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

项目摘要/摘要 骨骼肌再生受损和相关的病理性组织重塑(肌肉丧失、 损伤后的纤维组织和脂肪组织)是功能和代谢衰退的基础，这是衰老的标志。 再生依赖于一个精心安排的生肌程序，其中包括激活和扩张 骨骼肌干/祖细胞的分化与成熟的终末分化 多核肌肉细胞。我们以前证明过，MPC依赖于细胞外的 在营养上，非必需氨基酸L-丝氨酸(丝氨酸)和甘氨酸(甘氨酸)。丝氨酸/甘氨酸损伤的可用性降低 MPC的扩张，在损伤后诱导肌肉内脂肪细胞，并诱导有毒的脱氧鞘磷脂 在肌肉中堆积。此外，我们还证明了内源性丝氨酸/甘氨酸水平随着年龄的增长而下降。这个 丝氨酸/甘氨酸扩增MPC代谢产物(即需要量)及其对肌肉的影响 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 以确定丝氨酸/甘氨酸在MPC种群扩张中的代谢需求。此外，使用 我们已经证明的减少(耗尽饮食)或增强(补充饮食)内源性丝氨酸/甘氨酸的模型 水平，我们将量化丝氨酸/甘氨酸对年龄和损伤相关肌肉再生的影响，以及 细胞(MPC)--外在肌肉环境。根据初步数据，我们假设MPC需要 从胞外丝氨酸和甘氨酸合成谷胱甘肽，以减轻氧化应激。此外，我们假设 饮食诱导的内源性丝氨酸/甘氨酸的减少加剧了与年龄相关的肌肉损伤 再生和(Ii)细胞-外源性肌肉环境中有毒的非典型鞘脂。此外，我们 预计补充丝氨酸/甘氨酸将抵消这些影响。捕捉饮食中丝氨酸/甘氨酸的调节作用 在肌肉再生和重塑中的年龄相关损伤我们将使用新的鞘脂体侧写和 转录学。该项目的成功完成将改变人们对 丝氨酸和甘氨酸对骨骼肌再生的代谢重要性及其与年龄的关系 相关的肌肉退化。这一结果将使可测试、有科学依据的疗法能够改善 肌肉再生受损的人群的再生能力，例如老年人。

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.