Aging and prolonged durations of physical inactivity contribute to physiological alterations that compromise skeletal muscle integrity, which reduces overall muscle mass, strength, and function. Macrophages, a central component of the innate immune system, are critical to muscle regrowth following disuse. However, relatively little is known about how macrophages are altered as a result of muscle disuse in the context of aging. The objective of this study was to determine the impact of skeletal muscle disuse on bone marrow-derived macrophages in young and aged mice. We hypothesize that physical disuse modulates macrophage functional responses, as well as their metabolic and transcriptional profiles, in an age-dependent manner. Young (4–5 months, n=4–8) and aged (23–24 months, n=4–8) male mice were either maintained as ambulatory controls (AMB) or subjected to 14 days of hindlimb unloading (HU) to induce muscle atrophy. Polarized bone marrow-derived macrophages were analyzed using metabolomics and bulk RNA sequencing. As expected, HU reduced hindlimb skeletal muscle mass and function (grip strength and rotarod performance) compared to AMB mice in both young and old mice. Alternatively, polarized bone marrow-derived macrophages from young HU mice exhibited enhanced phagocytosis compared to old HU mice. Metabolomic profiling supported that macrophages from young HU mice (vs AMB) had shifted metabolic profiles toward increased glycolytic intermediates and reductions in TCA cycle metabolites. On the other hand, transcriptional pathway enrichment analysis unmasked that old HU mice exhibited a heightened inflammatory response accompanied by reduced reparative and diminished cellular communication pathways. Collectively, these findings imply that skeletal muscle disuse disrupts intrinsic bone marrow-derived macrophage function in aged mice that may have deleterious consequences to subsequent muscle regrowth. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Yee et al. (Fri,) studied this question.