The essentiality of serine and glycine for skeletal muscle regeneration in aging

丝氨酸和甘氨酸对于衰老过程中骨骼肌再生的重要性

• 批准号: 10341618
• 负责人: Anna E. Thalacker-Mercer
• 金额: $ 35.1万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10341618
• 关键词: Activities of Daily Living; Address; Adipocytes; Adipose tissue; Affect; Age; Aging; Amino Acids; Biochemical; Biological Assay; Biology; Cell Count; Cell Proliferation; Cells; Cellular Metabolic Process; Cellular Stress; Coupled; Creatine; Data; Deterioration; Development; Diet; Elderly; Environment; Fatty acid glycerol esters; Glutathione; Glycine; Goals; Health; Homeostasis; Image; Impairment; Infiltration; Inflammation; Injury; Intramuscular; Isotopes; Knowledge; Label; Measures; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mission; Modeling; Morphology; Mus; Muscle; Muscle Cells; Muscle function; Muscle satellite cell; Muscular Atrophy; Myopathy; Natural regeneration; Non-Essential Amino Acid; Nutrient; Nutritive Value; Obesity; Outcome; Oxidative Stress; Pathologic; Phosphorylation; Physical Function; Physiological; Population; Process; Protein Biosynthesis; Quality of life; Regenerative capacity; Research; Risk; Serine; Skeletal Muscle; Sphingolipids; Supplementation; Testing; Tissues; United States National Institutes of Health; age related; age-related muscle loss; aged; aging population; base; dietary; efficacy evaluation; extracellular; improved; in vivo; injured; muscle regeneration; muscular structure; novel; programs; regenerative; stem cell biomarkers; stem cell differentiation; stem cell function; stem cell proliferation; stem cells; therapeutic target; therapy development; tissue regeneration; transcriptome; transcriptomics

PROJECT SUMMARY/ABSTRACT Impaired skeletal muscle regeneration and associated pathological tissue remodeling (loss of muscle, gain of fibrotic and adipose tissues) following injury underlie functional and metabolic decline—hallmarks of aging. Regeneration is dependent on a well-orchestrated myogenic program that includes the activation and expansion of skeletal muscle stem cells/progenitor cells (MPCs) and terminal differentiation of MPCs into mature multinucleated muscle cells. We previously demonstrated that MPCs rely on extracellular availability of the nutritionally, non-essential amino acids L-serine (Ser) and glycine (Gly). Decreased availability of Ser/Gly impairs MPC expansion, induces intramuscular adipocytes following injury, and induces toxic deoxysphingolipid accumulation in the muscle. Further, we demonstrated that endogenous Ser/Gly levels decline with age. The metabolic product (i.e. requirement) of Ser/Gly for MPC expansion and the efficacy of dietary Ser/Gly for muscle regeneration and the cell (MPC)-extrinsic environment need to be resolved. We propose to use isotope tracing of Ser and Gly to define the metabolic requirement of Ser/Gly for MPC population expansion. Further, using models that we have demonstrated reduce (depleted diet) or enhance (supplemented diet) endogenous Ser/Gly levels, we will quantify the effects of Ser/Gly availability on age- and injury-related muscle regeneration and the cell (MPC)-extrinsic muscle environment. Based on preliminary data, we hypothesize that MPCs require glutathione synthesis, from extracellular Ser and Gly, to mitigate oxidative stress. Additionally, we hypothesize that diet-induced reduction of endogenous Ser/Gly exacerbates age-related (i) impairments in muscle regeneration and (ii) toxic non-canonical sphingolipids in the cell-extrinsic muscle environment. Further, we expect Ser/Gly supplementation will counter these effects. To capture the efficacy of dietary Ser/Gly to modulate age-related impairments in muscle regeneration and remodeling we will use novel sphingolipidome profiling and transcriptomics. Successful completion of this project will transform the fundamental understanding of the metabolic essentiality of Ser and Gly for skeletal muscle regeneration and the relationship of this loss to age- related muscle deterioration. The results will enable testable scientifically grounded therapies to improve the regenerative capacity in populations that have impaired muscle regeneration, such as older adults.

项目概要/摘要 骨骼肌再生受损和相关的病理组织重塑（肌肉损失、肌肉增加） 损伤后的纤维化和脂肪组织）是功能和代谢下降的基础——衰老的标志。 再生取决于精心策划的生肌程序，包括激活和扩张 骨骼肌干细胞/祖细胞 (MPC) 的形成以及 MPC 终末分化为成熟细胞 我们之前证明 MPC 依赖于细胞外的可用性。 营养上，非必需氨基酸 L-丝氨酸 (Ser) 和甘氨酸 (Gly)。Ser/Gly 的可用性降低会损害 MPC 扩张，损伤后诱导肌内脂肪细胞，并诱导有毒的脱氧鞘脂 此外，我们证明内源性丝氨酸/甘氨酸水平随着年龄的增长而下降。 MPC 扩张所需的 Ser/Gly 代谢产物（即需要量）以及膳食 Ser/Gly 对肌肉的功效 再生和细胞（MPC）外在环境需要解决，我们建议使用同位素示踪。 Ser 和 Gly 来定义 MPC 群体扩展的 Ser/Gly 代谢需求。 我们已经证明减少（贫乏饮食）或增强（补充饮食）内源性 Ser/Gly 的模型 水平，我们将量化 Ser/Gly 可用性对年龄和损伤相关肌肉再生的影响以及 根据初步数据，我们发现 MPC 需要细胞（MPC）外在肌肉环境。 来自细胞外的 Ser 和 Gly 的谷胱甘肽合成，以减轻氧化应激。 饮食引起的内源性 Ser/Gly 减少会加剧与年龄相关的 (i) 肌肉损伤 再生和（ii）细胞外肌肉环境中的有毒非典型鞘脂。 预计 Ser/Gly 补充剂将抵消这些影响，以捕获膳食 Ser/Gly 的调节功效。 肌肉再生和重塑中与年龄相关的损伤，我们将使用新型鞘脂组分析和 该项目的成功完成将改变对转录组学的基本理解。 Ser 和 Gly 对骨骼肌再生的代谢重要性以及这种损失与年龄的关系 研究结果将使可测试的、有科学依据的疗法得以改善。 肌肉再生受损的人群（例如老年人）的再生能力。