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Biomedical Physiology and Kinesiology, Department of

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The Energy of Muscle Contraction. III. Kinetic Energy During Cyclic Contractions

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2021-04-07
Abstract: 

During muscle contraction, chemical energy is converted to mechanical energy when ATP is hydrolysed during cross-bridge cycling. This mechanical energy is then distributed and stored in the tissue as the muscle deforms or is used to perform external work. We previously showed how energy is distributed through contracting muscle during fixed-end contractions; however, it is not clear how the distribution of tissue energy is altered by the kinetic energy of muscle mass during dynamic contractions. In this study we conducted simulations of a 3D continuum muscle model that accounts for tissue mass, as well as force-velocity effects, in which the muscle underwent sinusoidal work-loop contractions coupled with bursts of excitation. We found that increasing muscle size, and therefore mass, increased the kinetic energy per unit volume of the muscle. In addition to greater relative kinetic energy per cycle, relatively more energy was also stored in the aponeurosis, and less was stored in the base material, which represented the intra and extracellular tissue components apart from the myofibrils. These energy changes in larger muscles due to greater mass were associated lower mass-specific mechanical work output per cycle, and this reduction in mass-specific work was greatest for smaller initial pennation angles. When we compared the effects of mass on the model tissue behaviour to that of in situ muscle with added mass during comparable work-loop trials, we found that greater mass led to lower maximum and higher minimum acceleration in the longitudinal (x) direction near the middle of the muscle compared to at the non-fixed end, which indicates that greater mass contributes to tissue non-uniformity in whole muscle. These comparable results for the simulated and in situ muscle also show that this modelling framework behaves in ways that are consistent with experimental muscle. Overall, the results of this study highlight that muscle mass is an important determinant of whole muscle behaviour.

Document type: 
Article
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Utility of Zebrafish Models of Acquired and Inherited Long QT Syndrome

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2021-01-15
Abstract: 

Long-QT Syndrome (LQTS) is a cardiac electrical disorder, distinguished by irregular heart rates and sudden death. Accounting for ∼40% of cases, LQTS Type 2 (LQTS2), is caused by defects in the Kv11.1 (hERG) potassium channel that is critical for cardiac repolarization. Drug block of hERG channels or dysfunctional channel variants can result in acquired or inherited LQTS2, respectively, which are typified by delayed repolarization and predisposition to lethal arrhythmia. As such, there is significant interest in clear identification of drugs and channel variants that produce clinically meaningful perturbation of hERG channel function. While toxicological screening of hERG channels, and phenotypic assessment of inherited channel variants in heterologous systems is now commonplace, affordable, efficient, and insightful whole organ models for acquired and inherited LQTS2 are lacking. Recent work has shown that zebrafish provide a viable in vivo or whole organ model of cardiac electrophysiology. Characterization of cardiac ion currents and toxicological screening work in intact embryos, as well as adult whole hearts, has demonstrated the utility of the zebrafish model to contribute to the development of therapeutics that lack hERG-blocking off-target effects. Moreover, forward and reverse genetic approaches show zebrafish as a tractable model in which LQTS2 can be studied. With the development of new tools and technologies, zebrafish lines carrying precise channel variants associated with LQTS2 have recently begun to be generated and explored. In this review, we discuss the present knowledge and questions raised related to the use of zebrafish as models of acquired and inherited LQTS2. We focus discussion, in particular, on developments in precise gene-editing approaches in zebrafish to create whole heart inherited LQTS2 models and evidence that zebrafish hearts can be used to study arrhythmogenicity and to identify potential anti-arrhythmic compounds.

Document type: 
Article
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The Effect of Multidirectional Loading on Contractions of the M. Medial Gastrocnemius

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2021-01-18
Abstract: 

Research has shown that compression of muscle can lead to a change in muscle force. Most studies show compression to lead to a reduction in muscle force, although recent research has shown that increases are also possible. Based on methodological differences in the loading design between studies, it seems that muscle length and the direction of transverse loading influence the effect of muscle compression on force production. Thus, in our current study we implement these two factors to influence the effects of muscle loading. In contrast to long resting length of the medial gastrocnemius (MG) in most studies, we use a shorter MG resting length by having participant seated with their knees at a 90° angle. Where previous studies have used unidirectional loads to compress the MG, in this study we applied a multidirectional load using a sling setup. Multidirectional loading using a sling setup has been shown to cause muscle force reductions in previous research. As a result of our choices in experimental design we observed changes in the effects of muscle loading compared to previous research. In the present study we observed no changes in muscle force due to muscle loading. Muscle thickness and pennation angle showed minor but significant increases during contraction. However, no significant changes occurred between unloaded and loaded trials. Fascicle thickness and length showed different patterns of change compared to previous research. We show that muscle loading does not result in force reduction in all situations and is possibly linked to differences in muscle architecture and muscle length.

