Calcineurin in Prostaglandin Mediated Muscle Growth

描述（由申请人提供）：骨骼肌功能能力的丧失发生在疾病、废用和衰老中，主要归因于肌肉质量的丧失。肌肉质量的这种损失导致虚弱、活动能力和/或呼吸功能受损、生活质量低下和医疗保健费用高昂。骨骼肌的维持和生长强烈依赖于机械信号。将肌肉使用与随后的生长联系起来的信号转导途径还不清楚。前列腺素（PG）是已知的包括骨骼肌在内的许多细胞类型中的生长介质，并且响应于机械刺激而合成和释放。野牡丹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PGF 2a通过钙调神经磷酸酶/NFAT依赖性信号通路导致肌肉生长。这一假设是基于我们鉴定的PGF 2a作为该途径的新激活剂。该方案有三个总体目标：1）研究钙调神经磷酸酶在调节肌肉生长中的作用; 2）研究钙调神经磷酸酶及其下游效应物NFAT在调节COX 2表达中的作用。COX 2是一种关键的酶，必需的合成的mesylandins; 3）以确定是否mesylandins和IGF-1的工作一起或独立地调节肌肉生长，以响应机械刺激。我们将利用机械拉伸培养的肌管的存在和不存在的药理学和遗传抑制剂/激活剂的钙调磷酸酶/NFAT途径来研究肌肉生长的调节，以响应机械拉伸。这项工作将扩展到包括在体内的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，这些研究将确定一个信号转导途径，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。鉴于肌肉质量损失发生的临床条件的数量，了解调节肌纤维生长的分子途径对于开发用于在疾病，废用和衰老中操纵这种生长过程的康复治疗的新途径是重要的。

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.