Metabolic regulation of muscle satellite cell homeostasis

肌肉卫星细胞稳态的代谢调节

• 批准号: 10591847
• 负责人: Shihuan Kuang
• 金额: $ 50.3万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591847
• 关键词: Acetylation; Adipocytes; Adult; Affect; Aging; Biochemical; Biogenesis; Catabolism; Cell Cycle; Cell Differentiation process; Cell Fate Control; Cell Nucleus; Cell Proliferation; Cell Respiration; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Centrosome; Citric Acid Cycle; Cues; DNA; Data; Degenerative Disorder; Development; Energy Supply; Exhibits; Fatty Acids; Growth; Homeostasis; In Vitro; Injury; Knowledge; Label; Laboratories; Link; Lipids; Lipolysis; Maintenance; Maps; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Molecular Profiling; Muscle; Muscle function; Muscle satellite cell; Myoblasts; Natural regeneration; Nutrient; Organelles; Pathogenesis; Pathologic; Pattern; Phosphorylation; Play; Production; Proliferating; Protein Acetylation; Proteins; Regenerative capacity; Regulation; Reporting; Role; STK11 gene; Self-Injurious Behavior; Signal Transduction; Sister; Skeletal Muscle; Skeletal Muscle Satellite Cells; System; Testing; Translating; Transplantation; Work; fatty acid oxidation; glucose metabolism; improved; in vivo; injury and repair; insight; lipid biosynthesis; lipid mediator; lipid metabolism; lipidomics; metabolomics; muscle regeneration; nerve stem cell; novel; postnatal; regeneration function; repaired; response to injury; satellite cell; segregation; self renewing cell; self-renewal; stem cell biology; stem cell fate; stem cell function; stem cells; tissue stem cells; tumor metabolism

Metabolic regulation of muscle satellite cell homeostasis and function Abstract Muscle satellite cells (MuSCs) are resident stem cells in the skeletal muscle responsible for its postnatal growth, maintenance and regeneration. MuSCs in adult homeostatic muscles are predominantly in the quiescent state. In response to injury, quiescent MuSCs are activated, enter the cell cycle and proliferate as myoblasts, then differentiate to repair the injury or self-renew to replenish the stem cell pool. The homeostasis of these various cell states (quiescence, activation, proliferation, differentiation and self-renewal) is necessary to support multiple rounds of successful and sustainable regeneration throughout the lifetime. Despite the remarkable progress accomplished in the past decades, the key regulators and signaling mechanisms underlying the homeostasis and function of MuSCs remain elusive. Lipid droplets (LDs) are cellular organelles commonly found in adipocytes, where they function as a central hub for lipid biosynthesis, storage and utilization that are crucial for cell metabolism and signaling. Recent studies have begun to elucidate a paramount role of LDs in cancer cell metabolism and pathogenesis, but the presence and role of LDs in tissue stem cells including MuSCs have only been explored very recently. Preliminary studies in the PI's laboratory have led to the discovery of highly dynamic LDs in MuSCs along their myogenic progression in vitro and in vivo. Specifically, LDs are not present in any quiescent MuSCs but emerge in activated MuSCs and increase in abundance in proliferating myoblasts. Strikingly, unequal distribution of LDs is observed in some newly divided sister cells exhibiting hallmarks of asymmetric cell fate segregation. In addition, fatty acid metabolic pathways are dynamically regulated in a pattern similar to the dynamics of LDs, and perturbations of fatty acid oxidation (FAO) disrupts MuSC homeostasis and function. Based on these observations, it is hypothesized that LDs regulate MuSC homeostasis and function through influencing cellular energy supply and/or lipid metabolite-mediated signaling. Two aims are developed to test this central hypothesis. The first aim will examine the role of LDs in MuSC homeostasis and regenerative function in vivo. The second aim will dissect how LD dynamics are regulated and how lipid metabolism in turn regulates MuSC homeostasis and function. Completion of the proposed study is expected to establish LDs as a novel cell fate marker and understand how lipid metabolism regulates MuSC fates. Previous studies have identified immortal DNA strands, centrosomes, mitochondria and various proteins as cell fate determinants, the identification of LD as an additional cell fate regulator opens a new chapter in stem cell biology. The knowledge will also facilitate the development of mitigation strategies to improve the regeneration and function of skeletal muscles during aging or under pathological conditions.

肌卫星细胞稳态和功能的代谢调节 摘要 肌肉卫星细胞（MuSC）是骨骼肌中负责其出生后生长的常驻干细胞， 维护和再生。成年稳态肌肉中的MuSC主要处于静止状态。 作为对损伤的响应，静止的MuSC被激活，进入细胞周期并作为成肌细胞增殖，然后 分化以修复损伤或自我更新以补充干细胞库。这些不同的细胞的体内平衡 细胞状态（静止、活化、增殖、分化和自我更新）对于支持多个细胞周期是必要的。 在整个生命周期中进行成功和可持续的再生。尽管取得了显著的进步 在过去的几十年里，完成了关键的调节和信号机制的基础上的稳态 和功能仍然难以捉摸。脂滴（LD）是细胞器中常见的， 脂肪细胞，在那里它们作为脂质生物合成、储存和利用的中心枢纽， 细胞代谢和信号传导。最近的研究已经开始阐明LD在癌细胞中的重要作用 但是，LD在组织干细胞（包括MuSC）中的存在和作用仅具有 最近被探索过。PI实验室的初步研究发现， MuSC中的LD在体外和体内沿着其肌原性进展。具体地，LD不存在于任何 静止的MuSC，但在活化的MuSC中出现，并且在增殖的成肌细胞中丰度增加。 引人注目的是，在一些新分裂的姐妹细胞中观察到LD的不均匀分布， 不对称细胞命运分离。此外，脂肪酸代谢途径以一种模式动态调节， 类似于LD的动力学，并且脂肪酸氧化（FAO）的扰动破坏了MuSC的稳态， 功能基于这些观察，假设LD调节MuSC稳态和功能， 通过影响细胞能量供应和/或脂质代谢物介导的信号传导。两个目标是 来检验这个核心假设。第一个目标将检查LD在MuSC稳态中的作用， 体内再生功能。第二个目标将剖析LD动力学是如何调节的，以及脂质是如何调节的。 代谢反过来调节MuSC稳态和功能。预计拟议研究完成后， 建立LD作为一种新的细胞命运标志物，并了解脂质代谢如何调节MuSC的命运。先前 研究已经确定了不朽的DNA链，中心体，线粒体和各种蛋白质作为细胞的命运 决定因素，LD作为一个额外的细胞命运调节剂的鉴定开辟了干细胞生物学的新篇章。 这些知识还将有助于制定缓解战略，以改善再生和 在衰老或病理条件下骨骼肌的功能。