Cargando…
MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms
Rett syndrome (RTT) is an autism spectrum disorder mainly caused by mutations in the X-linked MECP2 gene and affecting roughly 1 out of 10.000 born girls. Symptoms range in severity and include stereotypical movement, lack of spoken language, seizures, ataxia and severe intellectual disability. Nota...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476581/ https://www.ncbi.nlm.nih.gov/pubmed/26098633 http://dx.doi.org/10.1371/journal.pone.0130183 |
_version_ | 1782377615747710976 |
---|---|
author | Conti, Valentina Gandaglia, Anna Galli, Francesco Tirone, Mario Bellini, Elisa Campana, Lara Kilstrup-Nielsen, Charlotte Rovere-Querini, Patrizia Brunelli, Silvia Landsberger, Nicoletta |
author_facet | Conti, Valentina Gandaglia, Anna Galli, Francesco Tirone, Mario Bellini, Elisa Campana, Lara Kilstrup-Nielsen, Charlotte Rovere-Querini, Patrizia Brunelli, Silvia Landsberger, Nicoletta |
author_sort | Conti, Valentina |
collection | PubMed |
description | Rett syndrome (RTT) is an autism spectrum disorder mainly caused by mutations in the X-linked MECP2 gene and affecting roughly 1 out of 10.000 born girls. Symptoms range in severity and include stereotypical movement, lack of spoken language, seizures, ataxia and severe intellectual disability. Notably, muscle tone is generally abnormal in RTT girls and women and the Mecp2-null mouse model constitutively reflects this disease feature. We hypothesized that MeCP2 in muscle might physiologically contribute to its development and/or homeostasis, and conversely its defects in RTT might alter the tissue integrity or function. We show here that a disorganized architecture, with hypotrophic fibres and tissue fibrosis, characterizes skeletal muscles retrieved from Mecp2-null mice. Alterations of the IGF-1/Akt/mTOR pathway accompany the muscle phenotype. A conditional mouse model selectively depleted of Mecp2 in skeletal muscles is characterized by healthy muscles that are morphologically and molecularly indistinguishable from those of wild-type mice raising the possibility that hypotonia in RTT is mainly, if not exclusively, mediated by non-cell autonomous effects. Our results suggest that defects in paracrine/endocrine signaling and, in particular, in the GH/IGF axis appear as the major cause of the observed muscular defects. Remarkably, this is the first study describing the selective deletion of Mecp2 outside the brain. Similar future studies will permit to unambiguously define the direct impact of MeCP2 on tissue dysfunctions. |
format | Online Article Text |
id | pubmed-4476581 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44765812015-06-25 MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms Conti, Valentina Gandaglia, Anna Galli, Francesco Tirone, Mario Bellini, Elisa Campana, Lara Kilstrup-Nielsen, Charlotte Rovere-Querini, Patrizia Brunelli, Silvia Landsberger, Nicoletta PLoS One Research Article Rett syndrome (RTT) is an autism spectrum disorder mainly caused by mutations in the X-linked MECP2 gene and affecting roughly 1 out of 10.000 born girls. Symptoms range in severity and include stereotypical movement, lack of spoken language, seizures, ataxia and severe intellectual disability. Notably, muscle tone is generally abnormal in RTT girls and women and the Mecp2-null mouse model constitutively reflects this disease feature. We hypothesized that MeCP2 in muscle might physiologically contribute to its development and/or homeostasis, and conversely its defects in RTT might alter the tissue integrity or function. We show here that a disorganized architecture, with hypotrophic fibres and tissue fibrosis, characterizes skeletal muscles retrieved from Mecp2-null mice. Alterations of the IGF-1/Akt/mTOR pathway accompany the muscle phenotype. A conditional mouse model selectively depleted of Mecp2 in skeletal muscles is characterized by healthy muscles that are morphologically and molecularly indistinguishable from those of wild-type mice raising the possibility that hypotonia in RTT is mainly, if not exclusively, mediated by non-cell autonomous effects. Our results suggest that defects in paracrine/endocrine signaling and, in particular, in the GH/IGF axis appear as the major cause of the observed muscular defects. Remarkably, this is the first study describing the selective deletion of Mecp2 outside the brain. Similar future studies will permit to unambiguously define the direct impact of MeCP2 on tissue dysfunctions. Public Library of Science 2015-06-22 /pmc/articles/PMC4476581/ /pubmed/26098633 http://dx.doi.org/10.1371/journal.pone.0130183 Text en © 2015 Conti et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Conti, Valentina Gandaglia, Anna Galli, Francesco Tirone, Mario Bellini, Elisa Campana, Lara Kilstrup-Nielsen, Charlotte Rovere-Querini, Patrizia Brunelli, Silvia Landsberger, Nicoletta MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms |
title | MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms |
title_full | MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms |
title_fullStr | MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms |
title_full_unstemmed | MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms |
title_short | MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms |
title_sort | mecp2 affects skeletal muscle growth and morphology through non cell-autonomous mechanisms |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476581/ https://www.ncbi.nlm.nih.gov/pubmed/26098633 http://dx.doi.org/10.1371/journal.pone.0130183 |
work_keys_str_mv | AT contivalentina mecp2affectsskeletalmusclegrowthandmorphologythroughnoncellautonomousmechanisms AT gandagliaanna mecp2affectsskeletalmusclegrowthandmorphologythroughnoncellautonomousmechanisms AT gallifrancesco mecp2affectsskeletalmusclegrowthandmorphologythroughnoncellautonomousmechanisms AT tironemario mecp2affectsskeletalmusclegrowthandmorphologythroughnoncellautonomousmechanisms AT bellinielisa mecp2affectsskeletalmusclegrowthandmorphologythroughnoncellautonomousmechanisms AT campanalara mecp2affectsskeletalmusclegrowthandmorphologythroughnoncellautonomousmechanisms AT kilstrupnielsencharlotte mecp2affectsskeletalmusclegrowthandmorphologythroughnoncellautonomousmechanisms AT roverequerinipatrizia mecp2affectsskeletalmusclegrowthandmorphologythroughnoncellautonomousmechanisms AT brunellisilvia mecp2affectsskeletalmusclegrowthandmorphologythroughnoncellautonomousmechanisms AT landsbergernicoletta mecp2affectsskeletalmusclegrowthandmorphologythroughnoncellautonomousmechanisms |