Meloxicam protects against muscle and metabolic decline in ageing through Cdon restoration and oxidative stress modulation.
Sarcopenia is characterized by progressive decline in skeletal muscle mass and function, driven in part by impaired mitochondrial homeostasis and redox imbalance. However, the upstream regulators that integrate metabolic resilience with muscle integrity during ageing remain poorly defined. Here, we identify the cell adhesion molecule Cdon as a conserved determinant of adult muscle maintenance whose expression declines with human aging, sarcopenia and muscle-wasting disease. Reduced Cdon expression was associated with transcriptional atrophy signatures, metabolic insufficiency and reduced myofibre size. Using a Cdon promoter-based screen, we identified meloxicam (Mcam) as a small molecule inducer of Cdon that enhances myogenic differentiation, increases muscle mass and function in young mice and mitigates age-related muscle atrophy. Mcam treatment also improved neuromuscular conduction and systemic metabolic parameters, including blood glucose regulation and hepatic lipid accumulation. In aged muscle, Mcam normalized cysteine accumulation, restored redox balance, improved mitochondrial metabolism and reduced oxidative stress. Mechanistically, Mcam activated Ampk signalling to preserve Cdon expression under oxidative challenge and support antioxidant and mitochondrial quality control pathways. Together, these findings identify Cdon decline as a hallmark of muscle ageing and demonstrate that Mcam preserves muscle integrity by reestablishing redox and metabolic homeostasis through Ampk-dependent maintenance of Cdon. Age-related decline of Cdon is a key molecular feature of skeletal muscle dysfunction. In this study, meloxicam restored Cdon expression through Ampk activation, thereby preserving muscle integrity and functional capacity in aged muscle. Mechanistically, meloxicam normalized cysteine metabolism and elevates Gpx4 expression, improving glutathione buffering and suppressing excessive reactive oxygen species accumulation. Activation of the Ampk-Cdon axis was associated with maintenance of mitochondrial homeostasis and redox balance. Together, these findings identify Cdon as a potential therapeutic target for age-associated skeletal muscle degeneration.