Muscle development and function in a MAGEL2 mouse model of Prader-Willi syndrome

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  • Background: Prader-Willi syndrome (PWS) is a multigene disorder commonly associated with hyperphagia and obesity. Children with PWS have increased fat mass and decreased lean mass before the onset of hyperphagia and obesity. Severe hypotonia and reduced muscle strength are typically present in PWS infants. Inactivating mutations in one PWS candidate gene, MAGEL2, cause a Prader- Willi-like syndrome (Schaaf-Yang syndrome) with neonatal hypotonia and joint contractures, highlighting the importance of loss of MAGEL2 in PWS phenotypes. The process of autophagy is essential in maintaining musculoskeletal homeostasis, and increased or decreased autophagy can lead to muscle atrophy. Autophagic markers such as ubiquitin (Ub), p62/SQSTM1 (p62) and microtubule associated protein 1-light chain 3 (LC3) are hypothesized to be connected to the MAGE family of proteins that includes MAGEL2, suggesting that loss of MAGEL2 could modulate autophagy in muscle. Methods and Results: Expression of MAGEL2 was detected in the murine nervous system and in developing muscle, connective tissue and bone. Neonatal mice lacking MAGEL2 had reduced muscle mass, increased fat mass and decreased bone mass compared to wild-type mice. Immunohistochemistry (IHC), and immunoblotting were used to determine whether loss of MAGEL2 affects the accumulation of
    autophagic markers or expression of genes associated with muscle atrophy, in neonatal mice. The p62 positive aggregates were increased in muscle from MAGEL2 mice and atrophy genes were up regulated. Conclusions: Abnormal autophagic processes likely contribute to muscle atrophy in mice lacking MAGEL2. Further studies are needed to determine how the inactivation of MAGEL2 causes muscle phenotypes at a cellular level. Our mouse strain carrying loss of MAGEL2 provides a model for muscular dysfunction in Prader-Willi syndrome. Summary: One of the symptoms of PWS is poor muscle tone, which could be caused by disruption in the autophagy process that regulates skeletal muscle.
    Autophagy is disrupted and atrophy is increased in muscle from mice lacking MAGEL2, one of the PWS candidate genes. We propose a mechanism by which loss of MAGEL2 causes hypotonia in children with PWS.

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    Attribution-NonCommercial 4.0 International