Periodontitis induces skeletal muscle atrophy by increasing circulating levels of activin A

Periodontitis, a chronic inflammatory disease, has been linked to various systemic conditions, including cardiovascular disease, type 2 diabetes, and premature birth. However, its impact on skeletal muscle remains unclear. Here, we utilize a ligature-induced periodontitis (LIP) mouse model and show that periodontitis significantly reduces muscle and bone mass without affecting fat mass or food intake. Interestingly, activin A, a well-documented inducer of muscle atrophy, was highly expressed in periodontitis-affected gingiva, surpassing its expression in the liver, a primary activin A-expressing organ. The activin A gene (Inhba) was highly expressed, particularly in gingival fibroblasts and epithelial cells, which undergo significant proliferation as periodontitis progresses, as well as in myeloid cells infiltrating inflamed periodontal tissues and in myeloid cell-derived osteoclasts. A similar upregulation pattern of INHBA was also confirmed in periodontitis-affected human tissues by scRNA-seq analysis. Furthermore, we demonstrate that serum activin A levels significantly increased in periodontitis-affected mice, while the intra-gingival injection of siInhba significantly reduced activin A levels and restored muscle mass and myofiber size compared to the siCtrl injection. Our findings indicate that activin A is a key mediator of muscle atrophy in periodontitis and that local injection of siInhba can prevent periodontitis-induced muscle atrophy without causing systemic adverse effects.