Cellular Basis for Radiation induced acceleration of sarcopenia in juvenile cancer survivors

摘要： 尽管估计表明，被诊断为恶性肿瘤的儿童的5年存活率接近 80%，这些人中的绝大多数在40岁之前表现出身体限制指数 通常与老年人口有关。在早先观察到的与年龄相关的表型中 儿童癌症幸存者是骨质疏松症，瘦身体骨骼肌组织和力量的加速丧失 随着年龄的增长。骨质疏松症的特征是肌肉干细胞(卫星细胞)的丧失和慢性低级别 炎症，导致肌肉纤维(肌纤维)萎缩。这项提议旨在澄清是否 幼年辐射治疗导致卫星细胞全身性丢失，从而1)损害幼年骨骼肌 成熟，2)加速儿童癌症幸存者的骨质疏松症。重要的是，我们建议这颗卫星 受体酪氨酸激酶反馈调节因子Sprouty1(Spry1)的细胞特异性强制表达可以防止 幼年引起的全身性卫星细胞丢失、骨骼肌萎缩和低度炎症 辐射。为了实现这些目标，卫星细胞特有的小鼠遗传模型，询问 将进行骨骼肌形态、生理学和对幼年辐射反应的炎症研究。 我们已经生成了初步数据，表明卫星细胞的活动和贡献在P21之后持续存在 (小鼠断奶年龄)和~P42(青春期开始)下降，这表明辐射可能会损害肌肉 发育到青春期。事实上，卫星细胞的耗尽，或幼体阶段的局部照射(第28页)会导致 肌核丢失和萎缩。此外，辐射还会导致持续性的卫星细胞丢失和升高。 巨噬细胞含量，导致细胞因子萎缩的来源。与全身效应相一致的，辐射 一条腿引起萎缩，肌核和卫星细胞丢失，巨噬细胞含量增加。 对侧肌。此外，在受辐射肌肉的卫星细胞中，我们发现Spry1的表达减少。 我们将巩固我们的初步发现，并评估卫星细胞枯竭和辐射的后果。 对幼年骨骼肌成熟和骨骼肌减少的影响。此外，我们将检查卫星细胞特异性 Spry1的强制表达可防止幼年辐射所致的骨骼肌减少加速。具体目标 这项建议的结论是：1)确定幼年阶段的卫星细胞枯竭是否会导致肌肉持续 下降，和低级别炎症，2)确定青少年放射治疗是否导致系统性和持久性 卫星细胞丢失、肌肉萎缩和低级别炎症，以及3)确定卫星细胞特异性 强制表达Spry1预防幼年放射治疗引起的卫星细胞、肌肉的全身性丢失 消退，和低度炎症。来自这项提案的数据应该严格定义卫星细胞的作用 并阐明Spry1通路是否是预防的潜在靶点 幼年放射治疗引起的全身星形细胞萎缩和加速的肌萎缩症。

ABSTRACT: Although estimates indicate the 5-year survival rate of children diagnosed with a malignancy is near 80%, the vast majority of these individuals prior to the age of 40 demonstrate indices of physical limitation normally associated with the elderly population. Among the age-related phenotypes observed earlier in childhood cancer survivors is sarcopenia, the accelerated loss of lean body skeletal muscle tissue and strength with age. Sarcopenia is characterized by loss of muscle stem cells (satellite cells) and chronic low-grade inflammation, which causes atrophy of muscle fibers (myofibers). This proposal is designed to elucidate if juvenile radiation treatments lead to systemic loss of satellite cells that 1) impairs juvenile skeletal muscle maturation, and 2) accelerates sarcopenia in childhood cancer survivors. Importantly, we propose that satellite cell-specific forced expression of sprouty1 (Spry1), a receptor tyrosine kinase feedback regulator, can prevent systemic loss of satellite cells, skeletal muscle declines, and low-grade inflammation induced by juvenile irradiation. To accomplish these objectives satellite cell-specific mouse genetic models, interrogation of skeletal muscle morphology, physiology, and inflammation in response to juvenile irradiation will be conducted. We have generated preliminary data that show satellite cell activity and contribution persists after P21 (weaning age in mice) and declines ~P42 (puberty onset), suggesting that radiation could damage muscle growth up to puberty. Indeed, depletion of satellite cells, or local irradiation at juvenile stages (P28) induced loss of myonuclei and atrophy. Furthermore, the irradiation leads to persistent satellite cell loss and elevated macrophage content, a source of atrophy inducing cytokines. Consistent with a systemic effect, irradiation of one leg triggered atrophy, loss of myonuclei and satellite cells, and increased macrophage content in contralateral muscles. In addition, in satellite cells from irradiated muscle we find reduced expression of Spry1. We will solidify our preliminary findings, and assess the consequences of satellite cell depletion and irradiation on juvenile skeletal muscle maturation and sarcopenia. In addition, we will examine if satellite cell specific Spry1 forced expression can prevent juvenile radiation induced acceleration of sarcopenia. The specific aims of this proposal are: 1) To determine if satellite cell depletion at juvenile stages leads to sustained muscle decline, and low-grade inflammation, 2) To determine if juvenile radiotherapy induces systemic and persistent satellite cell loss, muscle decline, and low-grade inflammation, and 3) To determine if satellite cell-specific forced Spry1 expression prevents juvenile radiotherapy-mediated systemic loss of satellite cells, muscle decline, and low-grade inflammation. Data from this proposal should rigorously define the role of satellite cells in juvenile radiotherapy-induced sarcopenia, and elucidate if the Spry1 pathway is a potential target to prevent systemic satellite cell decline and accelerated sarcopenia induced by juvenile radiotherapy.