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.

肌肉卫星细胞稳态和功能的代谢调节 抽象的 肌肉卫星细胞（MUSC）是骨骼肌中驻留的干细胞，负责其产后生长， 维护和再生。成人稳态肌肉的MUSC主要处于静止状态。 响应损伤，激活静态的MUSC，进入细胞周期并作为成肌细胞增殖，然后 区分以修复伤害或自我更新以补充干细胞池。这些不同的体内平衡 细胞状态（静止，激活，增殖，分化和自我更新）对于支持多个 整个一生中成功和可持续的再生一轮。尽管取得了显着的进展 在过去的几十年中，取得的关键调节器和信号机制是体内平衡的基础 MUSC的功能仍然难以捉摸。脂质液滴（LDS）是通常在 脂肪细胞，它们充当脂质生物合成，储存和利用的中心枢纽，对于至关重要 细胞代谢和信号传导。最近的研究已经开始阐明LDS在癌细胞中的重要作用 代谢和发病机理，但是LDS在包括MUSC在内的组织干细胞中的存在和作用仅具有 最近探索了。 PI实验室的初步研究导致发现高度动态 LDS在体外和体内沿着肌源性进展的MUSC中的LDS。具体来说，LD不存在 静止的MUSC，但在激活的MUSC中出现并增加了肌细胞增殖的丰度。 令人惊讶的是，在一些新近分裂的姊妹细胞中观察到LDS的不等分布，这些细胞具有标志 不对称细胞命运分离。另外，脂肪酸代谢途径以模式动态调节 类似于LD的动力学，脂肪酸氧化（FAO）的扰动破坏了MUSC稳态和 功能。基于这些观察结果，假设LDS调节MUSC稳态和功能 通过影响细胞能供应和/或脂质代谢物介导的信号传导。两个目标是 开发用于检验该中心假设。第一个目的将研究LDS在MUSC稳态中的作用和 体内再生功能。第二个目标将剖析如何调节LD动力学以及如何调节脂质 代谢反过来调节MUSC稳态和功能。拟议的研究的完成预计将是 将LDS建立为一种新颖的细胞命运标记，并了解脂质代谢如何调节MUSC命运。以前的 研究已将不朽的DNA链，中心体，线粒体和各种蛋白质确定为细胞命运 决定因素，将LD鉴定为额外的细胞命运调节剂，开辟了干细胞生物学的新章节。 知识还将促进制定缓解策略，以改善再生和 衰老或病理条件下骨骼肌的功能。