From Regenerative to Degenerative Niche: Multicellular Crosstalk and Population Dynamics in Skeletal Muscle Aging

ABSTRACT

Skeletal muscle aging is increasingly recognized as a failure of tissue‐level coordination rather than a consequence of isolated defects in individual cell types. Recent advances in single‐cell, spatial, and multimodal omics have revealed that aging remodels the abundance, functional states, and interactions of muscle‐resident populations, shifting the tissue from a regenerative niche toward a degenerative niche. In this Review, we summarize current evidence supporting this conceptual transition by focusing on multicellular crosstalk and population dynamics within the aging muscle microenvironment. We discuss how age‐dependent remodeling of muscle stem cells, fibro‐adipogenic progenitors, immune cells, vascular cells, and neuromuscular components collectively disrupts the temporal coordination required for effective regeneration. Rather than acting independently, these populations become locked in maladaptive signaling circuits that promote persistent inflammation, fibrosis, senescence, impaired vascular support, and neuromuscular dysfunction, ultimately compromising tissue repair and muscle function. We further distinguish ligand‐receptor interactions inferred from single‐cell atlases from signaling pathways that have been functionally validated in vivo, highlighting the importance of establishing causal mechanisms underlying intercellular communication. Finally, we discuss emerging therapeutic strategies aimed at restoring multicellular coordination—including modulation of stromal, immune, vascular, and neuromuscular interactions—rather than targeting single cell populations in isolation. We propose that rebuilding regenerative communication networks, instead of simply eliminating dysfunctional cells, represents a promising framework for developing interventions against sarcopenia and age‐related muscle decline.