Olfactory receptor signaling in skeletal muscle

描述（由申请人提供）：创伤性损伤后，适当的肌肉再生是恢复正常肌肉结构和功能所必需的。异常再生可导致肌纤维大小、数量和结构的改变。具有异常分支细胞结构的肌纤维常见于各种神经肌肉疾病以及包括人类在内的各种物种的严重肌肉损伤后。这些异常肌纤维是脆弱的，这些肌纤维含量高的肌肉与无力和损伤发生率增加之间存在相关性。含有高水平分支肌纤维的肌肉不可能以正常的生理方式发挥作用。迄今为止，调节肌纤维分支的机制和分子尚不清楚。从基础和临床的角度阐明调控肌纤维分支的机制具有重要意义。我们最近确定了小鼠气味受体23 （MOR23）在小鼠骨骼肌再生中的新作用，并确定了第一个在肌纤维分支中起功能作用的分子。嗅觉神经元中的气味受体信号通过腺苷酸环化酶3 （AC3）和蛋白激酶A （PKA）依赖的信号通路调节几种粘附和化学引诱分子的表达。骨骼肌中受MOR23信号调控的下游分子在肌纤维分支中发挥的作用尚不清楚。这一建议将阐明MOR23调控小鼠肌纤维分支的分子途径。根据我们的初步数据，我们假设骨骼肌中MOR23的激活刺激AC3和蛋白激酶A （PKA）信号传导，导致调节肌肉细胞迁移和粘附的下游分子的变化，从而导致肌纤维分支。我们将使用各种遗传小鼠模型来测试这些不同分子在调节肌肉细胞迁移和粘附以及肌纤维分支中的作用。提出的实验是新颖的，因为他们是第一个机械解剖肌纤维分支的调节。气味受体信号通路及其下游分子效应物可能是减少各种神经肌肉疾病中肌纤维分支的有效药理靶点。减少分支肌纤维的数量可能有利于改善肌肉生理学和肌肉疾病的细胞和基因治疗方法的效率。

DESCRIPTION (provided by applicant): Proper muscle regeneration is necessary to restore normal muscle architecture and function after traumatic injury. Aberrant regeneration can result in alterations in myofiber size, number and architecture. Myofibers with an abnormal branching cytoarchitecture are commonly found in various neuromuscular diseases as well as after severe muscle injury in various species, including human. These aberrant myofibers are fragile and a correlation exists between muscles containing a high percentage of these myofibers and weakness and increased incidence of injury. Muscles containing high levels of branched myofibers are unlikely to function in a normal physiologic manner. To date the mechanisms and molecules regulating myofiber branching have been obscure. The mechanisms regulating myofiber branching are significant to elucidate from both a basic and a clinical standpoint. We recently established a novel role for mouse odorant receptor 23 (MOR23) in skeletal muscle regeneration in mice and identified the first molecule with a functional role in myofiber branching. Odorant receptor signaling in olfactory neurons regulates expression of several adhesion and chemoattractant molecules through an adenylyl cyclase 3 (AC3) and protein kinase A (PKA) dependent signaling pathway. The downstream molecules regulated by MOR23 signaling in skeletal muscle that play a role in myofiber branching are unknown. This proposal will elucidate the molecular pathway by which MOR23 regulates myofiber branching in mice. Based on our preliminary data we hypothesize that activation of MOR23 in skeletal muscle stimulates AC3 and protein kinase A (PKA) signaling leading to changes in downstream molecules that regulate muscle cell migration and adhesion and thus, myofiber branching. We will use various genetic mouse models to test the roles of these different molecules in regulating muscle cell migration and adhesion as well as myofiber branching. The proposed experiments are novel because they are the first to mechanistically dissect regulation of myofiber branching. Odorant receptor signaling pathways and their downstream molecular effectors may serve as effective pharmacologic targets for decreasing myofiber branching in various neuromuscular disorders. Decreasing the number of branched myofibers will likely be beneficial for improving both muscle physiology and the efficiency of cell and gene therapy approaches for muscular disorders. PUBLIC HEALTH RELEVANCE: Muscle cells with an abnormal branching shape are commonly found in various muscle diseases as well as after severe muscle injury. These abnormal muscle cells are fragile and muscles containing a high percentage of these types of cells are weaker and become injured more easily. How these branched muscle cells arise is unknown. The mechanisms regulating the formation of these abnormal muscle cells is important to define from both a basic science and a clinical standpoint. We will use biochemical and genetic methods to manipulate the function of several molecules we hypothesize to play a role in muscle cell branching and analyze the outcome. The proposed experiments are novel because they are the first to mechanistically dissect regulation of muscle cell branching. In the future, the pathway under study may lead to drug therapies for eliminating these abnormal muscle cells in various muscle disorders.