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

项目总结/摘要 受损的骨骼肌再生和相关的病理性组织重塑（肌肉损失， 纤维化和脂肪组织）是功能和代谢下降的基础--衰老的标志。 再生是依赖于一个精心策划的生肌程序，包括激活和扩展 骨骼肌干细胞/祖细胞（MPCs）和MPCs终末分化为成熟的 多核肌细胞我们以前证明，MPCs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扩增，诱导损伤后肌内脂肪细胞，并诱导毒性脱氧鞘脂 在肌肉中积累。此外，我们证明了内源性Ser/Gly水平随着年龄的增长而下降。的 用于MPC扩增的Ser/Gly的代谢产物（即需求）和膳食Ser/Gly对肌肉的功效 再生和细胞（MPC）外部环境需要解决。我们建议使用同位素示踪 的Ser和Gly来定义MPC群体扩增的Ser/Gly的代谢需求。此外，使用 我们已经证明的模型减少（耗尽饮食）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， 细胞（MPC）-外部肌肉环境。根据初步数据，我们假设MPC需要 谷胱甘肽的合成，从细胞外的丝氨酸和甘氨酸，以减轻氧化应激。另外，我们假设 饮食诱导的内源性Ser/Gly减少加剧了年龄相关的（i）肌肉损伤， 再生和（ii）细胞外部肌肉环境中的毒性非规范鞘脂。我们还 补充Ser/Gly可以抵消这些影响。为了获得膳食Ser/Gly调节 在肌肉再生和重塑中与年龄相关的损伤，我们将使用新的鞘脂组分析， 转录组学该项目的成功完成将改变对 丝氨酸和甘氨酸对骨骼肌再生的代谢重要性以及这种损失与年龄的关系- 与肌肉退化有关。这些结果将使可测试的科学基础疗法能够改善 肌肉再生能力受损的人群，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.