Mitochondrial electron transfer chain activation in atrophic Muscle: Implications for calcium signaling and chondrocyte apoptosis in osteoarthritis.

Abstract

Skeletal muscle wasting directly impacts the stability of the knee joint, leading to the development of osteoarthritis (OA). However, the underlying mechanism of the interaction between skeletal muscle and cartilage remains unclear. Therefore, the cross-talk between skeletal muscle and cartilage was investigated in rat models of muscle atrophy and the combination of OA and muscle atrophy through gait analysis, grip strength testing, micro-CT, and histological staining. The underlying mechanism was identified through metabolomics, RNA-sequencing, and verification experiments. It is first confirmed that skeletal muscle wasting induces reduction of joint function and the acceleration of cartilage injury. Furthermore, OA chondrocytes exhibited worsened injury when co-cultured with atrophied muscle. Mechanistically, metabolomics revealed the differential metabolites in muscle mainly enriched mitochondrial electron transport chain signaling pathway, which is the primary source of reactive oxygen species (ROS). RNA-sequencing of cartilage combined with verification experiments further indicated that the calcium signaling pathway in injured cartilage was activated, leading to the increase in chondrocyte apoptosis and inflammation, which attributed to the elevated levels of ROS in muscle atrophy, which stimulates synovium to further produce ROS and then release it into knee joint fluid. These observations suggest that elevated ROS levels in atrophied muscle may activate the calcium signaling pathway, leading to the increase of chondrocyte apoptosis, and ultimately exacerbate OA, which have potential to be a novel therapeutic target for OA treatment.