Loss of dystrophin and the microtubule‐binding protein ELP‐1 causes progressive paralysis and death of adult <i>C. elegans</i>

Hueston, Jennifer L.; Suprenant, Kathy A.

doi:10.1002/dvdy.22007

Cited by 6 publications

(6 citation statements)

References 55 publications

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“…Additionally, we also showed that dys-1(cx18) display temperature sensitivity in their thrashing movement. Similar movement data for dys-1(cx18) were reported at 25°C (Hueston and Suprenant, 2009); thus, our data are consistent with published data. The nonsense mutation in dys-1(cx18) corresponds to termination at AA 2721, which is immediately before the start of spectrin repeat domain 5, which starts at AA 2725.…”

Section: Discussionsupporting

confidence: 93%

“…Given that strength and thrashing ability are not compromised to the same extent in dys-1(cx18) as in dys-1(eg33) , we wanted to further investigate the differences between the two strains. Upon reviewing the published literature on dys-1(cx18) , we found that Hueston and Suprenant (2009) had previously observed worse locomotion at 25°C than at 20°C, which would be consistent with cx18 being a temperature-sensitive allele. We confirmed that dys-1(cx18) , but not dys-1(eg33) , displays temperature sensitivity in the extent of thrashing ability (Fig.…”

Section: Resultssupporting

confidence: 73%

“…A standard assay for detecting locomotion defects is to record a worm's thrashing frequency when placed in a liquid environment, and this assay has been used previously to look at dystrophin-deficient worms, although not in both the dys-1 strains we used in this study (Hueston and Suprenant, 2009). We were curious to compare the outputs of an indirect measure of muscle function, thrashing, with our more direct measure, the strength measurement.…”

Section: Resultsmentioning

confidence: 99%

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Muscle strength deficiency and mitochondrial dysfunction in a muscular dystrophy model of C. elegans and its functional response to drugs

Hewitt

Pollard

Lesanpezeshki

et al. 2018

Disease Models &Amp; Mechanisms

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Muscle strength is a key clinical parameter used to monitor the progression of human muscular dystrophies, including Duchenne and Becker muscular dystrophies. Although Caenorhabditis elegans is an established genetic model for studying the mechanisms and treatments of muscular dystrophies, analogous strength-based measurements in this disease model are lacking. Here, we describe the first demonstration of the direct measurement of muscular strength in dystrophin-deficient C. elegans mutants using a micropillar-based force measurement system called NemaFlex. We show that dys-1(eg33) mutants, but not dys-1(cx18) mutants, are significantly weaker than their wild-type counterparts in early adulthood, cannot thrash in liquid at wild-type rates, display mitochondrial network fragmentation in the body wall muscles, and have an abnormally high baseline mitochondrial respiration. Furthermore, treatment with prednisone, the standard treatment for muscular dystrophy in humans, and melatonin both improve muscular strength, thrashing rate and mitochondrial network integrity in dys-1(eg33), and prednisone treatment also returns baseline respiration to normal levels. Thus, our results demonstrate that the dys-1(eg33) strain is more clinically relevant than dys-1(cx18) for muscular dystrophy studies in C. elegans. This finding, in combination with the novel NemaFlex platform, can be used as an efficient workflow for identifying candidate compounds that can improve strength in the C. elegans muscular dystrophy model. Our study also lays the foundation for further probing of the mechanism of muscle function loss in dystrophin-deficient C. elegans, leading to knowledge translatable to human muscular dystrophy.

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Section: Discussionsupporting

confidence: 93%

Section: Resultssupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

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Muscle strength deficiency and mitochondrial dysfunction in a muscular dystrophy model of C. elegans and its functional response to drugs

Hewitt

Pollard

Lesanpezeshki

et al. 2018

Disease Models &Amp; Mechanisms

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“…As indicated in Figure 2 , UNC-52 (perlecan), integrins (PAT-2/PAT-3), and the four-protein complex are found at the base of both M-lines and dense bodies. At the dense bodies, there are additional dense body-specific proteins such as DEB-1 (vinculin) [ 9 ], ATN-1 ( α -actinin) [ 27 ], UIG-1 (Cdc42 GEF) [ 28 ], ALP-1 (ALP/Enigma) [ 29 ], DYC-1 [ 30 ], and ELP-1 (EMAP-like protein) [ 31 ]. The only known nematode M-line-specific protein is UNC-89 (obscurin) [ 32 , 33 ]; as mentioned below, UNC-98 and UNC-96 are most prominent at M-lines.…”

