Sensitivity analysis of musculoskeletal parameters and motion variability on the mouse tibial loading

Accurate prediction of bone adaptation in mouse hindlimbs requires reliable estimates of forces applied to the bones during locomotion. Musculoskeletal models are commonly used for this purpose, but their predictions are sensitive to variations in input parameters. Identifying which parameters influence the bone loading most is essential to improve predictions of mechano-regulated bone adaptation based on personalized finite element models. In this study a global sensitivity analysis of a mouse musculoskeletal models was conducted using the Morris screening technique to assess the importance of 173 input parameters (musculotendon properties, joint angles, and ground reaction force) on the tibial forces estimated during the stance phase. The absolute mean and standard deviation of elementary effects were used to rank parameters according to their overall influence and potential nonlinear or interaction effects. The sensitivity analysis was done for two cases: with and without the force-length-velocity (F-L-V) relationship. Excluding the F-L-V relationship led to realistic results while including F-L-V relationship led to high reserve actuators and unrealistic simulations. When the F-L-V relationship was excluded, a subset of 19 parameters was found to have a significant effect on the magnitude of the loads applied to the tibia. These parameters were related to maximal isometric force of 14 muscles of the mouse hindlimb, hip and knee joint flexion, vertical and anteroposterior ground reaction force. These results suggest that personalizing these parameters is critical for accurate determination of the physiological loads that act on the tibia and should therefore be considered when modelling bone adaptation over time.