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.

Tibialis anterior moment arm: effects of measurement errors and assumptions.

UNLABELLED: 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.

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). Achilles tendon 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 (.72 ≤ r ≤ .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 CORMVC were 1-8% greater than for COR(rest).

Rapid force production in children and adults: mechanical and neural contributions.

PURPOSE: Children demonstrate lower force production capacities compared with adults, which has often been attributed to "neuromuscular immaturity." However, tendon stiffness, which influences both the electromechanical delay (EMD) and rate of force development (RFD) in adults, is lower in children and may influence rapid force production. The aims of this study were 1) to document EMD and RFD variation as a function of age, 2) to determine the relationships between tendon stiffness and parameters relating to rapid force production in children and adults, and 3) to estimate the relative neural and mechanical contributions to age-related changes in force production by examining the effects of tendon stiffness and muscle activation rate (rate of EMG increase [REI]) on RFD. METHODS: Achilles tendon stiffness, EMD, RFD, and REI were measured during plantarflexion contractions in 47 prepubertal children (5-12 yr) and 19 adults. Relationships were determined between 1) stiffness and EMD, 2) stiffness and RFD, and 3) REI and RFD. The relative contributions of age, stiffness, and REI on RFD were determined using a multiple regression analysis. Age-related differences in tendon stiffness, EMD, RFD, and REI were also examined according to chronological age (5-6, 7-8, and 9-10 yr) and compared with adults. RESULTS: Increases in tendon stiffness with age were correlated with decreases in EMD (r < -0.83). Stiffness and REI could account for up to 35% and 30% of RFD variability in children, respectively, which increased to 58% when these variables were combined. CONCLUSIONS: Both neural and mechanical factors influence rapid force production in prepubertal children. Children's longer EMD and slower RFD indicate a less effective development and transfer of muscular forces, which may have implications for complex movement performance.

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 (R(2) = 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.

Identification of interindividual and intraindividual movement patterns in handball players of varying expertise levels.

The authors examined the movement patterns of 5 left-handed handball players (ranging from beginner to national level) who threw a handball to different sections of a goal as if a goalkeeper were present. The authors used time-continuous, 3-dimensional kinematic data to assess interindividual movement patterns and considered participants' intraindividual differences relative to different targets. Cluster analysis yielded the highest assignment rates for level of expertise; a mean of 92% of trials was correctly assessed. The authors observed an interaction with expertise for the intraindividual movement patterns. Variability in the novice throwers was increased, whereas (a) advanced throwers experienced a period of stability, and (b) the expert thrower's variability was increased. The results indicate that random variability characterizes novice motor performance, whereas active functional variability may exemplify expert motor performance.