Calcineurin in Prostaglandin Mediated Muscle Growth

描述（由申请人提供）：骨骼肌功能的丧失发生在疾病、不使用和衰老中，主要是由于肌肉量的减少。这种肌肉量的损失会导致身体虚弱、行动能力和/或呼吸功能受损、生活质量低下和医疗费用高昂。骨骼肌强烈依赖机械信号来维持和生长。连接肌肉使用和随后生长的信号转导通路还没有被很好地理解。前列腺素（PG）是已知的多种细胞类型（包括骨骼肌）的生长介质，并在机械刺激下合成和释放。前列腺素导致骨骼肌生长的机制在很大程度上是未知的，这是本提案的重点。我们假设前列腺素PGF2a通过钙调磷酸酶/NFAT依赖的信号通路导致肌肉生长。这一假设是基于我们发现PGF2a是这一途径的一种新的激活剂。本研究有三个总体目标：1)研究钙调磷酸酶在调节肌肉生长中的作用；2)研究calcalineurin及其下游效应物NFAT在调节COX2表达中的作用。COX2是合成前列腺素必需的关键酶；3)确定前列腺素和IGF-1在机械刺激下是否共同或单独调节肌肉生长。我们将利用机械拉伸培养的肌管，在存在和不存在钙调磷酸酶/NFAT途径的药理学和遗传抑制剂/激活剂的情况下，研究机械拉伸对肌肉生长的调节。这项工作将扩展到包括体内机械刺激肌肉生长的研究，以证明所提出的途径是否具有生理活性。总之，这些研究将定义一个信号转导途径，通过该途径可以调节成人骨骼肌的生长，以响应肌肉的使用。考虑到肌肉质量损失的临床情况，了解调节肌纤维生长的分子途径对于开发新的康复治疗途径来控制疾病，废弃和衰老中的这种生长过程是重要的。

DESCRIPTION (provided by applicant): A loss of skeletal muscle functional capacity occurs in disease, disuse and aging mostly attributable to a loss of muscle mass. Such losses of muscle mass contribute to weakness, impaired mobility and/or respiratory function, low quality of life and high health care costs. Skeletal muscle is strongly dependent on mechanical signals for maintenance and growth. The signal transduction pathways that link muscle use to subsequent growth are not well understood. Prostaglandins (PG) are known mediators of growth in many cell types including skeletal muscle and are synthesized and released in response to mechanical stimuli. The mechanism by which prostaglandins lead to growth in skeletal muscle is largely unknown and is the focus of this proposal. We hypothesize that the prostaglandin PGF2a leads to muscle growth through a Calcineurin/NFAT dependent signaling pathway. This hypothesis is based on our identification of PGF2a as a novel activator of this pathway. This proposal has three overall goals: 1) to study the role of calcineurin in modulating muscle growth; 2) to study the role of calcineurin and its downstream effector NFAT in regulating the expression of COX2. COX2 is a key enzyme necessary for the synthesis of prostaglandins; 3) to determine if prostaglandins and IGF-1 work together or independently to regulate muscle growth in response to mechanical stimuli. We will utilize mechanical stretch of cultured myotubes in the presence and absence of pharmacologic and genetic inhibitors/activators of the Calcineurin/NFAT pathway to study the regulation of muscle growth in response to mechanical stretch. The work will be extended to encompass studies of mechanically stimulated muscle growth in vivo in order demonstrate whether the proposed pathways are physiologically active. Together, these studies will define a signal transduction pathway by which adult skeletal muscle growth can be regulated in response to muscle use. Given the number of clinical conditions in which loss of muscle mass occurs, understanding the molecular pathways regulating myofiber growth is important for developing new avenues of rehabilitative therapy for manipulating this growth process in disease, disuse and aging.