Age-related changes in the niche have long been postulated to impair the function of somatic stem cells. Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs). Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers. By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche. Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism.

Skeletal muscle regeneration is a finely tuned process involving the activation of various cellular and molecular processes. Satellite cells, the stem cells of skeletal muscle, are indispensable for skeletal muscle regeneration. Their functionality is critically modulated by intrinsic signaling pathways as well as by interactions with the stem cell niche. Here, we discuss the properties of satellite cells, including heterogeneity regarding gene expression and/or their phenotypic traits and the contribution of satellite cells to skeletal muscle regeneration. We also summarize the process of regeneration with a specific emphasis on signaling pathways, cytoskeletal rearrangements, the importance of miRNAs, and the contribution of non-satellite cells such as immune cells, fibro-adipogenic progenitor cells, and PW1-positive/Pax7-negative interstitial cells.

Summary The Sankey diagram is an important aid in identifying inefficiencies and potential for savings when dealing with resources. It was developed over 100 years ago by the Irish engineer Riall Sankey to analyze the thermal efficiency of steam engines and has since been applied to depict the energy and material balances of complex systems. The Sankey diagram is the main tool for visualizing industrial metabolism and hence is widely used in industrial ecology. In the history of the early 20th century, it played a major role when raw materials were scarce and expensive and engineers were making great efforts to improve technical systems. Sankey diagrams can also be used to map value flows in systems at the operational level or along global value chains. The article charts the historical development of the diagrams. After the First World War the diagrams were used to produce thermal balances of production plants for glass and cement and to optimize the energy input. In the 1930s, steel and iron ore played a strategic role in Nazi Germany. Their efficient use was highlighted with Sankey diagrams. Since the 1990s, these diagrams have become common for displaying data in life cycle assessments (LCAs) of products. Sankey diagrams can also be used to map value flows in systems at the operational level or along global value added chains. This article, the first of a pair, charts the historical development. The companion article discusses the methodology and the implicit assumptions of such Sankey diagrams.

SUMMARY The functionality of stem cells declines during aging thereby contributing to aging-associated impairments in tissue regeneration and function1. Alterations in developmental pathways have been associated with declines in stem cell function during aging2–6 but the nature of this process remains poorly defined. Hox genes are key regulators of stem cells and tissue patterning during embryogenesis with an unknown role in aging7,8. This study identifies an altered epigenetic stress response in muscle stem cells (also known as satellite cells = SCs) of aged compared to young mice. This includes aberrant global and site-specific induction of active chromatin marks in activated SCs from aged mice resulting in the specific induction of Hoxa9 among all Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor separating gene expression of SCs from aged compared to young mice. This includes most of the currently known inhibitors of SC function in aging muscle such as Wnt-, TGFß-, JAK/STAT- and senescence signaling2–4,6. Inhibition of aberrant chromatin activation or deletion of Hoxa9 suffices to improve SC function and muscle regeneration in aged mice, while overexpression of Hoxa9 mimics aging-associated defects in SCs from young mice, which can be rescued by inhibition of Hoxa9-targeted developmental pathways. Together, these data delineate an altered epigenetic stress response in activated SCs from aged mice, which limits SC function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.

Keywords:efficiency energy use industrial ecology industrial engineering material flow analysis (MFA) scarcity SummaryThe Sankey diagram is an important aid in pointing up inefficiencies and potential for savings in connection with resource use. This article, the second of a pair, examines the use of Sankey diagrams in operational material flow management. The previous article described the development of the diagram and its use in the past.Simple Sankey diagrams follow the requirement of conservation of energy or mass and allow a physical view of production systems. Advanced diagrams integrate stocks of materials beside the flows or show the different (ecological) quality of the materials. For the purpose of management, however, a further step is necessary: to illustrate the economic value of the energy and material flows and to use information from cost accounting. The use of flow charts showing added value or the costs of energy and material flows is particularly important for production systems. This article describes examples of each of these uses as well as assumptions that must be taken into account for Sankey diagrams to be used as an effective aid for decision-making in business and public policy.