A myoutube-specific deletion model for sarcopenia

描述（由申请人提供）：在衰老过程中，人类可以失去多达三分之一的骨骼肌质量。这种与衰老相关的肌肉损失被称为肌肉减少症。肌肉减少症是导致许多严重公共卫生问题的一个因素，包括老年人的骨折、截肢和整体虚弱。虽然使用动物模型在理解肌肉减少症方面取得了一些进展，但最常用于研究肌肉生物学这一方面的啮齿动物模型需要2-3岁的衰老动物，该年龄等于或超过动物的正常寿命。在这里，我们描述了一种新的肌肉减少症小鼠模型，其中最相关的标志，包括肌肉质量，大小和力量的损失在6个月大时是明显的。这些表型是由Pofut 1（骨骼α肌动蛋白（Sk）-CreTgPofut 1 loXP）或蛋白质O-岩藻糖基转移酶1的肌纤维特异性缺失引起的。Pofut 1是一种必需的糖基转移酶，是配体与Notch受体结合所必需的。Notch受体和Notch配体已被证明是卫星细胞（肌肉干细胞的主要再生池）的有丝分裂活性随年龄降低的生物学基础的重要介质。该提议将首次证明骨骼肌纤维ALS中的Notch活性有助于肌肉老化，并将允许对肌纤维Notch受体在肌肉再生中的作用进行具体研究，肌肉生长和肌肉疾病。

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.