title: MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms.
abstract: 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.
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Conti
authors.affiliation: San Raffaele Rett Research Unit, Division of Neuroscience, San Raffaele Scientific Insitute, Milan, Italy; University of Insubria, PhD School in Neurobiology, Busto Arsizio, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Gandaglia
authors.affiliation: San Raffaele Rett Research Unit, Division of Neuroscience, San Raffaele Scientific Insitute, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Galli
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy; Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Tirone
authors.affiliation: San Raffaele Rett Research Unit, Division of Neuroscience, San Raffaele Scientific Insitute, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bellini
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, School of Medicine, Milan, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Campana
authors.affiliation: Laboratory of Genetic and Epigenetic Control of Gene Expression, Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, Italy.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kilstrup-Nielsen
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, School of Medicine, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rovere-Querini
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Brunelli
authors.affiliation: San Raffaele Rett Research Unit, Division of Neuroscience, San Raffaele Scientific Insitute, Milan, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milan, Segrate Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Landsberger
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D013006:Growth Hormone / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009123:Muscle Hypotonia / Q000235:genetics / Q000473:pathology*; D018482:Muscle, Skeletal / Q000254:growth & development / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics / Q000473:pathology*; D019899:Paracrine Communication / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases