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Dystrophin deficiency leads to disturbance of LAMP1-vesicle-associated protein secretion

Duchenne muscular dystrophy results from loss of the protein dystrophin, which links the intracellular cytoskeletal network with the extracellular matrix, but deficiency in this function does not fully explain the onset or progression of the disease. While some intracellular events involved in the d... Full description

Journal Title: Cellular and molecular life sciences : CMLS 2013, Vol.70 (12), p.2159-2174
Main Author: Duguez, Stephanie
Other Authors: Duddy, William , Johnston, Helen , Lainé, Jeanne , Le Bihan, Marie Catherine , Brown, Kristy J , Bigot, Anne , Hathout, Yetrib , Butler-Browne, Gillian , Partridge, Terence
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: Basel: SP Birkhäuser Verlag Basel
ID: ISSN: 1420-682X
Link: https://www.ncbi.nlm.nih.gov/pubmed/23344255
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recordid: cdi_proquest_miscellaneous_1355479449
title: Dystrophin deficiency leads to disturbance of LAMP1-vesicle-associated protein secretion
format: Article
creator:
  • Duguez, Stephanie
  • Duddy, William
  • Johnston, Helen
  • Lainé, Jeanne
  • Le Bihan, Marie Catherine
  • Brown, Kristy J
  • Bigot, Anne
  • Hathout, Yetrib
  • Butler-Browne, Gillian
  • Partridge, Terence
subjects:
  • Actins - analysis
  • Amino Acids - metabolism
  • Analysis
  • Animals
  • Biochemistry
  • Biomedical and Life Sciences
  • Biomedicine
  • Blotting, Western
  • Cell Biology
  • Cell Line
  • Cellular biology
  • Chromatography, Liquid
  • Computational Biology
  • Cytoskeleton
  • Dystrophin
  • Dystrophin - deficiency
  • Dystrophinopathy LAMP Muscle cells SILAC Vesicle secretion DUCHENNE MUSCULAR
  • general
  • Immunoblotting
  • Isotope Labeling
  • Life Sciences
  • Lysosome-Associated Membrane Glycoproteins - metabolism
  • Male
  • Membrane Proteins - metabolism
  • Mice
  • Microscopy, Electron, Transmission
  • Molecular biology
  • Muscle Fibers, Skeletal - pathology
  • Muscle Fibers, Skeletal - secretion
  • Muscular Dystrophy, Duchenne - metabolism
  • Myosin
  • Proteins
  • Research Article
  • Resveratrol
  • Secretory Vesicles - metabolism
  • Secretory Vesicles - ultrastructure
  • Statistics, Nonparametric
  • Tandem Mass Spectrometry
ispartof: Cellular and molecular life sciences : CMLS, 2013, Vol.70 (12), p.2159-2174
description: Duchenne muscular dystrophy results from loss of the protein dystrophin, which links the intracellular cytoskeletal network with the extracellular matrix, but deficiency in this function does not fully explain the onset or progression of the disease. While some intracellular events involved in the degeneration of dystrophin-deficient muscle fibers have been well characterized, changes in their secretory profile are undescribed. To analyze the secretome profile of mdx myotubes independently of myonecrosis, we labeled the proteins of mdx and wild-type myotubes with stable isotope-labeled amino acids (SILAC), finding marked enrichment of vesicular markers in the mdx secretome. These included the lysosomal-associated membrane protein, LAMP1, that co-localized in vesicles with an over-secreted cytoskeletal protein, myosin light chain 1. These LAMP1/MLC1-3-positive vesicles accumulated in the cytosol of mdx myotubes and were secreted into the culture medium in a range of abnormal densities. Restitution of dystrophin expression, by exon skipping, to some 30 % of the control value, partially normalized the secretome profile and the excess LAMP1 accumulation. Together, our results suggest that a lack of dystrophin leads to a general dysregulation of vesicle trafficking. We hypothesize that disturbance of the export of proteins through vesicles occurs before, and then concurrently with, the myonecrotic cascade and contributes chronically to the pathophysiology of DMD, thereby presenting us with a range of new potential therapeutic targets.
language: eng
source:
identifier: ISSN: 1420-682X
fulltext: no_fulltext
issn:
  • 1420-682X
  • 1420-9071
url: Link