Document type: 
Article
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How Aging Affects Visuomotor Adaptation and Retention in a Precision Walking Paradigm

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2021-01-12
Abstract: 

Motor learning is a lifelong process. However, age-related changes to musculoskeletal and sensory systems alter the relationship (or mapping) between sensory input and motor output, and thus potentially affect motor learning. Here we asked whether age affects the ability to adapt to and retain a novel visuomotor mapping learned during overground walking. We divided participants into one of three groups (n = 12 each) based on chronological age: a younger-aged group (20–39 years old); a middle-aged group (40–59 years old); and an older-aged group (60–80 years old). Participants learned a new visuomotor mapping, induced by prism lenses, during a precision walking task. We assessed retention one-week later. We did not detect significant effects of age on measures of adaptation or savings (defined as faster relearning). However, we found that older adults demonstrated reduced initial recall of the mapping, reflected by greater foot-placement error during the first adaptation trial one-week later. Additionally, we found that increased age significantly associated with reduced initial recall. Overall, our results suggest that aging does not impair adaptation and that older adults can demonstrate visuomotor savings. However, older adults require some initial context during relearning to recall the appropriate mapping.

Document type: 
Article
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Biophysical Characterization of a Novel SCN5A Mutation Associated With an Atypical Phenotype of Atrial and Ventricular Arrhythmias and Sudden Death

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2020-12-22
Abstract: 

Background: Sudden cardiac death (SCD) is an unexpected death that occurs within an hour of the onset of symptoms. Hereditary primary electrical disorders account for up to 1/3 of all SCD cases in younger individuals and include conditions such as catecholaminergic polymorphic ventricular tachycardia (CPVT). These disorders are caused by mutations in the genes encoding cardiac ion channels, hence they are known as cardiac channelopathies. We identified a novel variant, T1857I, in the C-terminus of Nav1.5 (SCN5A) linked to a family with a CPVT-like phenotype characterized by atrial tachy-arrhythmias and polymorphic ventricular ectopy occurring at rest and with adrenergic stimulation, and a strong family history of SCD.

Objective: Our goal was to functionally characterize the novel Nav1.5 variant and determine a possible link between channel gating and clinical phenotype.

Methods: We first used electrocardiogram recordings to visualize the patient cardiac electrical properties. Then, we performed voltage-clamp of transiently transfected CHO cells. Lastly, we used the ventricular/atrial models to visualize gating defects on cardiac excitability.

Results: Voltage-dependences of both activation and inactivation were right-shifted, the overlap between activation and inactivation predicted increased window currents, the recovery from fast inactivation was slowed, there was no significant difference in late currents, and there was no difference in use-dependent inactivation. The O’Hara-Rudy model suggests ventricular after depolarizations and atrial Grandi-based model suggests a slight prolongation of atrial action potential duration.

Conclusion: We conclude that T1857I likely causes a net gain-of-function in Nav1.5 gating, which may in turn lead to ventricular after depolarization, predisposing carriers to tachy-arrhythmias.

Document type: 
Article
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The Energy of Muscle Contraction. II. Transverse Compression and Work

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2020-11-12
Abstract: 

In this study we examined how the strain energies within a muscle are related to changes in longitudinal force when the muscle is exposed to an external transverse load. We implemented a three-dimensional (3D) finite element model of contracting muscle using the principle of minimum total energy and allowing the redistribution of energy through different strain energy-densities. This allowed us to determine the importance of the strain energy-densities to the transverse forces developed by the muscle. We ran a series of in silica experiments on muscle blocks varying in initial pennation angle, muscle length, and external transverse load. As muscle contracts it maintains a near constant volume. As such, any changes in muscle length are balanced by deformations in the transverse directions such as muscle thickness or muscle width. Muscle develops transverse forces as it expands. In many situations external forces act to counteract these transverse forces and the muscle responds to external transverse loads while both passive and active. The muscle blocks used in our simulations decreased in thickness and pennation angle when passively compressed and pushed back on the load when they were activated. Activation of the compressed muscle blocks led either to an increase or decrease in muscle thickness depending on whether the initial pennation angle was less than or greater than 15°, respectively. Furthermore, the strain energy increased and redistributed across the different strain-energy potentials during contraction. The volumetric strain energy-density varied with muscle length and pennation angle and was reduced with greater transverse load for most initial muscle lengths and pennation angles. External transverse load reduced the longitudinal muscle force for initial pennation angles of β0 = 0°. Whereas for pennate muscle (β0 > 0°) longitudinal force changed (increase or decrease) depending on the muscle length, pennation angle and the direction of the external load relative to the muscle fibres. For muscle blocks with initial pennation angles β0 ≤ 20° the reduction in longitudinal muscle force coincided with a reduction in volumetric strain energy-density.

