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单细胞 profiling 揭示了 FOXO3 在灵长类骨骼肌衰老中的 geroprotective 作用。

Single-nucleus profiling unveils a geroprotective role of the FOXO3 in primate skeletal muscle aging.

机构信息

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.

University of Chinese Academy of Sciences, Beijing 100049, China.

出版信息

Protein Cell. 2023 Jun 28;14(7):497-512. doi: 10.1093/procel/pwac061.

DOI:10.1093/procel/pwac061
PMID:36921027
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10305740/
Abstract

Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia, and increases the risk of many aging-related metabolic diseases. Here, we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging. A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types, indicating a higher susceptibility of skeletal muscle fiber to aging. We found a downregulation of FOXO3 in aged primate skeletal muscle, and identified FOXO3 as a hub transcription factor maintaining skeletal muscle homeostasis. Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model, we revealed that silence of FOXO3 accelerates human myotube senescence, whereas genetic activation of endogenous FOXO3 alleviates human myotube aging. Altogether, based on a combination of monkey skeletal muscle and human myotube aging research models, we unraveled the pivotal role of the FOXO3 in safeguarding primate skeletal muscle from aging, providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-related disorders.

摘要

骨骼肌质量和功能随年龄的增长而下降是肌肉减少症的一个特征，增加了许多与衰老相关的代谢疾病的风险。在这里，我们报告了非人类灵长类动物骨骼肌衰老的表型和单核转录组分析。与其他间质细胞类型相比，肌核中的转录波动更高，这表明骨骼肌纤维对衰老的敏感性更高。我们发现衰老的灵长类骨骼肌中 FOXO3 的表达下调，并确定 FOXO3 是维持骨骼肌稳态的枢纽转录因子。通过建立基于人多能干细胞衍生的肌管模型的互补实验管道，我们揭示了沉默 FOXO3 会加速人类肌管衰老，而内源性 FOXO3 的遗传激活则可以减轻人类肌管衰老。总的来说，基于猴骨骼肌和人类肌管衰老研究模型的结合，我们揭示了 FOXO3 在保护灵长类骨骼肌免受衰老方面的关键作用，为开发针对人类骨骼肌衰老和衰老相关疾病的临床诊断和靶向治疗干预措施提供了全面的资源。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cb6/10305740/62b11c5266c4/pwac061_fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cb6/10305740/56b9fd42ed0a/pwac061_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cb6/10305740/e3be76d7c270/pwac061_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cb6/10305740/596f3873860c/pwac061_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cb6/10305740/10230c8bfcf8/pwac061_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cb6/10305740/bae0da8449dc/pwac061_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cb6/10305740/62b11c5266c4/pwac061_fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cb6/10305740/56b9fd42ed0a/pwac061_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cb6/10305740/e3be76d7c270/pwac061_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cb6/10305740/596f3873860c/pwac061_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cb6/10305740/10230c8bfcf8/pwac061_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cb6/10305740/bae0da8449dc/pwac061_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cb6/10305740/62b11c5266c4/pwac061_fig6.jpg

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