Autophagy is increased in laminin α2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A

Carmignac, Virginie; Svensson, Martina; Körner, Zandra; Elowsson, Linda; Matsumura, Cíntia Yuri; Gawlik, Kinga I.; Allamand, Valérie; Durbeej, Madeleine

doi:10.1093/hmg/ddr427

Cited by 111 publications

(113 citation statements)

References 49 publications

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“…It is widely accepted that, apart from the structural deficiencies, the pathology of different ECM disorders involves a broad spectrum of complex biological mechanisms, such as endoplasmic reticulum stress, dysregulated autophagy, or altered bioavailability of biologically active peptides and factors (42)(43)(44)(45)(46). Here, we demonstrate that this is also the case for RDEB.…”

Section: Discussionsupporting

confidence: 57%

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Nyström

Bornert

Kühl

et al. 2018

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

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Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB), a skin fragility disorder that, unexpectedly, manifests also with elevated colonization of commensal bacteria and frequent wound infections. Here, we describe an unprecedented systemic function of collagen VII as a member of a unique innate immune-supporting multiprotein complex in spleen and lymph nodes. In this complex, collagen VII specifically binds and sequesters the innate immune activator cochlin in the lumen of lymphoid conduits. In genetic mouse models, loss of collagen VII increased bacterial colonization by diminishing levels of circulating cochlin LCCL domain. Intraperitoneal injection of collagen VII, which restored cochlin in the spleen, but not in the skin, reactivated peripheral innate immune cells via cochlin and reduced bacterial skin colonization. Systemic administration of the cochlin LCCL domain was alone sufficient to diminish bacterial supercolonization of RDEB mouse skin. Human validation demonstrated that RDEB patients displayed lower levels of systemic cochlin LCCL domain with subsequently impaired macrophage response in infected wounds. This study identifies an intrinsic innate immune dysfunction in RDEB and uncovers a unique role of the lymphoid extracellular matrix in systemic defense against bacteria.collagen VII | innate immunity | bacteria | recessive dystrophic epidermolysis bullosa | cochlin

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Section: Discussionsupporting

confidence: 57%

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Nyström

Bornert

Kühl

et al. 2018

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

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“…The increased autophagic flux of dy 3K /dy 3K muscles is due to the inactivation of AKT, which in turn leads to enhanced expression of several autophagy genes that are under control of FoxO proteins. Increased activation of autophagy was also detected in primary myotubes and in muscle biopsies from two MDC1A patients (Carmignac et al, 2011a). Furthermore, pharmacological inhibition of autophagy in dy 3K /dy 3K mice significantly improves their dystrophic phenotype (Carmignac et al, 2011a).…”

Section: Role Of Autophagymentioning

confidence: 93%

“…Increased activation of autophagy was also detected in primary myotubes and in muscle biopsies from two MDC1A patients (Carmignac et al, 2011a). Furthermore, pharmacological inhibition of autophagy in dy 3K /dy 3K mice significantly improves their dystrophic phenotype (Carmignac et al, 2011a).…”

Section: Role Of Autophagymentioning

confidence: 93%

“…However, the effect of deregulated autophagy in muscular dystrophies is not always owing to excessive AKT-mTOR signaling or defective autophagic flux. In fact, studies in the dy 3K /dy 3K mutant mouse model for laminin a2, a protein that participates in the formation of the extracellular basal lamina that surrounds myofibers, indicated that autophagy is increased in these mice (Carmignac et al, 2011a) (Fig. 2).…”

Section: Role Of Autophagymentioning

confidence: 99%

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Misregulation of autophagy and protein degradation systems in myopathies and muscular dystrophies

Sandri

Coletto

Grumati

et al. 2013

Journal of Cell Science

157

151

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SummaryA number of recent studies have highlighted the importance of autophagy and the ubiquitin-proteasome in the pathogenesis of muscle wasting in different types of inherited muscle disorders. Autophagy is crucial for the removal of dysfunctional organelles and protein aggregates, whereas the ubiquitin-proteasome is important for the quality control of proteins. Post-mitotic tissues, such as skeletal muscle, are particularly susceptible to aged or dysfunctional organelles and aggregation-prone proteins. Therefore, these degradation systems need to be carefully regulated in muscles. Indeed, excessive or defective activity of the autophagy lysosome or ubiquitinproteasome leads to detrimental effects on muscle homeostasis. A growing number of studies link abnormalities in the regulation of these two pathways to myofiber degeneration and muscle weakness. Understanding the pathogenic role of these degradative systems in each inherited muscle disorder might provide novel therapeutic targets to counteract muscle wasting. In this Commentary, we will discuss the current view on the role of autophagy lysosome and ubiquitin-proteasome in the pathogenesis of myopathies and muscular dystrophies, and how alteration of these degradative systems contribute to muscle wasting in inherited muscle disorders. We will also discuss how modulating autophagy and proteasome might represent a promising strategy for counteracting muscle loss in different diseases.

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“…In keeping with these observations, we identified in blastocoel fluid from aged blastocysts an increased amount of Ubiquilin-2 (UBQLN2), which is involved in regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system and autophagy, a survival mechanism whose deregulation has been linked to non-apoptotic cell death through inducing cell cycle arrest [63,64]. Noteworthy, increased autophagy of aged blastocysts is further confirmed by absence in the blastocoel fluid of Laminin subunit gamma-1 (LAMC1), which is crucially involved in protection from autophagy [65,66].…”

Section: Discussionmentioning

confidence: 99%

Proteomic profile of maternal-aged blastocoel fluid suggests a novel role for ubiquitin system in blastocyst quality

Tedeschi

Albani

Borroni

et al. 2016

J Assist Reprod Genet

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Purpose The etiology of maternal aging, a common cause of female factor infertility and a rate-limiting step in vitro fertilization (IVF) success, remains still unclear. Proteomic changes responsible for the impaired successful pregnancy outcome after IVF with aged blastocysts have not been yet evaluated. The objective of this prospective study was to employ proteomic techniques and bioinformatic tools to enlight differences at the protein level in blastocoel fluid of aged and younger woman. Methods Protein composition of human blastocoel fluid isolated by micromanipulation from 46 blastocysts of women aged <37 years (group A) and 29 of women aged ≥37 years (group B) have been identified by a shotgun proteomic approach based on high-resolution nano-liquid chromatography electrospray-ionization-tandem mass spectrometry (nLC-ESI-MS/MS) using label free for the relative quantification of their expression levels. Results The proteomic analysis leads to the identification and quantification of 148 proteins; 132 and 116 proteins were identified in groups A and B, respectively. Interestingly, the identified proteins are mainly involved in processes aimed at fine tuning embryo implantation and development. Among the 100 proteins commonly expressed in both groups, 17 proteins are upregulated and 44 downregulated in group B compared to group A. Overall, the analysis identified 33 proteins, which were increased or present only in B while 76 were decreased in B or present only in A. Conclusions Data revealed that maternal aging mainly affects blastocyst survival and implantation through unbalancing the equilibrium of the ubiquitin system known to play a crucial role in fine-tuning several aspects required to ensure successful pregnancy outcome.

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Autophagy is increased in laminin α2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A

Cited by 111 publications

References 49 publications

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Misregulation of autophagy and protein degradation systems in myopathies and muscular dystrophies

Proteomic profile of maternal-aged blastocoel fluid suggests a novel role for ubiquitin system in blastocyst quality

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