Transcriptomic insights into exercise-induced trabecular bone microarchitectural adaptations following combined...

Osteoporosis is a prevalent musculoskeletal disorder, rising in incidence and impact as the global population ages. Peak bone mass (PBM), determined by bone mineral density (BMD) during adolescence, is a key determinant of skeletal health and later osteoporosis risk. Exercise enhances BMD, yet its molecular mechanisms remain unclear. This study examined combined exercise effects on bone health in early adult mice using RNA sequencing (RNA-seq) analysis. Nineteen-week-old mice were randomly assigned to control (CON, n=8) or combined exercise (EXE, n=8) groups. The 12-week intervention included aerobic and resistance training, with physical performance tests conducted before and after. Following intervention, tibial bone characteristics were assessed by dual-energy X-ray absorptiometry (DXA) and micro-computed tomography (μCT), while femoral gene expression was analyzed using transcriptomic analysis. EXE mice demonstrated significant increases in grip strength and exhaustion test performance, but not in the rotarod test. Proximal tibial trabecular bone microarchitecture was enhanced in the EXE group, with increased bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N), along with a trend toward reduced trabecular separation(Tb.Sp). Transcriptomic analysis revealed 109 upregulated and 551 downregulated differentially expressed genes. Gene ontology analysis highlighted enrichment of terms related to muscle cell differentiation, contraction, and ion regulation. Bone metabolism-related GO Biological Process terms were specifically enriched, with Pax1 and Dcstamp upregulated and Fgf18, Scx, and Scube2 downregulated. KEGG analysis identified eleven significantly enriched pathways, including Calcium signaling, ECM-receptor interaction, and PI3K-Akt signaling. These findings suggest that combined exercise enhances trabecular bone microarchitecture and induces transcriptomic changes involving genes associated with bone development, remodeling, and extracellular matrix organization, providing molecular-level evidence for exercise-induced skeletal adaptation.