SUMMARY During aging, there is a progressive loss of volume and function in skeletal muscle that impacts mobility and quality of life. The repair of skeletal muscle is regulated by tissue-resident stem cells called satellite cells (or muscle stem cells [MuSCs]), but in aging, MuSCs decrease in numbers and regenerative capacity. The transcriptional networks and epigenetic changes that confer diminished regenerative function in MuSCs as a result of natural aging are only partially understood. Herein, we use an integrative genomics approach to profile MuSCs from young and aged animals before and after injury. Integration of these datasets reveals aging impacts multiple regulatory changes through significant differences in gene expression, metabolic flux, chromatin accessibility, and patterns of transcription factor (TF) binding activities. Collectively, these datasets facilitate a deeper understanding of the regulation tissue-resident stem cells use during aging and healing.

All multicellular organisms rely on intercellular communication networks to coordinate physiological functions. As members of a dynamic social network, each cell receives, processes, and redistributes biological information to define and maintain tissue homeostasis. Uncovering the molecular programs underlying these processes is critical for prevention of disease and aging and development of therapeutics. The study of intercellular communication requires techniques that reduce the scale and complexity of in vivo biological networks while resolving the molecular heterogeneity in “omic” layers that contribute to cell state and function. Recent advances in microengineering and high‐throughput genomics offer unprecedented spatiotemporal control over cellular interactions and the ability to study intercellular communication in a high‐throughput and mechanistic manner. Herein, this review discusses how salient engineered approaches and sequencing techniques can be applied to understand collective cell behavior and tissue functions.

Significance Skeletal muscle is one of the largest tissues in the body and can regenerate when damaged through a population of resident muscle stem cells. A type of muscle trauma called volumetric muscle loss overwhelms the regenerative capacity of muscle stem cells and engenders fibrotic supplantation. A comparison of muscle injuries resulting in regeneration or fibrosis revealed that intercellular communication between neutrophils and natural killer cells impacts muscle stem cell-mediated repair. Perturbation of neutrophil–natural killer cell interactions resulted in a variation of healing outcomes and suggested that immunomodulatory interventions can be effective to prevent aberrant healing outcomes.

The health and homeostasis of skeletal muscle are preserved by a population of tissue-resident muscle stem cells (MuSCs) that maintain a state of mitotic and metabolic quiescence in adult tissues. The capacity of MuSCs to preserve the quiescent state declines with aging and metabolic insults, promoting premature activation and stem cell exhaustion. Sestrins are a class of stress-inducible proteins that act as antioxidants and inhibit the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Despite these pivotal roles, the role of Sestrins has not been explored in adult stem cells. We show that SESTRIN1,2 loss results in hyperactivation of the mTORC1 complex, increased propensity to enter the cell cycle, and shifts in metabolic flux. Aged SESTRIN1,2 knockout mice exhibited loss of MuSCs and a reduced ability to regenerate injured muscle. These findings demonstrate that Sestrins help maintain metabolic pathways in MuSCs that protect quiescence against aging.