Meloxicam protects against muscle and metabolic decline in ageing through Cdon restoration and oxidative stress modulation

Abstract

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. 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. Sarcopenia, the age-related loss of muscle mass and strength, significantly impacts older adults’ health, yet its regulatory mechanisms remain elusive. This study identifies Cdon, a protein whose expression declines with age, as a crucial factor in muscle maintenance. Researchers discovered meloxicam (Mcam), a compound that induces Cdon expression, through a chemical screen. Mcam enhances myogenesis, muscle mass, and function in both young and aged mice by activating AMP-activated protein kinase (Ampk), which supports mitochondrial function and redox balance. Mcam treatment improved mitochondrial bioenergetics, reduced oxidative stress and normalized cysteine metabolism, crucial for maintaining muscle integrity. These findings suggest that targeting the Ampk-Cdon pathway could offer therapeutic potential for combating age-related muscle degeneration, positioning Cdon as a promising target for future interventions in sarcopenia and related muscle diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.