Beyond hormone deficiency: a framework for endocrine-immune-niche integration in aging skeletal muscle regeneration.

Thyroid hormone (TH) signaling is widely recognized as an important regulator of skeletal muscle regeneration, yet the mechanisms by which aging alters TH-dependent regenerative responses remain unresolved. Current models generally assume that age-associated regenerative decline reflects reduced thyroid hormone receptor (THR) signaling resulting from alterations in hormone availability, receptor expression, or downstream transcriptional activity. However, several observations challenge this view, including the persistence of THR activity in aged tissues, the limited efficacy of thyroid hormone replacement in restoring regeneration, and the distinct regenerative phenotypes observed in aging and hypothyroidism. Here, we propose the hypothesis that aging does not primarily impair skeletal muscle regeneration through loss of THR signaling, but through disruption of endocrine-immune-niche integration. In this framework, THR signaling functions as a systems-level coordinator that integrates endocrine signals with stromal remodeling, immune responses, and intercellular communication networks required for effective tissue repair. To evaluate whether available evidence is consistent with this hypothesis, we integrate published studies with analyses of publicly available murine single-cell transcriptomic, chromatin-accessibility, and ligand-receptor datasets spanning skeletal muscle regeneration, aging, and hypothyroidism. These associative analyses suggest that substantial components of THR activity remain detectable during aging, whereas coordination between THR signaling, macrophage remodeling, extracellular-matrix programs, inflammatory pathways, and Notch-mediated communication is altered. The findings are associative and do not establish causality; rather, they provide a hypothesis-generating framework for experimental testing. We propose that aging represents a state of impaired endocrine-immune-niche integration in which thyroid hormone signaling remains partially active but becomes increasingly uncoupled from the regenerative programs it normally coordinates. This framework offers a possible unifying explanation for several previously disconnected observations and generates experimentally testable predictions regarding endocrine-immune communication during tissue repair and aging.