Extracellular serine and glycine are required for mouse and human skeletal muscle stem and progenitor cell function.
Extracellular serine and glycine are required for mouse and human skeletal muscle stem and progenitor cell function.
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DOI：
10.1016/j.molmet.2020.101106
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发表时间：
2021-01
影响因子：
8.1
通讯作者：
Thalacker-Mercer AE
中科院分区：
文献类型：
--
作者：
Gheller BJ;Blum JE;Lim EW;Handzlik MK;Hannah Fong EH;Ko AC;Khanna S;Gheller ME;Bender EL;Alexander MS;Stover PJ;Field MS;Cosgrove BD;Metallo CM;Thalacker-Mercer AE
骨骼肌再生依赖于肌肉特异性成体干细胞（MuSC）、MuSC后代、肌肉祖细胞（MPC）和受细胞外环境影响的协调的肌原性程序。损伤后，MPC经历短暂而快速的群体扩张期，这是修复受损肌纤维和恢复肌肉稳态所必需的。某些病理（例如，代谢疾病和肌肉营养不良）和高龄与肌肉再生失调有关。丝氨酸和甘氨酸这两种营养上非必需的氨基酸的可用性在具有这些病理的人类中改变，并且这些氨基酸已被证明影响非肌肉细胞的增殖状态。我们的目标是确定丝氨酸/甘氨酸在MuSC/MPC功能中的作用。原代人MPC（hMPC）用于体外实验，年轻（4-6月龄）和老年（>20月龄）小鼠用于体内实验。丝氨酸/甘氨酸的可用性，操纵使用专门配制的培养基在体外或饮食限制在体内，然后下游代谢和细胞增殖分析。我们确定丝氨酸/甘氨酸是hMPC增殖所必需的。在骨骼肌再生的小鼠模型中，丝氨酸/甘氨酸的饮食限制降低了损伤后3天MuSC的丰度。稳定同位素示踪研究表明，hMPC依赖于细胞外丝氨酸/甘氨酸的人口扩张，因为他们表现出有限的能力从头丝氨酸/甘氨酸生物合成。丝氨酸/甘氨酸限制hMPC导致细胞周期停滞在G 0/G1期。细胞外丝氨酸/甘氨酸是必要的，以支持谷胱甘肽和全球蛋白质合成的hMPC。使用老年小鼠模型，我们发现，减少丝氨酸/甘氨酸的可用性增强肌间脂肪细胞损伤后28天。这些研究表明，尽管MuSC/MPC增殖绝对需要丝氨酸/甘氨酸，但从头合成不足以支持这些需求，使得细胞外丝氨酸和甘氨酸对于有效的骨骼肌再生是条件性必需的。细胞外丝氨酸和甘氨酸是肌肉干/祖细胞群体扩增所必需的。人肌肉祖细胞具有有限的丝氨酸/甘氨酸从头生物合成能力。细胞外丝氨酸/甘氨酸限制增加活性氧并减少细胞内谷胱甘肽。细胞外丝氨酸/甘氨酸抑制蛋白质合成和细胞周期停滞。老年小鼠细胞外丝氨酸和甘氨酸减少损害骨骼肌再生。
Skeletal muscle regeneration relies on muscle-specific adult stem cells (MuSCs), MuSC progeny, muscle progenitor cells (MPCs), and a coordinated myogenic program that is influenced by the extracellular environment. Following injury, MPCs undergo a transient and rapid period of population expansion, which is necessary to repair damaged myofibers and restore muscle homeostasis. Certain pathologies (e.g., metabolic diseases and muscle dystrophies) and advanced age are associated with dysregulated muscle regeneration. The availability of serine and glycine, two nutritionally non-essential amino acids, is altered in humans with these pathologies, and these amino acids have been shown to influence the proliferative state of non-muscle cells. Our objective was to determine the role of serine/glycine in MuSC/MPC function. Primary human MPCs (hMPCs) were used for in vitro experiments, and young (4–6 mo) and old (>20 mo) mice were used for in vivo experiments. Serine/glycine availability was manipulated using specially formulated media in vitro or dietary restriction in vivo followed by downstream metabolic and cell proliferation analyses. We identified that serine/glycine are essential for hMPC proliferation. Dietary restriction of serine/glycine in a mouse model of skeletal muscle regeneration lowered the abundance of MuSCs 3 days post-injury. Stable isotope-tracing studies showed that hMPCs rely on extracellular serine/glycine for population expansion because they exhibit a limited capacity for de novo serine/glycine biosynthesis. Restriction of serine/glycine to hMPCs resulted in cell cycle arrest in G0/G1. Extracellular serine/glycine was necessary to support glutathione and global protein synthesis in hMPCs. Using an aged mouse model, we found that reduced serine/glycine availability augmented intermyocellular adipocytes 28 days post-injury. These studies demonstrated that despite an absolute serine/glycine requirement for MuSC/MPC proliferation, de novo synthesis was inadequate to support these demands, making extracellular serine and glycine conditionally essential for efficient skeletal muscle regeneration. Extracellular serine and glycine are necessary for muscle stem/progenitor cell population expansion. Human muscle progenitor cells possess limited capacity for de novo serine/glycine biosynthesis. Extracellular serine/glycine restriction increases reactive oxygen species and reduces intracellular glutathione. Extracellular serine/glycine inhibits protein synthesis and cell cycle arrest. Reduced extracellular serine and glycine in old mice impairs skeletal muscle regeneration.
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DOI：
10.1007/978-1-4939-9236-2_14
发表时间：
2019-01-01
期刊：
HIGH-THROUGHPUT METABOLOMICS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Cordes, Thekla;Metallo, Christian M.
通讯作者：
Metallo, Christian M.
影响因子：
6.3
作者：
Ham, Daniel J.;Murphy, Kate T.;Koopman, Rene
通讯作者：
Koopman, Rene
影响因子：
4.4
作者：
CARNWATH, JW;SHOTTON, DM
通讯作者：
SHOTTON, DM
影响因子：
11.8
作者：
Hosios AM;Hecht VC;Danai LV;Johnson MO;Rathmell JC;Steinhauser ML;Manalis SR;Vander Heiden MG
通讯作者：
Vander Heiden MG
影响因子：
5.5
作者：
Fry, Christopher S.;Porter, Craig;Finnerty, Celeste C.
通讯作者：
Finnerty, Celeste C.