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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

Mecp2-/y mice exhibit skeletal muscle disorganization and atrophy.(A) Representative pictures of TA and brain of 6 weeks old WT and Mecp2-/y mice. Scale bars = 0,5 mm. (B) Measures of organ weights are indicated as means ± s.e.m. Unpaired t-test was performed and P values are shown. Table also reports the percentage of reduction observed in Mecp2-/y mice (n≥6), calculated considering WT values as 100%. (C) Representative TA and gastrocnemius (Gast) muscle sections stained with H&E. Scale bar = 50 μm. (D) Representative TA and gastrocnemius muscle sections immunostained for Laminin. Scale bar = 50 μm. (E) CSA analysis of single muscle fibers, showing the abundance of smaller fibers in Mecp2-/y mice compared to WT mice. At least 150 myofibers were counted for each animal/muscle, n = 3 per genotype. Left panel: quantification of mean CSA ± s.e.m. Significance is calculated with t test (**, P value: 0.0059 for TA; **, P value: 0.0089 for Gast). Central and right panels: size distribution of single muscle fibers. x-Axis = fiber size (μm2); y-Axis = percentage of fibers. (F) TA sections (n = 3) were stained with Sirius Red and the total amount of collagen was quantified with ImageJ (G); ns, P value: 0.5593. (H) Collagen I mRNA expression was assessed in WT and Mecp2-/y gastrocnemius (n = 3). Significance is calculated with t test (ns, P value: 0.1126).
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pone.0130183.g001: Mecp2-/y mice exhibit skeletal muscle disorganization and atrophy.(A) Representative pictures of TA and brain of 6 weeks old WT and Mecp2-/y mice. Scale bars = 0,5 mm. (B) Measures of organ weights are indicated as means ± s.e.m. Unpaired t-test was performed and P values are shown. Table also reports the percentage of reduction observed in Mecp2-/y mice (n≥6), calculated considering WT values as 100%. (C) Representative TA and gastrocnemius (Gast) muscle sections stained with H&E. Scale bar = 50 μm. (D) Representative TA and gastrocnemius muscle sections immunostained for Laminin. Scale bar = 50 μm. (E) CSA analysis of single muscle fibers, showing the abundance of smaller fibers in Mecp2-/y mice compared to WT mice. At least 150 myofibers were counted for each animal/muscle, n = 3 per genotype. Left panel: quantification of mean CSA ± s.e.m. Significance is calculated with t test (**, P value: 0.0059 for TA; **, P value: 0.0089 for Gast). Central and right panels: size distribution of single muscle fibers. x-Axis = fiber size (μm2); y-Axis = percentage of fibers. (F) TA sections (n = 3) were stained with Sirius Red and the total amount of collagen was quantified with ImageJ (G); ns, P value: 0.5593. (H) Collagen I mRNA expression was assessed in WT and Mecp2-/y gastrocnemius (n = 3). Significance is calculated with t test (ns, P value: 0.1126).

Mentions: Mecp2- mice show evident muscle hypotonia, postural defects and locomotor deficits. To investigate possible skeletal muscle defects associated with these features, we initially verified the integrity and the structure of the tissue. We retrieved muscles and other organs from 6 weeks old Mecp2-/y mice [10] and wild-type (WT) littermates. Mecp2- muscles analyzed were much smaller than those of WT littermates (39.2% to 49.5% weight reduction ± s.e.m., Fig 1A and 1B). The reduction is in line with the overall reduced body weight of this Mecp2 mouse model (Fig 1A and 1B).


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)

Mecp2-/y mice exhibit skeletal muscle disorganization and atrophy.(A) Representative pictures of TA and brain of 6 weeks old WT and Mecp2-/y mice. Scale bars = 0,5 mm. (B) Measures of organ weights are indicated as means ± s.e.m. Unpaired t-test was performed and P values are shown. Table also reports the percentage of reduction observed in Mecp2-/y mice (n≥6), calculated considering WT values as 100%. (C) Representative TA and gastrocnemius (Gast) muscle sections stained with H&E. Scale bar = 50 μm. (D) Representative TA and gastrocnemius muscle sections immunostained for Laminin. Scale bar = 50 μm. (E) CSA analysis of single muscle fibers, showing the abundance of smaller fibers in Mecp2-/y mice compared to WT mice. At least 150 myofibers were counted for each animal/muscle, n = 3 per genotype. Left panel: quantification of mean CSA ± s.e.m. Significance is calculated with t test (**, P value: 0.0059 for TA; **, P value: 0.0089 for Gast). Central and right panels: size distribution of single muscle fibers. x-Axis = fiber size (μm2); y-Axis = percentage of fibers. (F) TA sections (n = 3) were stained with Sirius Red and the total amount of collagen was quantified with ImageJ (G); ns, P value: 0.5593. (H) Collagen I mRNA expression was assessed in WT and Mecp2-/y gastrocnemius (n = 3). Significance is calculated with t test (ns, P value: 0.1126).
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pone.0130183.g001: Mecp2-/y mice exhibit skeletal muscle disorganization and atrophy.(A) Representative pictures of TA and brain of 6 weeks old WT and Mecp2-/y mice. Scale bars = 0,5 mm. (B) Measures of organ weights are indicated as means ± s.e.m. Unpaired t-test was performed and P values are shown. Table also reports the percentage of reduction observed in Mecp2-/y mice (n≥6), calculated considering WT values as 100%. (C) Representative TA and gastrocnemius (Gast) muscle sections stained with H&E. Scale bar = 50 μm. (D) Representative TA and gastrocnemius muscle sections immunostained for Laminin. Scale bar = 50 μm. (E) CSA analysis of single muscle fibers, showing the abundance of smaller fibers in Mecp2-/y mice compared to WT mice. At least 150 myofibers were counted for each animal/muscle, n = 3 per genotype. Left panel: quantification of mean CSA ± s.e.m. Significance is calculated with t test (**, P value: 0.0059 for TA; **, P value: 0.0089 for Gast). Central and right panels: size distribution of single muscle fibers. x-Axis = fiber size (μm2); y-Axis = percentage of fibers. (F) TA sections (n = 3) were stained with Sirius Red and the total amount of collagen was quantified with ImageJ (G); ns, P value: 0.5593. (H) Collagen I mRNA expression was assessed in WT and Mecp2-/y gastrocnemius (n = 3). Significance is calculated with t test (ns, P value: 0.1126).
Mentions: Mecp2- mice show evident muscle hypotonia, postural defects and locomotor deficits. To investigate possible skeletal muscle defects associated with these features, we initially verified the integrity and the structure of the tissue. We retrieved muscles and other organs from 6 weeks old Mecp2-/y mice [10] and wild-type (WT) littermates. Mecp2- muscles analyzed were much smaller than those of WT littermates (39.2% to 49.5% weight reduction ± s.e.m., Fig 1A and 1B). The reduction is in line with the overall reduced body weight of this Mecp2 mouse model (Fig 1A and 1B).

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