Methodological and anatomical modifiers of Achilles tendon moment arm estimates implications for biomechanical modelling: Implications for biomechanical modelling

This thesis was submitted for the degree of Doctor of Philosophy and was awarded by Brunel University.Moment arms are important in many contexts. Various methods have been used to estimate moment arms. It has been shown that a moment arm changes as a function of joint angle and contraction state. However, besides the influence of these anatomical factors, results from recent studies suggest that the estimation of moment arm is also dependent on the methods employed. The overall goal of this thesis was to explore the interaction between the methodological and anatomical influences on moment arm and their effect on estimates of muscle-tendon forces during biomechanical modelling. The first experiment was a direct comparison between two different moment arm methods that have been previously used for the estimation of Achilles tendon moment arm. The results of this experiment revealed a significant difference in Achilles tendon moment arm length dependent on the moment arm method employed. However, besides the differences found, results from both methods were well correlated. Based on these results, methodological differences between these two methods were compared across different joint angles and contraction states in study two. Results of experiment two revealed that Achilles tendon moment arms obtained using both methods change in a similar way as a function of joint angle and contraction state. In the third experiment, results from the first two experiments were used to determine how methodological and anatomical influences on Achilles tendon moment arm would change muscle-tendon forces during the task of submaximal cycling. Results of the third experiment showed the importance of taking the method, ankle angle and contraction state dependence of Achilles tendon moment arm into account when using biomechanical modelling techniques. Together, these findings emphasis the importance of carefully considering methodological and anatomical modifiers when estimating Achilles tendon moment arm

Interactive effects of joint angle, contraction state and method on estimates of Achilles tendon moment arms

The muscle-tendon moment arm is an important input parameter for musculoskeletal models. Moment arms change as a function of joint angle and contraction state and depend on the method being employed. The overall purpose was to gain insights into the interactive effects of joint angle, contraction state and method on the Achilles tendon moment arm using the center of rotation (COR) and the tendon excursion method (TE). Moment arms were obtained at rest (TErest, CORrest) and during a maximum voluntary contraction (CORMVC) at four angles. We found strong correlations between TErest and CORMVC for all angles (0.72 ≤ r ≤ 0.93) with Achilles tendon moment arms using CORMVC being 33 - 36% greater than those obtained from TErest. The relationship between Achilles tendon moment arms and angle was similar across both methods and both levels of muscular contraction. Finally, Achilles tendon moment arms for CORrest were 1 – 8% greater than for CORMVC. [NB rendition of scientific symbols is approximate in this display; please check full text for precise rendition]

Direct comparison of in vivo Achilles tendon moment arms obtained from ultrasound and MR scans

Accurate and reliable estimation of muscle moment arms is a prerequisite for the development of musculoskeletal models. Numerous techniques are available to estimate the Achilles tendon moment arm in vivo. The purposes of this study were 1) to compare in vivo Achilles tendon moment arms obtained using the center of rotation (COR) and tendon excursion (TE) methods and 2) to assess the reliability of each method. For the COR method, magnetic resonance (MR) images from nine participants were obtained at ankle angles of −15°, 0°, and +15° and analyzed using Reuleaux' method. For the TE method, the movement of the gastrocnemius medialis-Achilles tendon junction was recorded using ultrasonography as the ankle was passively rotated through its range of motion. The Achilles tendon moment arm was obtained by differentiation of tendon displacement with respect to ankle angular excursion using seven different differentiation techniques. Moment arms obtained using the COR method were significantly greater than those obtained using the TE method (P < 0.01), but results from both methods were well correlated. The coefficient of determination between moment arms derived from the COR and TE methods was highest when tendon displacement was linearly differentiated over a ±10° interval (R2 = 0.94). The between-measurement coefficient of variation was 3.9% for the COR method and 4.5–9.7% for the TE method, depending on the differentiation technique. The high reliabilities and strong relationship between methods demonstrate that both methods are robust against their limitations. The large absolute between-method differences (∼25–30%) in moment arms have significant implications for their use in musculoskeletal models

Calpains as novel players in the molecular pathogenesis of spinocerebellar ataxia type 17

Spinocerebellar ataxia type 17 (SCA17) is a neurodegenerative disease caused by a polyglutamine-encoding trinucleotide repeat expansion in the gene of transcription factor TATA box-binding protein (TBP). While its underlying pathomechanism is elusive, polyglutamine-expanded TBP fragments of unknown origin mediate the mutant protein’s toxicity. Calcium-dependent calpain proteases are protagonists in neurodegenerative disorders. Here, we demonstrate that calpains cleave TBP, and emerging C-terminal fragments mislocalize to the cytoplasm. SCA17 cell and rat models exhibited calpain overactivation, leading to excessive fragmentation and depletion of neuronal proteins in vivo. Transcriptome analysis of SCA17 cells revealed synaptogenesis and calcium signaling perturbations, indicating the potential cause of elevated calpain activity. Pharmacological or genetic calpain inhibition reduced TBP cleavage and aggregation, consequently improving cell viability. Our work underlines the general significance of calpains and their activating pathways in neurodegenerative disorders and presents these proteases as novel players in the molecular pathogenesis of SCA17. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04274-6

Tibialis anterior moment arm: effects of measurement errors and assumptions

Accurate estimates of tibialis anterior (TA) muscle force are important in many contexts. Two approaches commonly used to estimate moment arms are the tendon excursion (TE) and geometric (GEO) methods. Previous studies report poor agreement between the two approaches. PURPOSE: The purposes of this study were to 1) assess the effect of methodological variations in the two methods of moment arm estimation and 2) determine how these variations affect agreement between the methods. METHODS: TA moment arms were determined using TE and GEO. Errors associated with tendon stretch/hysteresis, talus rotation relative to the foot, and the location of the line of action were investigated. RESULTS: For TE, large errors in moment arm estimates across the range of motion were found when tendon length changes (P = 0.001) were not corrected for. For GEO, the estimated moment arm was reduced at an ankle angle of -15° when discrepancies between talus and foot rotations were accounted for or when an alternative tendon line of action was used either separately (effect size (ES), 0.46 and 0.58, respectively; P > 0.05) or together (ES, 0.89; P > 0.05). TE-derived moment arms were smaller than GEO-derived moment arms (ES, 0.68-4.86, varying by angle) before accounting for sources of error. However, these differences decreased after error correction (ES, 0.09-1.20, P > 0.05). Nonetheless, the shape of the moment arm-joint angle relation was curvilinear for TE but linear for GEO. CONCLUSIONS: Of all methodological modifications, accounting for tendon length changes had the largest effect on TA moment arm estimates. We conclude that the TE method is viable to determine TA moment arms as long as changes in tendon length are accounted for