Immune metabolic remodeling during exercise rehabilitation: Linking skeletal muscle regeneration, bone homeostasis,...

Exercise rehabilitation harnesses immune metabolic remodeling to drive coordinated skeletal muscle regeneration, bone homeostasis, and systemic immune adaptation. Physical activity functions as a controlled metabolic stressor that reprograms immune cell metabolism-shifting macrophages from glycolytic M1 to oxidative M2 phenotypes, expanding regulatory T cells through fatty acid oxidation and ketone body signaling, and modulating neutrophils, NK cells, and B cells via lactate, succinate, itaconate, ROS, NAD⁺, and gut-derived SCFAs. These metabolic shifts regulate immune cell polarization, efferocytosis, cytokine profiles, and growth factor release (IGF-1, amphiregulin, GDF-15), creating an optimal regenerative niche for satellite cell activation, proliferation, and differentiation in muscle while supporting bone remodeling through mechanosensory osteocyte signaling and osteokine secretion (osteocalcin, sclerostin, RANKL/OPG). Distinct exercise modalities generate characteristic immune-metabolic signatures: aerobic training promotes sustained oxidative phosphorylation and anti-inflammatory tolerance beneficial for both muscle and bone; resistance training induces controlled glycolytic bursts followed by anabolic M2 polarization, muscle hypertrophy, and improved bone microarchitecture; HIIT generates oscillatory stress that trains innate immune memory and enhances muscle-bone resilience. Energy-sensing pathways (AMPK, mTOR, HIF-1α, SIRT1/3, PGC-1α) and metabolite checkpoints integrate mechanical loading with immune and endocrine signals to balance pro-regenerative inflammation with timely resolution across the musculoskeletal system. Clinically, this framework enables precision rehabilitation protocols based on immune metabolic phenotyping, lactate kinetics, and skeletal imaging (BMD, microarchitecture) to optimize outcomes in sarcopenia, osteosarcopenia, postoperative recovery, chronic inflammatory diseases, cancer cachexia, and post-viral syndromes. Exercise-induced immune metabolic remodeling thus serves as a master regulator of muscle-bone-immune coupling, offering a mechanism-driven foundation for next-generation rehabilitation medicine that enhances tissue repair, bone quality, and systemic homeostasis.