Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA; Musculoskeletal Research Center, Bioengineering Institute, Department of Orthopedic Surgery, NYU School of Medicine, New York, NY 10010, USA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell Stem Cell. 2021 Jul 1;28(7):1323-1334.e8. doi: 10.1016/j.stem.2021.04.008. Epub 2021 May 3.
Intramuscular fatty deposits, which are seen in muscular dystrophies and with aging, negatively affect muscle function. The cells of origin of adipocytes constituting these fatty deposits are mesenchymal stromal cells, fibroadipogenic progenitors (FAPs). We uncover a molecular fate switch, involving miR-206 and the transcription factor Runx1, that controls FAP differentiation to adipocytes. Mice deficient in miR-206 exhibit increased adipogenesis following muscle injury. Adipogenic differentiation of FAPs is abrogated by miR-206 mimics. Using a labeled microRNA (miRNA) pull-down and sequencing (LAMP-seq), we identified Runx1 as a miR-206 target, with miR-206 repressing Runx1 translation. In the absence of miR-206 in FAPs, Runx1 occupancy near transcriptional start sites of adipogenic genes and expression of these genes increase. We demonstrate that miR-206 mimicry in vivo limits intramuscular fatty infiltration. Our results provide insight into the underlying molecular mechanisms of FAP fate determination and formation of harmful fatty deposits in skeletal muscle.
肌内脂肪沉积，可见于肌肉营养不良症和衰老，会对肌肉功能产生负面影响。构成这些脂肪沉积的脂肪细胞的起源细胞是间充质基质细胞、纤维脂肪祖细胞 (FAP)。我们揭示了一种涉及 miR-206 和转录因子 Runx1 的分子命运开关，它控制着 FAP 向脂肪细胞的分化。缺乏 miR-206 的小鼠在肌肉损伤后表现出脂肪生成增加。miR-206 模拟物可阻断 FAP 的脂肪生成分化。使用标记 miRNA（miRNA）下拉和测序 (LAMP-seq)，我们鉴定出 Runx1 是 miR-206 的靶标，miR-206 抑制 Runx1 的翻译。在 FAP 中缺乏 miR-206 时，脂肪生成基因的转录起始位点附近的 Runx1 占据和这些基因的表达增加。我们证明了体内 miR-206 模拟物限制了肌内脂肪浸润。我们的研究结果为 FAP 命运决定和骨骼肌中有害脂肪沉积形成的潜在分子机制提供了深入的了解。
