Abstract Background: Knee osteoarthritis is associated with damage to ligaments and skeletal muscles around the knee joint. Since inhibiting atrophy can help improve this disease; therefore, this study aimed to determine the effect of mesenchymal stem cell (MSCs), hyaluronic acid (HA) and aerobic exercise on the expression of myonectin and myogenin genes and the production of CD44 protein in the quadriceps muscle tissue of osteoarthritis rats. Materials and Methods: Forty-five adult male rats aged 6-8 weeks were placedin 9 groups of 5including healthy control, patient control, MSCs, HA, aerobic exercise, MSCs+HA, exercise+HA, exercise+MSCs and exercise+MSCs+HA. Osteoarthritis was surgically induced. Aerobic exercise was done for 8 weeks, 3 sessions a week and at a speed of 16m/min. MSCs were injected at the rate of 1×106cells/kg and HA at a concentration of 10mg/ml. Forty-eight hours after completing the protocol, the quadriceps muscle tissue was isolated and the expression of myonectin and myogenin genes was measured by Real-Time PCR and the expression of CD44 proteinwas measured by immunohistochemistry method. Results: The gene expression of myonectin, myogenin, and CD44 protein expression was significantly increased in aerobic exercise, HA and MSCs groups alone(P=0.001) and CD44 in exercise+HA(P=0.024); While myogenin in exercise+MSCs group(P=0.037) and myonectin in exercise+MSCs, exercise+HA(P=0.001) and MSCs+HA(P=0.012) groups increased significantly. Conclusion: Aerobic exercise, HA and MSCs alone and exercise+MSCs synergistically led to the inhibition of muscle atrophy by increasing the activity of myokines;but exercise+HA play a role in muscle building in osteoarthritis rats. Keywords: Aerobicexercise, Mesenchymal stem cells, Hyaluronic acid, Myonectin and Myogenin, Osteoarthritis