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MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms.

Conti V, Gandaglia A, Galli F, Tirone M, Bellini E, Campana L, Kilstrup-Nielsen C, Rovere-Querini P, Brunelli S, Landsberger N - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.

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- 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- 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.

No MeSH data available.


Related in: MedlinePlus

Muscle specific deletion of Mecp2 does not lead to the observed muscular alterations.(A) WBs confirm the specific skeletal muscle deletion of Mecp2 in the transgenic Mecp2FloxMyoDiCre mice. WT, Mecp2Flox and MyoDiCre genotypes are used as controls. (B) Representative TA cross-sections stained with Hematoxylin and Eosin (upper panels) or immunostained for Laminin (bottom panels). Scale bar = 50 μm. (C) Mean CSA ± s.e.m. showing no statistically significant differences between Mecp2FloxMyoDiCre mice fibers and control ones. At least 130 myofibers were counted for each animal. Significance was calculated using one-way ANOVA (ns: 0.8520). (D) Mecp2FloxMyoDiCre mice and controls show similar levels of Gast IGF-1 mRNA. Significance was calculated using one-way ANOVA (n≥3; ns: 0.9283). (E) Graph showing similar levels of P-rpS6 between Mecp2FloxMyoDiCre quadriceps and the corresponding controls. Data are represented as mean ± s.e.m. (n = 2).
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pone.0130183.g004: Muscle specific deletion of Mecp2 does not lead to the observed muscular alterations.(A) WBs confirm the specific skeletal muscle deletion of Mecp2 in the transgenic Mecp2FloxMyoDiCre mice. WT, Mecp2Flox and MyoDiCre genotypes are used as controls. (B) Representative TA cross-sections stained with Hematoxylin and Eosin (upper panels) or immunostained for Laminin (bottom panels). Scale bar = 50 μm. (C) Mean CSA ± s.e.m. showing no statistically significant differences between Mecp2FloxMyoDiCre mice fibers and control ones. At least 130 myofibers were counted for each animal. Significance was calculated using one-way ANOVA (ns: 0.8520). (D) Mecp2FloxMyoDiCre mice and controls show similar levels of Gast IGF-1 mRNA. Significance was calculated using one-way ANOVA (n≥3; ns: 0.9283). (E) Graph showing similar levels of P-rpS6 between Mecp2FloxMyoDiCre quadriceps and the corresponding controls. Data are represented as mean ± s.e.m. (n = 2).

Mentions: So far, our results suggest that fiber growth is affected in the absence of MeCP2; however, they do not permit to address whether the observed phenotype is cell- or non cell-autonomous. To get insight into the muscle-specific role of MeCP2, we crossed heterozygous Mecp2flox/+ female mice [10,22] with MyoDiCre males [23] thus obtaining mice with the deletion of Mecp2 in all myoblasts and muscle fibers. Mecp2flox/y;MyoDiCre mice do not spontaneously develop RTT and are fertile. WB analyses confirmed that muscles of adult Mecp2flox/y;MyoDiCre mice do not express MeCP2, while the expression is conserved in other organs and tissues. In accordance with a previous publication, we observed reduced MeCP2 expression in Mecp2flox animals (Fig 4A) [24].


MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms.

Conti V, Gandaglia A, Galli F, Tirone M, Bellini E, Campana L, Kilstrup-Nielsen C, Rovere-Querini P, Brunelli S, Landsberger N - PLoS ONE (2015)

Muscle specific deletion of Mecp2 does not lead to the observed muscular alterations.(A) WBs confirm the specific skeletal muscle deletion of Mecp2 in the transgenic Mecp2FloxMyoDiCre mice. WT, Mecp2Flox and MyoDiCre genotypes are used as controls. (B) Representative TA cross-sections stained with Hematoxylin and Eosin (upper panels) or immunostained for Laminin (bottom panels). Scale bar = 50 μm. (C) Mean CSA ± s.e.m. showing no statistically significant differences between Mecp2FloxMyoDiCre mice fibers and control ones. At least 130 myofibers were counted for each animal. Significance was calculated using one-way ANOVA (ns: 0.8520). (D) Mecp2FloxMyoDiCre mice and controls show similar levels of Gast IGF-1 mRNA. Significance was calculated using one-way ANOVA (n≥3; ns: 0.9283). (E) Graph showing similar levels of P-rpS6 between Mecp2FloxMyoDiCre quadriceps and the corresponding controls. Data are represented as mean ± s.e.m. (n = 2).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4476581&req=5

pone.0130183.g004: Muscle specific deletion of Mecp2 does not lead to the observed muscular alterations.(A) WBs confirm the specific skeletal muscle deletion of Mecp2 in the transgenic Mecp2FloxMyoDiCre mice. WT, Mecp2Flox and MyoDiCre genotypes are used as controls. (B) Representative TA cross-sections stained with Hematoxylin and Eosin (upper panels) or immunostained for Laminin (bottom panels). Scale bar = 50 μm. (C) Mean CSA ± s.e.m. showing no statistically significant differences between Mecp2FloxMyoDiCre mice fibers and control ones. At least 130 myofibers were counted for each animal. Significance was calculated using one-way ANOVA (ns: 0.8520). (D) Mecp2FloxMyoDiCre mice and controls show similar levels of Gast IGF-1 mRNA. Significance was calculated using one-way ANOVA (n≥3; ns: 0.9283). (E) Graph showing similar levels of P-rpS6 between Mecp2FloxMyoDiCre quadriceps and the corresponding controls. Data are represented as mean ± s.e.m. (n = 2).
Mentions: So far, our results suggest that fiber growth is affected in the absence of MeCP2; however, they do not permit to address whether the observed phenotype is cell- or non cell-autonomous. To get insight into the muscle-specific role of MeCP2, we crossed heterozygous Mecp2flox/+ female mice [10,22] with MyoDiCre males [23] thus obtaining mice with the deletion of Mecp2 in all myoblasts and muscle fibers. Mecp2flox/y;MyoDiCre mice do not spontaneously develop RTT and are fertile. WB analyses confirmed that muscles of adult Mecp2flox/y;MyoDiCre mice do not express MeCP2, while the expression is conserved in other organs and tissues. In accordance with a previous publication, we observed reduced MeCP2 expression in Mecp2flox animals (Fig 4A) [24].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.

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- 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- 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.

No MeSH data available.


Related in: MedlinePlus