Compartmental Aging of the Skeletal Muscle Stem Cell Niche

全球预期寿命的延长使当代人能够享有更多健康和活跃的岁月。然而，老龄化也与较高的疾病发病率有关，这会影响生活质量并增加医疗保健系统的压力。骨骼肌（SkM）质量和功能的下降以及组织愈合能力的降低是老年人丧失独立性的主要驱动因素之一。皮肤组织非常复杂，由多种不同类型的细胞组成。存在于SkM中的肌肉干细胞（MuSCs）对于组织的维持和再生是必不可少的，并且长期以来被描述为在老年生物体中数量较少且功能较差。我们的团队之前已经表明，衰老的musc表现出由细胞外基质（ECM）脱离介导的锚定依赖性细胞死亡，也称为anoikis （Lukjanenko等人，Nature Medicine, 2016）。我们还能够证明纤维脂肪源性祖细胞（FAPs），一种在损伤后的SkM中高度丰富的细胞群，并在组织中分泌大部分ECM分子，会受到衰老过程的损害（Lukjanenko等人，cell Stem cell, 2019; sch<e:1>等人，cell Reports, 2021）。肌细胞也受其附着于肌纤维的调节。重要的是，研究表明，肌肉纤维在衰老过程中经历了主要的基因表达变化（Murgia等人，Cell Reports, 2017）。与这些观察结果一致，我们的初步数据显示，钙粘蛋白介导的老年musc及其宿主肌纤维的细胞-细胞接触较少，分布也发生了深刻的变化。因此，可以想象，除了ECM外，干细胞-肌纤维界面也受到衰老过程的影响，并导致锚定依赖性MuSC功能障碍。在这里，我们建议使用创新的遗传模型来切除ECM和肌纤维对musc的贡献。为此，我们建立了小鼠系，使我们能够分别通过基因诱导仅限musc、FAPs和肌肉纤维的加速衰老。这些模型将使我们第一次能够研究内在MuSC衰老的贡献，以及ECM和肌纤维壁龛室对干细胞粘附和功能的作用。利用下一代组学，我们的目标是研究隔室老化对ECM和肌纤维蛋白质组组成的影响，并将它们与衰老musc的表达谱相关联。最终，这些实验将使我们能够深入了解驱动MuSC衰老的分子机制以及锚定依赖途径的参与。总之，我们的工作不仅将提供MuSC粘附生物学的基本见解，还将揭示SkM老化及其相关病理的新治疗靶点。

Global gains in life expectancy allow current generations to enjoy many extra healthy and active years. However, aging is also associated with a higher incidence of disease, which affects the quality of life and increases pressure on healthcare systems. Declining skeletal muscle (SkM) mass and function coupled with a reduced tissue healing capacity is one of the main drivers of loss of independence in the elderly. SkM tissue is highly complex and composed of a wide range of different cell types. Muscle stem cells (MuSCs) residing in SkM are essential for maintenance and regeneration of the tissue and have long been described to be less abundant and functional in aged organisms.Our group has previously shown that aged MuSCs display anchorage-dependent cell death mediated by detachment from the extracellular matrix (ECM), also known as anoikis (Lukjanenko et al., Nature Medicine, 2016). We were also able to demonstrate that fibro-adipogenic progenitors (FAPs), a cell population that is highly abundant in SkM following injury and that secretes the majority of ECM molecules in the tissue, is impaired by the aging process (Lukjanenko et al., Cell Stem Cell, 2019; Schüler et al., Cell Reports, 2021). MuSCs are also regulated by their attachment to muscle fibers. Importantly, it has been shown that muscle fibers undergo major gene expression changes during aging (Murgia et al., Cell Reports, 2017). In agreement with these observations, our preliminary data have revealed that cadherin mediated cell-cell contacts of aged MuSCs and their host muscle fibers are less abundant and display a profoundly altered distribution. Therefore, it is conceivable that, next to the ECM, the stem cell-muscle fiber interface is affected by the aging process and contributes to anchorage-dependent MuSC dysfunction.Here, we propose to resect the contribution of the ECM and muscle fibers on MuSCs using innovative genetic models. To this end, we generated mouse lines allowing us to genetically induce accelerated aging restricted to MuSCs, FAPs and muscle fibers, respectively. For the first time, these models will allow us to study the contribution of intrinsic MuSC aging, as well as the role of the ECM and muscle fiber niche-compartments on stem cell adhesion and function. Using next-generation omics we are aiming to study the impact of compartmental aging on the composition of the ECM and the muscle fiber proteome and correlate them with the expression profile of aged MuSCs. Ultimately, these experiments will allow us to obtain insights into the molecular mechanisms driving MuSC aging and the involvement of anchorage dependent pathways. Altogether, our work will not only provide fundamental insights into the biology of MuSC adhesion but will also reveal novel therapeutic targets for SkM aging and its associated pathologies.