A myoutube-specific deletion model for sarcopenia

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DESCRIPTION (provided by applicant): During aging, humans can lose up to one third of their skeletal muscle mass. Such aging-associated muscle loss is referred to as sarcopenia. Sarcopenia is a contributing factor to a number of serious public health issues, including bone fractures, loss of ambulation and overall frailty in the elderly. While some advances have been made in understanding sarcopenia using animal models, rodent models most commonly used to study this aspect of muscle biology require aging animals 2-3 years, an age that is at or beyond the animal's normal lifespan. Here we describe a new mouse model for sarcopenia where most relevant hallmarks, including loss of muscle mass, size and strength are evident by 6 months of age. These phenotypes result from myofiber-specific deletion of Pofut1 (Skeletal alpha actin (Sk)-CreTgPofut1loxP), or Protein O-fucosyltransferase 1. Pofut1 is an essential glycosyltransferase that is required for ligands to bind to Notch receptors. Notch receptors and Notch ligands have been shown to be important mediators of the biology underlying the reduced mitotic activity of satellite cells, the principal regenerative pool of muscle stem cells, with age This proposal will provide the first demonstration that Notch activity in the skeletal myofiber als contributes to muscle aging and will allow the specific study of the role of myofiber Notch receptors in muscle regeneration, muscle growth and muscle disease.