin gene, cx36.7/early cardiac connexin (ecx), expressed during early heart development. We further showed by a rescue experiment that Nkx2.5 is the downstream mediator of Ecx-mediated signaling. From these results, we propose that the cardiac connexin Ecx and its downstream signaling are crucial for establishing nkx2.5 expression, which in turn promotes unidirectional, parallel alignment of myofibrils and the subsequent proper heart morphogenesis.cardiomyocyte ͉ congenital heart disease ͉ trabeculation ͉ futka ͉ positional cloning N ormal development and function of the heart are indispensable for the survival of vertebrates. Cardiogenesis involves a precisely coordinated process of cellular proliferation, migration, and differentiation, and integrated morphogenetic interactions. Because of the complexity of these embryonic processes, heart development is highly susceptible to developmental anomalies collectively known as congenital heart diseases (CHD). The syndrome threatens the lives of as many as 1% of newborns (1, 2). Studies have uncovered that several transcription factors, including TBX5, NKX2.5, GATA4, and SALL4, cooperate to direct the cardiac cell lineage commitment and/or morphogenesis through the regulation of proteins characteristic of cardiomyocytes and that mutations in these transcription factors are responsible for many cases of CHD (3-7). Recent data have also suggested the significant roles of these transcription factors for maintenance of the functional heart in postnatal life as well (8-12). In the past decade, zebrafish (Danio rerio) has emerged as a valuable model system to study many developmental processes, including heart development, and a number of important insights have been gained from analyses of zebrafish mutants (13)(14)(15)(16)(17). In addition to the early determination and differentiation of heart primordium, zebrafish mutations are also expected to contribute to the clarification of a molecular mechanism that governs myofibrillogenesis and morphogenesis of the heart. The unidirectional alignment of myofibrils is essential for proper functio...

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Myofibrillogenesis in Skeletal Muscle Cells

Cited by 115 publications

References 33 publications

Obscure functions: the location–function relationship of obscurins

Obscure functions: the location–function relationship of obscurins

N-RAP scaffolds I-Z-I assembly during myofibrillogenesis in cultured chick cardiomyocytes

Zebrafish early cardiac connexin, Cx36.7/Ecx, regulates myofibril orientation and heart morphogenesis by establishing Nkx2.5 expression

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