Endocrine Abstracts

Background: Macrophages are key regulators of skeletal muscle regeneration, orchestrating both inflammatory and reparative processes. Glucocorticoids, including cortisone(E) and cortisol(F), critically influence muscle anabolic and catabolic pathways. Previous work has demonstrated that inflammation dynamically regulates glucocorticoid metabolism in macrophages, yet the consequences for muscle cell function and regeneration remain poorly understood. This study aimed to investigate how macrophage-mediated glucocorticoid metabolism affects muscle cell proliferation, differentiation, and metabolic function.

Methods: Primary human macrophages were polarized with TNFα/IFNγ or left unpolarized and treated with cortisone(E;100 nmol/l). Treated macrophages or their conditioned media(CM) were co-cultured with human myotubes and myoblasts. Cortisol synthesis was quantified via LC-MS/MS. Muscle cell responses (myotube thickness, proliferation, protein synthesis, migration, and metabolic gene expression) were assessed using microscopy, BrdU incorporation, fluorescent synthesis assays, scratch assays, and qRT-PCR. Mitochondrial function was evaluated by measuring respiration and glycolysis, and the 11β-HSD1 inhibitor LJ1 was used to block cortisone-to-cortisol activation in macrophages.

Results: Inflammatory macrophages exhibited enhanced cortisol activation from cortisone. CM or co-culture with activated macrophages reduced myotube fibre size without altering metabolic gene expression. Cortisone CM significantly decreased myoblast proliferation (P = 0.0009) and promoted a catabolic gene expression profile(↑Foxo1, ↑Fbox32, ↓Igf-1). Direct cortisol treatment further suppressed proliferation(P < 0.0001) without increasing protein synthesis. While macrophage CM stimulated baseline myoblast migration and proliferation, these effects were blunted by cortisone exposure. Cortisone CM also impaired mitochondrial function, reducing maximal respiration, basal proton efflux rate(P < 0.01), and spare respiratory capacity, while inducing glycolysis(P < 0.05); the inhibitor reversed these deficits. Conclusions Inflammatory macrophages dynamically regulate glucocorticoid metabolism, enhancing cortisol activation and promoting catabolic responses in muscle cells. Dysregulated macrophage glucocorticoid metabolism during inflammation may impair muscle regeneration and contribute to muscle wasting in chronic disease. Pharmacological inhibition of 11β-HSD1 represents a potential strategy to preserve muscle function.