Section: Discovery Of Muscle Attachment Components Through Immunolmentioning

confidence: 99%

Molecular Structure of Sarcomere-to-Membrane Attachment at M-Lines inC. elegansMuscle

Qadota

Benian

2010

Journal of Biomedicine and Biotechnology

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C. elegans is an excellent model for studying nonmuscle cell focal adhesions and the analogous muscle cell attachment structures. In the major striated muscle of this nematode, all of the M-lines and the Z-disk analogs (dense bodies) are attached to the muscle cell membrane and underlying extracellular matrix. Accumulating at these sites are many proteins associated with integrin. We have found that nematode M-lines contain a set of protein complexes that link integrin-associated proteins to myosin thick filaments. We have also obtained evidence for intriguing additional functions for these muscle cell attachment proteins.

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“…␣ -Dystroglycan, localized extracellularly, is heavily glycosylated and binds to laminin and perlecan in the BM and ␤ -dystroglycan in the basal membrane [Hemler, 1999;Henry and Campbell, 1999;Barresi and Campbell, 2006]. ␤ -Dystroglycan, through the dystrophin-glycoprotein complex, has been reported to interact intracellularly with both actin filaments and microtubules [Campbell, 1995;Henry and Campbell, 1999;Barresi and Campbell, 2006;Ayalon et al, 2008;Cerecedo et al, 2008;Bozzi et al, 2009;Hueston and Suprenant, 2009;Prins et al, 2009]. DAG1-null mice were embryonic lethal due to a poor assembly of Reichert's membrane, in addition to gastrulation and mesoderm formation defects [Williamson et al, 1997].…”

mentioning

confidence: 99%

Involvement of Dystroglycan in Epithelial-Mesenchymal Transition during Chick Gastrulation

Nakaya¹,

Sukowati²,

Alev³

et al. 2010

Cells Tissues Organs

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Regulated disruption of the basement membrane (BM) is a critical step in many epithelial-mesenchymal transition (EMT) processes. Molecular mechanisms controlling the interaction between the BM and the basal membrane of epithelial cells and its subsequent disruption during EMT are poorly understood. Using chick embryos as a model, we analyzed the molecular complexity of this interaction during gastrulation EMT. Transcriptome data indicated that the BM of the gastrulation stage chick epiblast contains a full range of BM component proteins with unique subtype combinations. Integrins and dystroglycan are 2 major groups of basal membrane proteins involved in BM interaction. We provide evidence that dystroglycan gene expression is restricted to the epiblast during early development and its expression is downregulated in cells undergoing gastrulation EMT. The β-dystroglycan protein is localized to the basolateral membrane in epiblast cells and the basal localization is lost in cells undergoing EMT. Disruption of actin filaments leads to a decrease in the lateral membrane localization of β-dystroglycan and a relative increase in basal membrane localization, whereas disruption of microtubules leads to the loss of BM/basal membrane interaction and basal membrane β-dystroglycan localization. Overall, these data suggest an involvement of dystroglycan, especially the regulation of its expression and localization, in gastrulation EMT.

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Loss of dystrophin and the microtubule‐binding protein ELP‐1 causes progressive paralysis and death of adult C. elegans

Abstract: EMAP-like proteins (ELPs

Cited by 6 publications

References 55 publications

Muscle strength deficiency and mitochondrial dysfunction in a muscular dystrophy model of C. elegans and its functional response to drugs

Muscle strength deficiency and mitochondrial dysfunction in a muscular dystrophy model of C. elegans and its functional response to drugs

Molecular Structure of Sarcomere-to-Membrane Attachment at M-Lines inC. elegansMuscle

Involvement of Dystroglycan in Epithelial-Mesenchymal Transition during Chick Gastrulation

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