Hoang Dieu-Huong, Bouvière Jessica, Galvis Johanna, Moullé Pauline, Mercier Orane, Migliavacca Eugenia, Ghosh Ananga, Juban Gaëtan, Liot Sophie, Stuelsatz Pascal, Le Grand Fabien, Feige Jérôme N, Mounier Rémi, Chazaud Bénédicte
Institut NeuroMyoGène, Unité Physiopathologie et Génétique du Neurone et du Muscle, Université Claude Bernard Lyon 1, Inserm U1315, CNRS 5261, Lyon, France.
Nestlé Institute of Health Sciences, Nestlé Research, Lausanne, Switzerland.
EMBO Rep. 2025 Jul 18. doi: 10.1038/s44319-025-00516-3.
Muscle regeneration is impaired with aging, due to both intrinsic defects of muscle stem cells (MuSCs) and alterations of their niche. Here, we monitor the cells constituting the MuSC niche over time in young and old regenerating mouse muscle. Aging alters the expansion of all niche cells, with prominent phenotypes in macrophages that show impaired resolution of inflammation. RNA sequencing of FACS-isolated mononucleated cells uncovers specific profiles and kinetics of genes and molecular pathways in old versus young muscle cells, indicating that each cell type responds to aging in a specific manner. Moreover, we show that macrophages have an altered expression of Selenoprotein P (Sepp1). Macrophage-specific deletion of Sepp1 is sufficient to impair the acquisition of their restorative profile and causes inefficient skeletal muscle regeneration. When transplanted in aged mice, bone marrow from young WT mice, but not Sepp1-KOs, restores muscle regeneration. This work provides a unique resource to study MuSC niche aging, reveals that niche cell aging is asynchronous and establishes the antioxidant Selenoprotein P as a driver of age-related decline of muscle regeneration.
随着年龄增长，肌肉再生能力受损，这是由于肌肉干细胞（MuSCs）的内在缺陷及其微环境的改变所致。在此，我们在年轻和年老的再生小鼠肌肉中，长期监测构成MuSC微环境的细胞。衰老改变了所有微环境细胞的增殖，巨噬细胞表现出显著的表型，其炎症消退受损。对通过荧光激活细胞分选（FACS）分离的单核细胞进行RNA测序，揭示了老年与年轻肌肉细胞中基因和分子途径的特定图谱及动力学，表明每种细胞类型对衰老的反应方式各不相同。此外，我们发现巨噬细胞中硒蛋白P（Sepp1）的表达发生了改变。巨噬细胞特异性缺失Sepp1足以损害其恢复性表型的获得，并导致骨骼肌再生效率低下。当将年轻野生型小鼠而非Sepp1基因敲除小鼠的骨髓移植到老年小鼠体内时，可恢复肌肉再生。这项工作为研究MuSC微环境衰老提供了独特的资源，揭示了微环境细胞衰老的不同步性，并确立了抗氧化剂硒蛋白P是肌肉再生与年龄相关衰退的驱动因素。
