Rheumatoid arthritis (RA) is one of the most common inflammatory diseases globally and skeletal muscle dysfunction is an integral aspect of the pathology. Skeletal muscle dysfunction in patients with RA has often been attributed to the exacerbated autoimmune and inflammatory response. However, we and others have shown that patients on DMARDs and low state of disease activity, still exhibit muscle weakness and dysfunction. This contributes to lack of ability to work, restricts their independence, and reduces their quality of life. Disease-modifying anti-rheumatic drugs (DMARDs) with broad immunosuppressive activity, or specific activity targeting pro-inflammatory cytokines (e.g., TNF-α or IL-6) are the first-line treatment for RA patients. DMARDs are efficient in retaining patients in a low disease activity state, however, we and others have shown that they fail to improve muscle force and physical function. Thus, anti-inflammatory treatment alone is not enough to counteract the negative effects on skeletal muscle function and physical performance. This stresses the urge for better understanding of this comorbidity to identify molecular targets for future therapeutic interventions. Here we aim to unveil the molecular determinants that link inflammation to mitochondrial alterations and skeletal muscle dysfunction. Transgenic and knock-out mice models targeting genes of interest will be used to assess the functional and morphological effects on the skeletal muscle tissue from these. In the various mouse models, RA inflammation with be mimicked to elucidate the link between RA inflammation and muscle weakness. Subsequently, a variety of in vivo and ex vivo experiments will be carried out to illuminate potential druggable targets.