Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

Azakir, Bilal; Fulvio, Sabrina Di; Kinter, Jochen; Sinnreich, Michael

doi:10.1074/jbc.m111.329078

Cited by 34 publications

(25 citation statements)

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“…Therefore, in addition to the deficit in membrane repair mechanism found in dysferlin-mutated myofibers [ 4 ], we propose herein a second pathological mechanism as a consequence of dysferlin mutations, which involves Cx HCs. These non-selective channels could explain several of the reported features in dysferlin-deficient muscles, including the increased membrane permeability [ 4 ], higher proteasome activity [ 26 , 28 ], activation of inflammation signals [ 8 – 10 ] and muscle degeneration [ 29 ]. The latter interpretation is supported by prior reports showing the role of Cx HC in altered membrane permeability and atrophy of skeletal muscles induced by denervation [ 11 , 12 ].…”

Section: Discussionmentioning

confidence: 99%

The absence of dysferlin induces the expression of functional connexin-based hemichannels in human myotubes

et al. 2016

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BackgroundMutations in the gene encoding for dysferlin cause recessive autosomal muscular dystrophies called dysferlinopathies. These mutations induce several alterations in skeletal muscles, including, inflammation, increased membrane permeability and cell death. Despite the fact that the etiology of dysferlinopathies is known, the mechanism that explains the aforementioned alterations is still elusive. Therefore, we have now evaluated the potential involvement of connexin based hemichannels in the pathophysiology of dysferlinopathies.ResultsHuman deltoid muscle biopsies of 5 Chilean dysferlinopathy patients exhibited the presence of muscular connexins (Cx40.1, Cx43 and Cx45). The presence of these connexins was also observed in human myotubes derived from immortalized myoblasts derived from other patients with mutated forms of dysferlin. In addition to the aforementioned connexins, these myotubes expressed functional connexin based hemichannels, evaluated by ethidium uptake assays, as opposed to myotubes obtained from a normal human muscle cell line, RCMH. This response was reproduced in a knock-down model of dysferlin, by treating RCMH cell line with small hairpin RNA specific for dysferlin (RCMH-sh Dysferlin). Also, the presence of P2X7 receptor and the transient receptor potential channel, TRPV2, another Ca2+ permeable channels, was detected in the myotubes expressing mutated dysferlin, and an elevated resting intracellular Ca2+ level was found in the latter myotubes, which was in turn reduced to control levels in the presence of the molecule D4, a selective Cx HCs inhibitor.ConclusionsThe data suggests that dysferlin deficiency, caused by mutation or downregulation of dysferlin, promotes the expression of Cx HCs. Then, the de novo expression Cx HC causes a dysregulation of intracellular free Ca2+ levels, which could underlie muscular damage associated to dysferlin mutations. This mechanism could constitute a potential therapeutical target in dysferlinopathies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12860-016-0096-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The absence of dysferlin induces the expression of functional connexin-based hemichannels in human myotubes

et al. 2016

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“…Similar to LGMD2A, dysferlinopathy patients exhibited more abundant mRNA and protein of MuRF-1 but not atrogin-1 [89]. Activation of UPS in dysferlinopathy has also been reported in cellular models (patient-derived muscle cells) [90]. UCMD is a common form of muscular dystrophy associated with defects in collagen VI, characterized by loss of muscle fibers and proliferation of connective and adipose tissues.…”

Section: The Adaptation Of Ups In Muscular Dystrophymentioning

confidence: 88%

Molecular Mechanisms Controlling Skeletal Muscle Mass

Sakuma¹,

Yamaguchi²

2015

Muscle Cell and Tissue

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The interplay between multiple signaling pathways regulates the maintenance of skeletal muscle. Under physiological conditions, a network of interconnected signals serves to coordinate hypertrophic and atrophic inputs, culminating in a delicate balance between muscle protein synthesis and proteolysis. Loss of skeletal muscle mass, termed "atrophy," is a diagnostic feature of cachexia such as cancer, heart disease, and chronic obstructive pulmonary disease. Recent studies have further defined the pathways leading to gain and loss of skeletal muscle as well as the signaling events that induce post-injury regeneration. In this review, we summarize the relevant recent literature demonstrating these previously undiscovered mediators governing anabolism and catabolism of skeletal muscle.

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“…Togo et al, 1999). Other cell types require longer: 100-300s for syncytial Drosophila embryos (Abreu-Blanco et al, 2011), ~60-120s for myoblasts (Azakir et al, 2012), 60-300s for muscle fibers (Bansal et al, 2003; Jaiswal et al, 2014b), 90s for cancer cells (Jaiswal et al, 2014a), 120-240s for HeLa cells (Jimenez et al, 2014), 20-120s for Xenopus blastomeres (Clark et al, 2009) and 60s-15m for frog oocytes (Luxardi et al, 2014; our unpublished results).…”

Section: ) How Are Wound Holes Stopped?mentioning

confidence: 99%

Cell healing: Calcium, repair and regeneration

Moe

Golding

Bement

2015

Seminars in Cell & Developmental Biology

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Cell repair is attracting increasing attention due to its conservation, its importance to health, and its utility as a model for cell signaling and cell polarization. However, some of the most fundamental questions concerning cell repair have yet to be answered. Here we consider three such questions: 1) How are wound holes stopped? 2) How is cell regeneration achieved after wounding? 3) How is calcium inrush linked to wound stoppage and cell regeneration?

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Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

Cited by 34 publications

References 35 publications

The absence of dysferlin induces the expression of functional connexin-based hemichannels in human myotubes

The absence of dysferlin induces the expression of functional connexin-based hemichannels in human myotubes

Molecular Mechanisms Controlling Skeletal Muscle Mass

Cell healing: Calcium, repair and regeneration

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