Browsing by Author "Leonard, Timothy"
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Item Open Access Computing Average Passive Forces in Sarcomeres in Length-Ramp Simulations(PLOS Computational Biology, 2016-06) Herzog, Walter; Schnappacher-Tilp, Gudrun; Leonard, Timothy; Desch, GertrudPassive forces in sarcomeres are mainly related to the giant protein titin. Titin’s extensible region consists of spring-like elements acting in series. In skeletal muscles these elements are the PEVK segment, two distinct immunoglobulin (Ig) domain regions (proximal and distal), and a N2A portion. While distal Ig domains are thought to form inextensible end filaments in intact sarcomeres, proximal Ig domains unfold in a force- and time-dependent manner. In length-ramp experiments of single titin strands, sequential unfolding of Ig domains leads to a typical saw-tooth pattern in force-elongation curves which can be simulated by Monte Carlo simulations. In sarcomeres, where more than a thousand titin strands are arranged in parallel, numerous Monte Carlo simulations are required to estimate the resultant force of all titin filaments based on the non-uniform titin elongations. To simplify calculations, the stochastic model of passive forces is often replaced by linear or non-linear deterministic and phenomenological functions. However, new theories of muscle contraction are based on the hypothesized binding of titin to the actin filament upon activation, and thereby on a prominent role of the structural properties of titin. Therefore, these theories necessitate a detailed analysis of titin forces in ength-ramp experiments. In our study we present a simple and efficient alternative to Monte Carlo simulations. Based on a structural titin model, we calculate the exact probability distributions of unfolded Ig domains under length-ramp conditions needed for rigorous analysis of expected forces, distribution of unfolding forces, etc. Due to the generality of our model, the approach is applicable to a wide range of stochastic protein unfolding problems.Item Open Access Relationship of muscle morphology to hip displacement in cerebral palsy: a pilot study investigating changes intrinsic to the sarcomere(2019-06-21) Larkin-Kaiser, Kelly A; Howard, Jason J; Leonard, Timothy; Joumaa, Venus; Gauthier, Luke; Logan, Karl; Orlik, Benjamin; El-Hawary, Ron; Herzog, WalterAbstract Background Cerebral palsy (CP) is the most common cause of childhood disability, typified by a static encephalopathy with peripheral musculoskeletal manifestations—most commonly related to spasticity—that are progressive with age. Hip displacement is one of the most common manifestations, observed to lead to painful degenerative arthritis over time. Despite the key role that spasticity-related adductor muscle contractures are thought to play in the development of hip displacement in CP, basic science research in this area to date has been limited. This study was initiated to correlate hip adductor muscle changes intrinsic to the sarcomere—specifically, titin isoforms and sarcomere length—to the severity of hip displacement in children with spastic cerebral palsy. Methods Single gracilis muscle biopsies were obtained from children with CP (Gross Motor Function Classification System (GMFCS) III-V; n = 10) who underwent adductor muscle release surgery for the treatment of hip displacement. Gel electrophoresis was used to estimate titin molecular weight. Sarcomere lengths were measured from muscle fascicles using laser diffraction. The severity of hip displacement was determined by measuring by Reimers migration percentage (MP) from anteroposterior pelvic x-rays. Correlation analyses between titin, sarcomere lengths, and MP were performed. Results The mean molecular weight of titin was 3588 kDa. The mean sarcomere length was 3.51 μm. Increased MP was found to be associated with heavier isoforms of titin (R2 = 0.65, p < 0.05) and with increased sarcomere lengths (R2 = 0.65, p < 0.05). Heavier isoforms of titin were also associated with increased sarcomere lengths (R2 = 0.80, p < 0.05). Conclusions Our results suggest that both larger titin isoforms and sarcomere lengths are positively correlated with increased severity of hip displacement and may represent adaptations in response to concomitant increases in spasticity and muscle shortening. Trial registration As this study does not report the results of a health care intervention on human participants, it has not been registered.