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Dynamic changes in butyrate levels regulate satellite cell homeostasis by preventing spontaneous activation during aging

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Abstract

The gut microbiota plays a pivotal role in systemic metabolic processes and in particular functions, such as developing and preserving the skeletal muscle system. However, the interplay between gut microbiota/metabolites and the regulation of satellite cell (SC) homeostasis, particularly during aging, remains elusive. We propose that gut microbiota and its metabolites modulate SC physiology and homeostasis throughout skeletal muscle development, regeneration, and aging process. Our investigation reveals that microbial dysbiosis manipulated by either antibiotic treatment or fecal microbiota transplantation from aged to adult mice, leads to the activation of SCs or a significant reduction in the total number. Furthermore, employing multi-omics (e.g., RNA-seq, 16S rRNA gene sequencing, and metabolomics) and bioinformatic analysis, we demonstrate that the reduced butyrate levels, alongside the gut microbial dysbiosis, could be the primary factor contributing to the reduction in the number of SCs and subsequent impairments during skeletal muscle aging. Meanwhile, butyrate supplementation can mitigate the antibiotics-induced SC activation irrespective of gut microbiota, potentially by inhibiting the proliferation and differentiation of SCs/myoblasts. The butyrate effect is likely facilitated through the monocarboxylate transporter 1 (Mct1), a lactate transporter enriched on membranes of SCs and myoblasts. As a result, butyrate could serve as an alternative strategy to enhance SC homeostasis and function during skeletal muscle aging. Our findings shed light on the potential application of microbial metabolites in maintaining SC homeostasis and preventing skeletal muscle aging.

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Acknowledgement

This work was supported by the Guangdong Basic and Applied Basic Research Foundation (2020B1515020046), “GDAS” Project of Science and Technology Development (2021GDASYL-20210102003, 2018GDASCX-0102), the National Natural Science Foundation of China (82072436, 32130099), Open Program of Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics (GPKLMMD-OP202102), Outstanding Youth Fund of Hunan Natural Science Foundation (2021JJ20045), the Outstanding Youth Fund of Hunan Natural Science Foundation (2021JJ20045), and Youth Innovation Promotion Association of Chinese Academy of Sciences (2022370). This project spanned more than five years, with the initial testing of the original hypothesis and subsequent adjustments to the plan. Dr. Shujie Chen made significant contributions to this project, including repeatedly treating the animals, inducing muscle injuries, and isolating and culturing single myofibers. We also appreciate the contributions of Dr. Bingdong Liu, who was instrumental in the creation of the original hypothesis, discussions regarding data feasibility, and the collection of samples at the outset of the project. Ms. Liujing Huang joined our lab in the summer of 2020 and swiftly mastered data analysis. Her significant contributions during the final stages of data analysis, preparation, image generation, manuscript drafting, revision, and discussion were instrumental, especially her distinctive perspective on image color matching and selection. The invaluable contributions of these three co-first authors were vital to the novel discovery made in this study. We’re also appreciative of the generous help and assistance from others in measurements, data collection, and even the donation of aged mice for our study, particularly during the manuscript revision phase. We extend our thanks to the entire lab team and support staff for their unwavering support and dedication to the project. Without their hard work and commitment, this study would not have been possible. We appreciate Mr. Wei Zhao from BGI-Shenzhen for assisting us with the RNA sequencing and Ms. Baoli Wei from Jiangsu Gene & Peace CO. LTD for donating the adult (~10 wk old) and aged (~100 wk old) mice during the manuscript revision.

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  1. Contributed equally to this work

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China

    Shujie Chen, Liujing Huang, Bingdong Liu & Liwei Xie

  2. State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, 510070, China

    Shujie Chen, Liujing Huang, Bingdong Liu, Huimin Duan, Ze Li, Yifan Liu & Liwei Xie

  3. School of Public Health, Xinxiang Medical University, Xinxiang, 453003, China

    Ze Li, Yinlan Xu & Liwei Xie

  4. Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Li Liu & Liwei Xie

  5. Metabo-Profile Biotechnology (Shanghai) Co. Ltd., Shanghai, 201315, China

    Jingchao Lin

  6. Institute of Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, 524023, China

    Yifan Liu, Dan Wan & Yulong Yin

  7. Department of Rehabilitation Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510000, China

    Shujie Chen & Huimin Duan

  8. Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China

    Dan Wan & Yulong Yin

  9. Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510005, China

    Hu Li & Xiang Fu

Authors
  1. Shujie Chen
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  2. Liujing Huang
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  14. Liwei Xie
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Corresponding authors

Correspondence to Dan Wan, Yulong Yin or Liwei Xie.

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The author(s) declare that they have no conflict of interest. All animal experiment procedures were approved by the Institute Animal Care Use Committees of the Institute of Microbiology (Animal Use Protocol number: GT-IACUC201704071).

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Chen, S., Huang, L., Liu, B. et al. Dynamic changes in butyrate levels regulate satellite cell homeostasis by preventing spontaneous activation during aging. Sci. China Life Sci. 67, 745–764 (2024). https://doi.org/10.1007/s11427-023-2400-3

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  • DOI: https://doi.org/10.1007/s11427-023-2400-3

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