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Article
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Drug Screening Platform Using Human Induced Pluripotent Stem Cell-Derived Atrial Cardiomyocytes and Optical Mapping

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2020-09-14
Abstract: 

Current drug development efforts for the treatment of atrial fibrillation are hampered by the fact that many preclinical models have been unsuccessful in reproducing human cardiac physiology and its response to medications. In this study, we demonstrated an approach using human induced pluripotent stem cell‐derived atrial and ventricular cardiomyocytes (hiPSC‐aCMs and hiPSC‐vCMs, respectively) coupled with a sophisticated optical mapping system for drug screening of atrial‐selective compounds in vitro. We optimized differentiation of hiPSC‐aCMs by modulating the WNT and retinoid signaling pathways. Characterization of the transcriptome and proteome revealed that retinoic acid pushes the differentiation process into the atrial lineage and generated hiPSC‐aCMs. Functional characterization using optical mapping showed that hiPSC‐aCMs have shorter action potential durations and faster Ca2+ handling dynamics compared with hiPSC‐vCMs. Furthermore, pharmacological investigation of hiPSC‐aCMs captured atrial‐selective effects by displaying greater sensitivity to atrial‐selective compounds 4‐aminopyridine, AVE0118, UCL1684, and vernakalant when compared with hiPSC‐vCMs. These results established that a model system incorporating hiPSC‐aCMs combined with optical mapping is well‐suited for preclinical drug screening of novel and targeted atrial selective compounds.

Document type: 
Article
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The Energy of Muscle Contraction. I. Tissue Force and Deformation During Fixed-End Contractions

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2020-08-31
Abstract: 

During contraction the energy of muscle tissue increases due to energy from the hydrolysis of ATP. This energy is distributed across the tissue as strain-energy potentials in the contractile elements, strain-energy potential from the 3D deformation of the base-material tissue (containing cellular and extracellular matrix effects), energy related to changes in the muscle's nearly incompressible volume and external work done at the muscle surface. Thus, energy is redistributed through the muscle's tissue as it contracts, with only a component of this energy being used to do mechanical work and develop forces in the muscle's longitudinal direction. Understanding how the strain-energy potentials are redistributed through the muscle tissue will help enlighten why the mechanical performance of whole muscle in its longitudinal direction does not match the performance that would be expected from the contractile elements alone. Here we demonstrate these physical effects using a 3D muscle model based on the finite element method. The tissue deformations within contracting muscle are large, and so the mechanics of contraction were explained using the principles of continuum mechanics for large deformations. We present simulations of a contracting medial gastrocnemius muscle, showing tissue deformations that mirror observations from magnetic resonance imaging. This paper tracks the redistribution of strain-energy potentials through the muscle tissue during fixed-end contractions, and shows how fibre shortening, pennation angle, transverse bulging and anisotropy in the stress and strain of the muscle tissue are all related to the interaction between the material properties of the muscle and the action of the contractile elements.

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Article
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ADP is the Dominant Controller of AMPactivated Protein Kinase Activity Dynamics in Skeletal Muscle during Exercise

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2020-07-30
Abstract: 

Exercise training elicits profound metabolic adaptations in skeletal muscle cells. A key molecule in coordinating these adaptations is AMP-activated protein kinase (AMPK), whose activity increases in response to cellular energy demand. AMPK activity dynamics are primarily controlled by the adenine nucleotides ADP and AMP, but how each contributes to its control in skeletal muscle during exercise is unclear. We developed and validated a mathematical model of AMPK signaling dynamics, and then applied global parameter sensitivity analyses with data-informed constraints to predict that AMPK activity dynamics are determined principally by ADP and not AMP. We then used the model to predict the effects of two additional direct-binding activators of AMPK, ZMP and Compound 991, further validating the model and demonstrating its applicability to understanding AMPK pharmacology. The relative effects of direct-binding activators can be understood in terms of four properties, namely their concentrations, binding affinities for AMPK, abilities to enhance AMPK phosphorylation, and the magnitudes of their allosteric activation of AMPK. Despite AMP’s favorable values in three of these four properties, ADP is the dominant controller of AMPK activity dynamics in skeletal muscle during exercise by virtue of its higher concentration compared to that of AMP.

Document type: 
Article
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Exploring Knowledge and Perspectives of South Asian Children and Their Parents Regarding Healthy Cardiovascular Behaviors: A Qualitative Analysis

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2020-07-01
Abstract: 

South Asian children and parents have been shown to have a higher risk for cardiovascular disease (CVD) relative to white individuals. To design interventions aimed at addressing the comparatively higher burden in South Asians, a better understanding of attitudes and perspectives regarding CVD-associated behaviors is needed. As a result, we sought to understand knowledge about CVD risk in both children and parents, and attitudes toward physical activity and diet in both the children and parents, including potential cultural influences. In-depth interviews were conducted with 13 South Asian child-and-parent dyads representing a range of child body mass index (BMI) levels, ages, and with both sexes. South Asian children and parents demonstrated good knowledge about CVD prevention; however, knowledge did not always translate into behavior. The influence of social and cultural dynamics on behavior was also highlighted. To ensure that interventions aimed at this population are effective, an understanding of the unique social dynamics that influence diet and physical activity–related behaviors is needed.

Document type: 
Article
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