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.

项目摘要/摘要 骨骼肌再生和相关的病理组织重塑受损（肌肉丧失，增益 损伤后的纤维化和脂肪组织）功能和代谢下降是衰老的标准。 再生取决于一个精心策划的肌源程序，该程序包括激活和扩展 骨骼肌干细胞/祖细胞（MPC）和MPC终末分化成熟 多核肌肉细胞。我们先前证明MPC依赖于细胞外的可用性 在营养上，非必需氨基酸L-丝氨酸（Ser）和甘氨酸（Gly）。 ser/gly损伤的可用性降低 MPC膨胀，损伤后诱导肌内脂肪细胞，并诱导有毒的脱氧脂质脂质。 肌肉积聚。此外，我们证明了内源性Ser/Gly水平随着年龄的增长而下降。这 Ser/Gly的代谢产物（即需求）用于MPC扩展和饮食Ser/Gly肌肉的效率 再生和细胞（MPC） - 超支环境需要解决。我们建议使用同位素跟踪 Ser和Gly的定义Ser/Gly对MPC种群扩展的代谢需求。此外，使用 我们已经证明的模型减少了（饮食枯竭）或增强（补充饮食）内源性Ser/Gly 水平，我们将量化Ser/Gly可用性对年龄和损伤相关的肌肉再生的影响以及 细胞（MPC） - 超支肌肉环境。根据初步数据，我们假设MPC需要 谷胱甘肽合成，从细胞外Ser和Gly到减轻氧化应激。另外，我们假设 饮食引起的内源性SER/GLY加剧与年龄相关的（i）肌肉损害的减少 再生和（ii）在细胞超支肌肉环境中的有毒非经典鞘脂。此外，我们 期望补充服务将应对这些影响。捕获饮食中/胶的效率调节的效率 与年龄相关的肌肉再生和重塑障碍，我们将使用新型的鞘脂术分析和 转录组学。该项目的成功完成将改变对 Ser和Gly对于骨骼肌再生的代谢本质以及这种损失与年龄的关系 确定相关的肌肉。结果将使可科学的基础疗法能够改善 肌肉再生的人群的再生能力，例如老年人。