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

摘要： 虽然估计表明，诊断为恶性肿瘤的儿童的5年生存率接近 80%，这些人中的绝大多数在40岁之前表现出身体限制的指数 通常与老年人有关。在早期观察到的年龄相关表型中， 儿童癌症幸存者是肌肉减少症，加速损失精益身体骨骼肌组织和力量 随年龄肌肉减少症的特征是肌肉干细胞（卫星细胞）的损失和慢性低度 炎症，导致肌肉纤维（肌纤维）萎缩。本建议旨在阐明， 幼年辐射处理导致卫星细胞的系统性损失，其1）损害幼年骨骼肌 成熟，和2）加速儿童癌症幸存者的肌肉减少症。重要的是，我们建议卫星 细胞特异性强制表达受体酪氨酸激酶反馈调节因子sprougty 1（Spry 1），可以防止 全身性卫星细胞丢失，骨骼肌衰退，以及由青少年引起的低度炎症 辐照为了实现这些目标，卫星细胞特异性小鼠遗传模型， 将进行骨骼肌形态学、生理学和炎症对幼年照射的反应。 我们已经产生了初步的数据，显示卫星细胞的活动和贡献持续后P21 （小鼠断奶年龄）和~P42（青春期开始）下降，表明辐射可能损害肌肉 生长到青春期。事实上，卫星细胞的耗竭或幼年期的局部照射（P28）诱导了 肌核丢失和萎缩。此外，辐射导致持续的卫星细胞损失和升高的细胞毒性。 巨噬细胞含量，萎缩诱导细胞因子的来源。与全身效应一致， 一条腿引发萎缩，肌核和卫星细胞丢失， 对侧肌肉此外，在来自辐照肌肉的卫星细胞中，我们发现Spry 1的表达减少。 我们将巩固我们的初步发现，并评估卫星细胞耗尽和辐射的后果 对幼年骨骼肌成熟和肌肉减少症的影响。此外，我们将检查是否卫星细胞特定 Spry 1基因的强制表达可以防止幼年辐射引起的骨骼肌减少症的加速。具体目标 该建议的主要内容是：1）确定幼年期卫星细胞的缺失是否会导致持续的肌肉生长， 2）确定幼年放射治疗是否诱导全身性和持续性炎症， 卫星细胞损失、肌肉衰退和低度炎症，以及3）确定卫星细胞特异性 Spry 1的强制表达可防止幼年放疗介导的卫星细胞、肌肉 衰退和轻度炎症从这一建议中获得的数据应能严格界定卫星细胞的作用 在青少年放疗诱导的肌肉减少症，并阐明如果Spry 1途径是一个潜在的目标，以防止 全身卫星细胞下降和加速肌肉减少症。

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.