Compartmental Aging of the Skeletal Muscle Stem Cell Niche

• Applicant: Dr. Svenja Caren Schüler
• Subject Area: Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505064275

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.

• DFG Programme: WBP Fellowship
• International Connection: Canada
• Host: Professor Dr. Florian Bentzinger