Generation of skeletal muscles with forms adapted to their function is essential for normal movement. Muscle shape is patterned by the coordinated polarity of collectively migrating myoblasts. Constitutive inactivation of the protocadherin gene Fat1 uncoupled individual myoblast polarity within chains, altering the shape of selective groups of muscles in the shoulder and face. These shape abnormalities were followed by early onset regionalised muscle defects in adult Fat1-deficient mice. Tissue-specific ablation of Fat1 driven by Pax3-cre reproduced muscle shape defects in limb but not face muscles, indicating a cell-autonomous contribution of Fat1 in migrating muscle precursors. Strikingly, the topography of muscle abnormalities caused by Fat1 loss-of-function resembles that of human patients with facioscapulohumeral dystrophy (FSHD). FAT1 lies near the critical locus involved in causing FSHD, and Fat1 mutant mice also show retinal vasculopathy, mimicking another symptom of FSHD, and showed abnormal inner ear patterning, predictive of deafness, reminiscent of another burden of FSHD. Muscle-specific reduction of FAT1 expression and promoter silencing was observed in foetal FSHD1 cases. CGH array-based studies identified deletion polymorphisms within a putative regulatory enhancer of FAT1, predictive of tissue-specific depletion of FAT1 expression, which preferentially segregate with FSHD. Our study identifies FAT1 as a critical determinant of muscle form, misregulation of which associates with FSHD.

Myostatin, a member of the TGF-␤ family, has been identified as a powerful inhibitor of muscle growth. Absence or blockade of myostatin induces massive skeletal muscle hypertrophy that is widely attributed to proliferation of the population of muscle fiber-associated satellite cells that have been identified as the principle source of new muscle tissue during growth and regeneration. Postnatal blockade of myostatin has been proposed as a basis for therapeutic strategies to combat muscle loss in genetic and acquired myopathies. But this approach, according to the accepted mechanism, would raise the threat of premature exhaustion of the pool of satellite cells and eventual failure of muscle regeneration. Here, we show that hypertrophy in the absence of myostatin involves little or no input from satellite cells. Hypertrophic fibers contain no more myonuclei or satellite cells and myostatin had no significant effect on satellite cell proliferation in vitro, while expression of myostatin receptors dropped to the limits of detectability in postnatal satellite cells. Moreover, hypertrophy of dystrophic muscle arising from myostatin blockade was achieved without any apparent enhancement of contribution of myonuclei from satellite cells. These findings contradict the accepted model of myostatin-based control of size of postnatal muscle and reorient fundamental investigations away from the mechanisms that control satellite cell proliferation and toward those that increase myonuclear domain, by modulating synthesis and turnover of structural muscle fiber proteins. It predicts too that any benefits of myostatin blockade in chronic myopathies are unlikely to impose any extra stress on the satellite cells. muscle growth ͉ muscular dystrophy ͉ TGF-beta ͉ muscle stem cells ͉ myonuclear domain L oss of muscle mass and strength is a major clinical feature of inherited myopathies such as Duchenne muscular dystrophy (DMD) and also of more common acquired atrophies associated with disuse, aging, and cancer. This loss has fostered widespread interest in the powerful inhibitory effect of myostatin, a member of the TGF-␤ family of signaling molecules, on muscle growth (1) with specific focus on the prospect of modulating this system to counteract atrophic processes. Indeed, muscle fiber hypertrophy arising from absence or blockade of myostatin has been reported to be associated with therapeutic benefits in the mdx mouse model of DMD (2, 3). This hypertrophy has been attributed to proliferation of satellite cells (4, 5), the principal cellular source for growing and regenerating skeletal muscle (6-10), consequent upon their release from myostatin inhibition (5,11,12).Here, we have investigated the contribution of satellite cells in 2 myostatin-null mouse models, constitutive (mstn Ϫ/Ϫ ) and compact (BEH c/c ), and following myostatin blockade by AAVmediated overexpression of myostatin propeptide. These data, together with our results from in vitro studies on the effect of presence or absence of myostatin on satellite cells contradict co...