Chronic Hypoxia Impairs Muscle Function in the Drosophila Model of Duchenne's Muscular Dystrophy (DMD)

Mosqueira, Matías; Willmann, Gabriel; Ruohola‐Baker, Hannele; Khurana, Tejvir S.

doi:10.1371/journal.pone.0013450

Cited by 18 publications

(15 citation statements)

References 79 publications

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“…Previously, it has been demonstrated that mice with different genetic backgrounds have different HVR patterns and resistance to hypoxia [59], [63], [65], and those that display a blunted HVR response also have a weaker compensation in response to severe hypoxia [65]. Interestingly, we have previously reported that dystrophic Drosophila also has an impaired capacity to respond to hypoxic stress [68]. Our ventilatory data from mdx mice (bradypneic, blunted HVR during normoxia and lower resistance to severe hypoxia challenges) would also support previous data showing a severe functional deficit of the damaged diaphragm.…”

Section: Discussionmentioning

confidence: 90%

Ventilatory Chemosensory Drive Is Blunted in the mdx Mouse Model of Duchenne Muscular Dystrophy (DMD)

et al. 2013

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Duchenne Muscular Dystrophy (DMD) is caused by mutations in the DMD gene resulting in an absence of dystrophin in neurons and muscle. Respiratory failure is the most common cause of mortality and previous studies have largely concentrated on diaphragmatic muscle necrosis and respiratory failure component. Here, we investigated the integrity of respiratory control mechanisms in the mdx mouse model of DMD. Whole body plethysmograph in parallel with phrenic nerve activity recordings revealed a lower respiratory rate and minute ventilation during normoxia and a blunting of the hypoxic ventilatory reflex in response to mild levels of hypoxia together with a poor performance on a hypoxic stress test in mdx mice. Arterial blood gas analysis revealed low PaO2 and pH and high PaCO2 in mdx mice. To investigate chemosensory respiratory drive, we analyzed the carotid body by molecular and functional means. Dystrophin mRNA and protein was expressed in normal mice carotid bodies however, they are absent in mdx mice. Functional analysis revealed abnormalities in Dejours test and the early component of the hypercapnic ventilatory reflex in mdx mice. Together, these results demonstrate a malfunction in the peripheral chemosensory drive that would be predicted to contribute to the respiratory failure in mdx mice. These data suggest that investigating and monitoring peripheral chemosensory drive function may be useful for improving the management of DMD patients with respiratory failure.

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Section: Discussionmentioning

confidence: 90%

Ventilatory Chemosensory Drive Is Blunted in the mdx Mouse Model of Duchenne Muscular Dystrophy (DMD)

et al. 2013

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“…One potential drawback to the use of Drosophila is linked to the extent of genome and pathway conservation, although this organism does display a high degree of conservation in genes, structures and functional processes characterized in vertebrate skeletal muscle ( Tixier et al, 2010 ). This makes Drosophila particularly well-suited to modeling and studying muscular disorders ( García-López et al, 2008 ; Lloyd and Taylor, 2010 ; Mosqueira et al, 2010 ; Timmerman and Sanyal, 2012 ). Regarding alternative splicing, although important functional conservation occurs between Drosophila and mammals ( Venables et al, 2012 ), dissimilarities have also been described ( Mount et al, 1992 ; Irion, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Development of aDrosophila melanogasterspliceosensor system forin vivohigh-throughput screening in myotonic dystrophy type 1

Garcia-Alcover

Colonques-Bellmunt

Garijo

et al. 2014

Disease Models &Amp; Mechanisms

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Alternative splicing of pre-mRNAs is an important mechanism that regulates cellular function in higher eukaryotes. A growing number of human genetic diseases involve splicing defects that are directly connected to their pathology. In myotonic dystrophy type 1 (DM1), several clinical manifestations have been proposed to be the consequence of tissue-specific missplicing of numerous genes. These events are triggered by an RNA gain-of-function and resultant deregulation of specific RNA-binding factors, such as the nuclear sequestration of muscleblind-like family factors (MBNL1–MBNL3). Thus, the identification of chemical modulators of splicing events could lead to the development of the first valid therapy for DM1 patients. To this end, we have generated and validated transgenic flies that contain a luciferase-reporter-based system that is coupled to the expression of MBNL1-reliant splicing (spliceosensor flies), to assess events that are deregulated in DM1 patients in a relevant disease tissue. We then developed an innovative 96-well plate screening platform to carry out in vivo high-throughput pharmacological screening (HTS) with the spliceosensor model. After a large-scale evaluation (>16,000 chemical entities), several reliable splicing modulators (hits) were identified. Hit validation steps recognized separate DM1-linked therapeutic traits for some of the hits, which corroborated the feasibility of the approach described herein to reveal promising drug candidates to correct missplicing in DM1. This powerful Drosophila-based screening tool might also be applied in other disease models displaying abnormal alternative splicing, thus offering myriad uses in drug discovery.

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“…A Drosophila model for DMD has been used extensively to study the effects of Dystrophin gene mutations (Pilgram et al, 2010;Shcherbata et al, 2007;van der Plas et al, 2007). From DMD muscles it is known they are affected by hypoxia (Mosqueira et al, 2010). It would be interesting to further explore the function of SGs and their involvement in animal models for myopathies.…”

Section: Mrna Cycles Through Stress Granules In Vivo 707mentioning

confidence: 99%

mRNA cycles through hypoxia-induced stress granules in live Drosophila embryonic muscles

Laan¹,

Vangemert²,

Dirks³

et al. 2012

Int. J. Dev. Biol.

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In some myopathies, hypoxia can be the result of pathologic effects like muscle necrosis and abnormal blood flow. At the molecular level, the consequence of hypoxic conditions is not yet fully understood. Under stress conditions, many housekeeping gene mRNAs are translationally silenced, while translation of other mRNAs increases. Alterations to the pool of mRNAs available for translation lead to the formation of so-called stress granules containing both mRNAs and proteins. Stress granule formation and dynamics have been investigated using cells in culture, but have not yet been examined in vivo. In Drosophila embryonic muscles, we found that hypoxia induces the formation of sarcoplasmic granules containing the established stress granule markers RIN and dFMR1. Upon restoration of normoxia, the observed granules were decreased in size, indicating that their formation might be reversible. Employing photobleaching approaches, we found that a cytoplasmic reporter mRNA rapidly shuttles in and out of the granules. Hence, stress granules are highly dynamic complexes and not simple temporary storage sites. Although mRNA rapidly cycles through the granules, its movement throughout the muscle is, remarkably, spatially restricted by the presence of yet undefined myofiber domains. Our results suggest that in hypoxic muscles mRNA remains highly mobile; however, its movement throughout the muscle is restricted by certain boundaries. The development of this Drosophila hypoxia model makes it possible to study the formation and dynamics of stress granules and their associated mRNAs and proteins in a living organism.

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Chronic Hypoxia Impairs Muscle Function in the Drosophila Model of Duchenne's Muscular Dystrophy (DMD)

Cited by 18 publications

References 79 publications

Ventilatory Chemosensory Drive Is Blunted in the mdx Mouse Model of Duchenne Muscular Dystrophy (DMD)

Ventilatory Chemosensory Drive Is Blunted in the mdx Mouse Model of Duchenne Muscular Dystrophy (DMD)

Development of aDrosophila melanogasterspliceosensor system forin vivohigh-throughput screening in myotonic dystrophy type 1

mRNA cycles through hypoxia-induced stress granules in live Drosophila embryonic muscles

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