Differential response of tissue engineered skeletal muscle from rheumatoid arthritis patients and healthy controls

Rheumatoid arthritis (RA) is a chronic inflammatory disease, causing pain, increased mortality, and profound disability rates. RA affects articular joints and multiple organs, including skeletal muscle. Loss of muscle mass is associated with increased disability in RA. We developed an in vitro tissue-engineered human skeletal muscle model (myobundle) to better understand the disease mechanisms driving muscle loss in RA. Myobundles were generated using primary skeletal muscle cells from the vastus lateralis muscle of 5 RA patients and 4 age-matched healthy controls. Compared to controls, RA myobundles were more sensitive to IFN-γ, leading to reduced contractile force. Gene sets enriched in IFN-γ-treated RA myobundles, but not IFN-γ-treated controls, were involved in the response to hypoxia and the unfolded protein response. We identified PIM1 as a selectively upregulated gene and verified altered protein expression by Western blotting. Tofacitinib restored contractile force and myosin heavy chain protein levels in RA myobundles with IFN-γ-induced dysfunction. Thus, human myobundles can model inflammation of muscle in RA and other diseases.