Glycine Enhances Satellite Cell Proliferation, Cell Transplantation, and Oligonucleotide Efficacy in Dystrophic Muscle
Glycine Enhances Satellite Cell Proliferation, Cell Transplantation, and Oligonucleotide Efficacy in Dystrophic Muscle
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甘氨酸增强卫星细胞增殖、细胞移植和寡核苷酸对营养不良性肌肉的功效
DOI：
10.1016/j.ymthe.2020.03.003
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发表时间：
2020-05-06
影响因子：
12.4
通讯作者：
Yin, HaiFang
中科院分区：
文献类型：
--
作者：
Lin, Caorui;Han, Gang;Yin, HaiFang
需要在体内的大量肌肉中均匀地分配治疗，这使得Duchenne肌营养不良症(DMD)治疗成为一个挑战。细胞和外显子跳过疗法前景看好，但效果有限，因此提高它们的治疗效力对于增加DMD患者获得这些疗法的可及性至关重要。在这项研究中，我们证明了联合给予甘氨酸可以显著改善mdx小鼠的磷酸二脂吗啉低聚物(PMO)的效力，并显著改善功能，与生理盐水中的PMO相比，腹肌中dystrophin的含量增加了50倍。甘氨酸通过增加哺乳动物雷帕霉素复合体靶标1(MTORC1)的活性和补充一碳单位池来促进卫星细胞的增殖和肌肉再生。再生肌纤维数量的增加会导致PMO摄取的增加。甘氨酸还可以提高mdx小鼠体内外源卫星细胞和原代成肌细胞的移植效率。我们的数据提供了证据，证明甘氨酸增强了mdx小鼠的卫星细胞增殖、细胞移植和寡核苷酸疗效，因此它对肌肉萎缩疾病的细胞治疗和药物输送具有治疗作用。
The need to distribute therapy evenly systemically throughout the large muscle volume within the body makes Duchenne muscular dystrophy (DMD) therapy a challenge. Cell and exon-skipping therapies are promising but have limited effects, and thus enhancing their therapeutic potency is of paramount importance to increase the accessibility of these therapies to DMD patients. In this study, we demonstrate that co-administered glycine improves phosphorodiamidate morpholino oligomer (PMO) potency in mdx mice with marked functional improvement and an up to 50-fold increase of dystrophin in abdominal muscles compared to PMO in saline. Glycine boosts satellite cell proliferation and muscle regeneration by increasing activation of mammalian target of rapamycin complex 1 (mTORC1) and replenishing the one-carbon unit pool. The expanded regenerating myofiber population then results in increased PMO uptake. Glycine also augments the transplantation efficiency of exogenous satellite cells and primary myoblasts in mdx mice. Our data provide evidence that glycine enhances satellite cell proliferation, cell transplantation, and oligonucleotide efficacy in mdx mice, and thus it has therapeutic utility for cell therapy and drug delivery in muscle-wasting diseases.