Rett syndrome (RTT) is an autism spectrum disorder mainly caused by mutations in the Xlinked 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.

MeCP2 affects skeletal muscle growth and morphology through non cell-autonomous mechanisms / V. Conti, A. Gandaglia, F. Galli, M. Tirone, E. Bellini, L. Campana, C. Kilstrup Nielsen, P. Rovere Querini, S. Brunelli, N. Landsberger. - In: PLOS ONE. - ISSN 1932-6203. - 10:6(2015 Jun 22), pp. e0130183.1-e0130183.16. [10.1371/journal.pone.0130183]

MeCP2 affects skeletal muscle growth and morphology through non cell-autonomous mechanisms

N. Landsberger
2015-06-22

Abstract

Rett syndrome (RTT) is an autism spectrum disorder mainly caused by mutations in the Xlinked 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.
MeCP2; Rett syndrome; skeletal muscle; non cell autonomous; GH/IGF1 axis
Settore BIO/11 - Biologia Molecolare
Article (author)
File in questo prodotto:
File Dimensione Formato  
httpjournal.pone.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 5.59 MB
Formato Adobe PDF
5.59 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/326521
Citazioni
  • ???jsp.display-item.citation.pmc??? 13
  • Scopus 19
  • ???jsp.display-item.citation.isi??? 20
social impact