RPS27L Enhances Myogenesis and Muscle Mass by Targeting IGF1 Through Liquid-Liquid Phase Separation

  • Adv Sci (Weinh). 2025 Aug 31:e12354. doi: 10.1002/advs.202512354.
Xiaoqin Liu  1  2  3 ,  Yilong Yao  1  2 ,  Junyu Yan  1  2 ,  Mu Zeng  1  2 ,  Xinhao Fan  1  2 ,  Yijie Tang  1  2 ,  Jiju Li  1  2 ,  Yanwen Liu  1  2 ,  Shanying Yan  1  2 ,  Wei Wang  1  2 ,  Lijuan Chen  1  2 ,  Ruipu Chen  1  2 ,  Yuxin Huang  1  2 ,  Honor Calnan  3 ,  Heng Wang  4 ,  Graham Gardner  3 ,  Yalan Yang  1  2 ,  Zhonglin Tang  1  2
Affiliations
  • 1. Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, 518124, China.
  • 2. Kunpeng Institute of Modern Agriculture at Foshan, Agricultural Genomics Institute, Chinese Academy of Agricultural Sciences, Foshan, 528226, China.
  • 3. College of Environmental and Life Sciences, Murdoch University, Murdoch, WA, 6150, Australia.
  • 4. College of Animal Science, Shandong Provincial Key Laboratory for Livestock Germplasm Innovation & Utilization, Shandong Agricultural University, Taian, 271000, China.
PMID: 40886325 DOI: 10.1002/advs.202512354
Abstract

RNA-binding proteins (RBPs) play a pivotal role in post-transcriptional regulation of gene expression, critically influencing skeletal myogenesis, muscle growth, and regeneration. Despite the recent identification of RBP Rps27l (ribosomal protein S27-like) as a regulator affecting myogenic proliferation and differentiation, its functions and regulatory mechanisms in skeletal muscle development remain largely unknown. In this study, it is observed that muscle-specific Rps27l knock-in (M─KI) mice exhibit significantly increased muscle mass, enlarged myofiber size, a higher proportion of fast-twitch myofibers, and enhanced muscle regeneration capabilities compared to wild-type controls. Overexpression of Rps27l promotes myoblast proliferation while inhibiting differentiation in skeletal muscle cells. Mechanistically, it is revealed that the expression of Rps27l is negatively regulated by SIX4, a myogenic transcription factor. The N-terminal intrinsically disordered region of RPS27L facilitates liquid-liquid phase separation (LLPS) and interacts with IGF1 to collaboratively regulate myogenesis. The findings uncover the novel regulatory roles of RPS27L in skeletal muscle and highlight the significance of RPS27L-driven LLPS in myogenesis.

Keywords
IGF1; RPS27L; liquid‐liquid phase separation; muscle mass; myofiber sizes; skeletal muscle.
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