Overall, these studies have supported the contention that RTT is NSC 319726 mainly, if not exclusively, a neuronal disease. However, the demonstration of increased glialgene expression in post-mortem female RTT brains and an altered glial metabolism in Mecp2 mouse models have prompted the study of a possible role of gliain MeCP2-related conditions. It has been demonstrated that Mecp2-null astrocytes affect neuronal growth and health invitro and mouse breathing and locomotor activity in vivo. Further, a role for microglia in RTT has been suggested by the benefit of transplanting wild-type bonemarrow stem cells into irradiated young Mecp2-null mice. Although no conditional mouse models inactivating Mecp2 inorgans different from brain have yet been generated, a role for MeCP2 in the development of heart and skeleton has been proposed. In light of these considerations and of the severe hypotonia affecting RTT patients and mice, we investigated whether MeCP2 expression is required for the development and homeostasis of the skeletal muscle using two mouse models. The PJ34 results demonstrate that the muscle of the Mecp2-null mouse suffers of a severe hypotonia that is not directly mediated by the lack of MeCP2 in this tissue. To investigate the overall organization of the Mecp2-null muscle, we analyzed the histological and histochemical features of the tissue after staining of muscle sections. As shown in Fig 1C, Mecp2-null skeletal muscles are characterized by a disrupted architectural structure. No necrotic or regenerating centronucleated fibers were observed, indicating that RTT muscles are not dystrophic. Muscle fibers lacking MeCP2 have a reduced cross section area, which is consistent with reduced muscle mass. Sirius Red staining and collagen I mRNA expression indicate a tendency of increased accumulation of fibrotict issue in Mecp2-null muscles, even if not statistically significant. Most skeletal muscles contain a mixture of different types of myofibers; in particular, type I myofibers are slow twitch, and fatigue resistant, whereas type II are fast twitch, either moderately fatigue-resistant or not fatigue-resistant.