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titleDystrophin deficiency leads to disturbance of LAMP1-vesicle-associated protein secretion
creatorDuguez, Stephanie ; Duddy, William ; Johnston, Helen ; Lainé, Jeanne ; Le Bihan, Marie Catherine ; Brown, Kristy J ; Bigot, Anne ; Hathout, Yetrib ; Butler-Browne, Gillian ; Partridge, Terence
creatorcontribDuguez, Stephanie ; Duddy, William ; Johnston, Helen ; Lainé, Jeanne ; Le Bihan, Marie Catherine ; Brown, Kristy J ; Bigot, Anne ; Hathout, Yetrib ; Butler-Browne, Gillian ; Partridge, Terence
descriptionDuchenne muscular dystrophy results from loss of the protein dystrophin, which links the intracellular cytoskeletal network with the extracellular matrix, but deficiency in this function does not fully explain the onset or progression of the disease. While some intracellular events involved in the degeneration of dystrophin-deficient muscle fibers have been well characterized, changes in their secretory profile are undescribed. To analyze the secretome profile of mdx myotubes independently of myonecrosis, we labeled the proteins of mdx and wild-type myotubes with stable isotope-labeled amino acids (SILAC), finding marked enrichment of vesicular markers in the mdx secretome. These included the lysosomal-associated membrane protein, LAMP1, that co-localized in vesicles with an over-secreted cytoskeletal protein, myosin light chain 1. These LAMP1/MLC1-3-positive vesicles accumulated in the cytosol of mdx myotubes and were secreted into the culture medium in a range of abnormal densities. Restitution of dystrophin expression, by exon skipping, to some 30 % of the control value, partially normalized the secretome profile and the excess LAMP1 accumulation. Together, our results suggest that a lack of dystrophin leads to a general dysregulation of vesicle trafficking. We hypothesize that disturbance of the export of proteins through vesicles occurs before, and then concurrently with, the myonecrotic cascade and contributes chronically to the pathophysiology of DMD, thereby presenting us with a range of new potential therapeutic targets.
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subjectActins - analysis ; Amino Acids - metabolism ; Analysis ; Animals ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Blotting, Western ; Cell Biology ; Cell Line ; Cellular biology ; Chromatography, Liquid ; Computational Biology ; Cytoskeleton ; Dystrophin ; Dystrophin - deficiency ; Dystrophinopathy LAMP Muscle cells SILAC Vesicle secretion DUCHENNE MUSCULAR ; general ; Immunoblotting ; Isotope Labeling ; Life Sciences ; Lysosome-Associated Membrane Glycoproteins - metabolism ; Male ; Membrane Proteins - metabolism ; Mice ; Microscopy, Electron, Transmission ; Molecular biology ; Muscle Fibers, Skeletal - pathology ; Muscle Fibers, Skeletal - secretion ; Muscular Dystrophy, Duchenne - metabolism ; Myosin ; Proteins ; Research Article ; Resveratrol ; Secretory Vesicles - metabolism ; Secretory Vesicles - ultrastructure ; Statistics, Nonparametric ; Tandem Mass Spectrometry
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descriptionDuchenne muscular dystrophy results from loss of the protein dystrophin, which links the intracellular cytoskeletal network with the extracellular matrix, but deficiency in this function does not fully explain the onset or progression of the disease. While some intracellular events involved in the degeneration of dystrophin-deficient muscle fibers have been well characterized, changes in their secretory profile are undescribed. To analyze the secretome profile of mdx myotubes independently of myonecrosis, we labeled the proteins of mdx and wild-type myotubes with stable isotope-labeled amino acids (SILAC), finding marked enrichment of vesicular markers in the mdx secretome. These included the lysosomal-associated membrane protein, LAMP1, that co-localized in vesicles with an over-secreted cytoskeletal protein, myosin light chain 1. These LAMP1/MLC1-3-positive vesicles accumulated in the cytosol of mdx myotubes and were secreted into the culture medium in a range of abnormal densities. Restitution of dystrophin expression, by exon skipping, to some 30 % of the control value, partially normalized the secretome profile and the excess LAMP1 accumulation. Together, our results suggest that a lack of dystrophin leads to a general dysregulation of vesicle trafficking. We hypothesize that disturbance of the export of proteins through vesicles occurs before, and then concurrently with, the myonecrotic cascade and contributes chronically to the pathophysiology of DMD, thereby presenting us with a range of new potential therapeutic targets.
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authorDuguez, Stephanie ; Duddy, William ; Johnston, Helen ; Lainé, Jeanne ; Le Bihan, Marie Catherine ; Brown, Kristy J ; Bigot, Anne ; Hathout, Yetrib ; Butler-Browne, Gillian ; Partridge, Terence
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issn1420-682X
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abstractDuchenne muscular dystrophy results from loss of the protein dystrophin, which links the intracellular cytoskeletal network with the extracellular matrix, but deficiency in this function does not fully explain the onset or progression of the disease. While some intracellular events involved in the degeneration of dystrophin-deficient muscle fibers have been well characterized, changes in their secretory profile are undescribed. To analyze the secretome profile of mdx myotubes independently of myonecrosis, we labeled the proteins of mdx and wild-type myotubes with stable isotope-labeled amino acids (SILAC), finding marked enrichment of vesicular markers in the mdx secretome. These included the lysosomal-associated membrane protein, LAMP1, that co-localized in vesicles with an over-secreted cytoskeletal protein, myosin light chain 1. These LAMP1/MLC1-3-positive vesicles accumulated in the cytosol of mdx myotubes and were secreted into the culture medium in a range of abnormal densities. Restitution of dystrophin expression, by exon skipping, to some 30 % of the control value, partially normalized the secretome profile and the excess LAMP1 accumulation. Together, our results suggest that a lack of dystrophin leads to a general dysregulation of vesicle trafficking. We hypothesize that disturbance of the export of proteins through vesicles occurs before, and then concurrently with, the myonecrotic cascade and contributes chronically to the pathophysiology of DMD, thereby presenting us with a range of new potential therapeutic targets.
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