An exploration of the mechanisms of naturally occurring limb muscle loss during neonatal development

数百万美国人受到肌肉损失的影响-作为疾病，受伤或衰老的影响-然而， 目前没有任何形式的肌肉退化的治愈方法。符合国家人权委员会的使命 关节炎和肌肉骨骼和皮肤疾病研究所，因此了解肌肉是必不可少的 在最广泛的背景下发展和退化。库珀实验室发现了天然存在的 一种两足的沙漠啮齿动物，小埃及跳鼠在发育过程中的肌肉损失。细胞的方面 这一过程发生在动物出生后的早期和迅速，违背了基于数十年肌肉生长的预测。 在传统模式生物的研究，并强调在目前的理解状态的差距。 最令人惊讶的是，尽管肌肉结构蛋白表达迅速而完全丧失，但并没有 跳鼠足中细胞死亡或免疫反应的可检测证据。肌肉成熟早期 似乎正常进行，但新生的肌肉结构随后通过一种迄今未知的 机制肌肉祖细胞持续存在，直到后期的肌肉细胞损失，但他们是不够的 来恢复肌肉对这种非凡的表型的深入了解将改变我们的 了解肌节解体的细胞和分子机制， 鉴定新生肌细胞意外的发育可塑性。 具体来说，第一个目标将解决令人困惑的观察，没有特征的 检测到细胞死亡的多种机制与广泛和快速的肌细胞损失同时发生。我们将 应用电穿孔介导的细胞跟踪方法来跟踪肌肉谱系的命运， 细胞不能再通过肌肉蛋白的表达来鉴定。第二个目标将实施RNA 测序方法来鉴定在肌肉损失开始时展开的细胞和分子过程。 每一个目的调查一个方面的跳鼠足肌肉细胞损失，可能与人类肌肉交叉 然而，退化性疾病发生在有机体正常发育的背景下。 本提案中概述的实验是实现更广泛目标的重要第一步， 了解后足肌肉损失的惊人解剖学特异性的分子机制 在跳鼠身上由于细胞和组织功能的基本原理在物种间是保守的， 传统的模式生物将没有价值，在这个建议中概述的问题的答案将启发 在各种组织和环境中探索细胞生物学的新维度。

Millions of Americans are impacted by muscle loss – as an effect of disease, injury, or aging – and yet there is currently no cure for any form of muscle degeneration. Consistent with the mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, it is therefore essential to understand muscle development and degeneration in the broadest context. The Cooper lab has identified naturally occurring muscle loss during development of a bipedal desert rodent, the lesser Egyptian jerboa. Aspects of the cellular process, which occurs early and rapidly after birth of the animal, defy predictions based on decades of muscle research in traditional model organisms and highlight gaps in the current state of understanding. Most surprising, despite the rapid and complete loss of muscle structural protein expression, there is no detectable evidence of cell death or an immune response in the jerboa foot. Early stages of muscle maturation appear to proceed normally, but nascent muscle structure subsequently disassembles by an as yet unknown mechanism. Muscle progenitor cells persist until late in the phase of muscle cell loss, but they are insufficient to restore muscle. A deep understanding of this remarkable phenotype stands to transform our understanding of the cellular and molecular mechanisms of sarcomere disassembly and to potentially identify unexpected developmental plasticity of neonatal muscle cells. Specifically, the First Aim will address the perplexing observation that no characteristic features of multiple mechanisms of cell death are detected concurrent with widespread and rapid muscle cell loss. We will apply an electroporation-mediated cell tracking approach to follow the fate of the muscle lineage after muscle cells can no longer be identified by expression of muscle proteins. The Second Aim will implement an RNA sequencing approach to identify the cellular and molecular processes unfolding at the initiation of muscle loss. Each Aim investigates an aspect of jerboa foot muscle cell loss that potentially intersects with human muscle degenerative disorders yet here occurs in the context of normal development of the organism. The experiments outlined in this proposal are essential first steps toward a broader goal of understanding the molecular mechanisms that underlie the striking anatomic specificity of hindfoot muscle loss in the jerboa. Since the fundamentals of cell and tissue function are conserved across species, or indeed traditional model organisms would have no value, answers to the questions outlined in this proposal will inspire explorations of new dimensions of cell biology in a variety of tissues and contexts.