To address whether Mecp2 deficiency might affect fiber-type composition we tested immune reactivity to myosin heavy chain I and II b, respectively used as markers of slow and fast fibers. Analyses were performed in adult gastrocnemii; as shown in S1Fig, no difference was revealed. Muscleatrophy in the absence of overtnecros is could be caused by abnormal innervation and/or functioning of the neuro muscular plaque. The number, shape and density of the neuromuscular junctions are comparable between WT and Mecp2-/y mice at 5 weeks of age, as K02288 assessed by immune fluorescence, suggesting that the overall morphology of the neuromuscular plaque is maintained in the absence of MeCP2. This is in accordance with earlier studies demonstrating that in RTT subjects motor action potentials could be evoked easily following electromagnetic stimulation of the motor cortex, therefore confirming that innervation is functional. So far, RTT research has focused mainly on the nervous system and genetic deletion studies have shown that inactivation of Mecp2 in post-mitotic neurons leads to several symptoms common with those of Mecp2-null mice. However, the concept of RTT as an exclusively neuronal disease is changing, therefore, high lighting the relevance of searching for tissue dysfunctions associated with the absence of MeCP2. RTT patients are characterized by a significant hypotonia; concordantly, the Mecp2-null mouse model is characterized by a decreased growth and severe hypotonia. Skeletal muscles account for approximately 40% of the total body mass and represent a major player in energy balance. Muscle fiber size changes physiologically in function of the environmental demand and it adapts to the various pathological conditions. One of the main mechanisms of this dynamics is the regulation of protein homeostasis obtained through the balance between protein synthesis and degradation. Here we show that MeCP2 deficiency leads to a severe muscle hypotrophy by regulating myofiber size in a GSK2656157 noncell-autonomous way.Indeed, while the Mecp2-null mice are characterized by a reduced skeletal muscle mass, the novel Mecp2flox/y; MyoDiCre transgenic line, in which Mecp2 has been deleted only in myoblasts and skeletal muscle fibers, does not show any of the RTT-like myopathy: in particular, weight and size of skeletal muscles do not differ from those of control littermates.