Biomedical Physiology and Kinesiology, Department of

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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.

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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.

Document type: 
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.

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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.

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Article
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Cardio-postural Interactions and Muscle-pump Baroreflex Are Severely Impacted by 60-day Bedrest Immobilization

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2020-07-21
Abstract: 

To understand fundamental mechanisms associated with post-flight orthostatic intolerance we investigated the interaction between the cardiovascular and postural functions before and after 60 days of head down bedrest (HDBR). Twenty healthy young males (35.0 ± 1.7 years) were subjected to 60-day HDBR at 6˚ to simulate spaceflight-induced fluid shifts. A supine-to-stand (STS) test was conducted to evaluate cardio-postural control before and after (R) HDBR while an assessment of cardiovascular function was performed during HDBR. Beat-to-beat heart period, systolic blood pressure, and electromyography impulses were derived for wavelet transform coherence and causality analyses of the cardio-postural control and used to assess changes in the muscle-pump baroreflex. During quiet stand of the STS test, compared to baseline, heart rate was 50% higher on the day of exit from bedrest (R0) and 20% higher eight days later (R8). There was a 50% increase in deoxygenated hemoglobin on R0 and R8. Leg muscle activity reduced, and postural sway increased after HDBR. Causality of the muscle-pump baroreflex was reduced on R0 (0.73 ± 0.2) compared to baseline (0.87 ± 0.2) with complete recovery by R8. The muscle-pump baroreflex also had decreased gain and fraction time active following HDBR. Overall, our data show a significantly impaired muscle-pump baroreflex following bedrest.

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Article
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Subthreshold Stochastic Vestibular Stimulation Affects Balance-challenged Standing and Walking

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2020-04-10
Abstract: 

Subthreshold stochastic vestibular stimulation (SVS) is thought to enhance vestibular sensitivity and improve balance. However, it is unclear how SVS affects standing and walking when balance is challenged, particularly when the eyes are open. It is also unclear how different methods to determine stimulation intensity influence the effects. We aimed to determine (1) whether SVS affects stability when balance is challenged during eyes-open standing and overground walking tasks, and (2) how the effects differ based on whether optimal stimulation amplitude is derived from sinusoidal or cutaneous threshold techniques. Thirteen healthy adults performed balance-unchallenged and balance-challenged standing and walking tasks with SVS (0–30 Hz zero-mean, white noise electrical stimulus) or sham stimulation. For the balance-challenged condition, participants had inflatable rubber hemispheres attached to the bottom of their shoes to reduce the control provided by moving the center of pressure under their base of support. In different blocks of trials, we set SVS intensity to either 50% of participants’ sinusoidal (motion) threshold or 80% of participants’ cutaneous threshold. SVS reduced medial-lateral trunk velocity root mean square in the balance-challenged (p < 0.05) but not in the balance-unchallenged condition during standing. Regardless of condition, SVS decreased step-width variability and marginally increased gait speed when walking with the eyes open (p < 0.05). SVS intensity had minimal effect on the standing and walking measures. Taken together, our results provide insight into the effectiveness of SVS at improving balance-challenged, eyes-open standing and walking performance in healthy adults.

Document type: 
Article
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Scaling of Inertial Delays in Terrestrial Mammals

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2020-02-04
Abstract: 

As part of its response to a perturbation, an animal often needs to reposition its body. Inertia acts to oppose the corrective motion, delaying the completion of the movement—we refer to this elapsed time as inertial delay. As animal size increases, muscle moment arms also increase, but muscles are proportionally weaker, and limb inertia is proportionally larger. Consequently, the scaling of inertial delays is complex. Our intent is to determine how quickly different sized animals can produce corrective movements when their muscles act at their force capacity, relative to the time within which those movements need to be performed. Here, we quantify inertial delay using two biomechanical models representing common scenarios in animal locomotion: a distributed mass pendulum approximating swing limb repositioning (swing task), and an inverted pendulum approximating whole body posture recovery (posture task). We parameterized the anatomical, muscular, and inertial properties of these models using literature scaling relationships, then determined inertial delay for each task across a large range of movement magnitudes and the full range of terrestrial mammal sizes. We found that inertial delays scaled with an average of M0.28 in the swing task and M0.35 in the posture task across movement magnitudes—larger animals require more absolute time to perform the same movement as small animals. The time available to complete a movement also increases with animal size, but less steeply. Consequently, inertial delays comprise a greater fraction of swing duration and other characteristic movement times in larger animals. We also compared inertial delays to the other component delays within the stimulus-response pathway. As movement magnitude increased, inertial delays exceeded these sensorimotor delays, and this occurred for smaller movements in larger animals. Inertial delays appear to be a challenge for motor control, particularly for bigger movements in larger animals.

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Article
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Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2020-02-28
Abstract: 

The hERG (human-ether-à-go-go-related gene) channel underlies the rapid delayed rectifier current, Ikr, in the heart, which is essential for normal cardiac electrical activity and rhythm. Slow deactivation is one of the hallmark features of the unusual gating characteristics of hERG channels, and plays a crucial role in providing a robust current that aids repolarization of the cardiac action potential. As such, there is significant interest in elucidating the underlying mechanistic determinants of slow hERG channel deactivation. Recent work has shown that the hERG channel S4 voltage sensor is stabilized following activation in a process termed relaxation. Voltage sensor relaxation results in energetic separation of the activation and deactivation pathways, producing a hysteresis, which modulates the kinetics of deactivation gating. Despite widespread observation of relaxation behaviour in other voltage-gated K+ channels, such as Shaker, Kv1.2 and Kv3.1, as well as the voltage-sensing phosphatase Ci-VSP, the relationship between stabilization of the activated voltage sensor by the open pore and voltage sensor relaxation in the control of deactivation has only recently begun to be explored. In this review, we discuss present knowledge and questions raised related to the voltage sensor relaxation mechanism in hERG channels and compare structure-function aspects of relaxation with those observed in related ion channels. We focus discussion, in particular, on the mechanism of coupling between voltage sensor relaxation and deactivation gating to highlight the insight that these studies provide into the control of hERG channel deactivation gating during their physiological functioning.

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Article
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Intermittent Calf Compression Delays the Onset of Presyncope in Young Healthy Individuals

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2020-01-23
Abstract: 

Orthostatic fluid shifts reduce the effective circulating volume and thus contribute to syncope susceptibility. Recurrent syncope has a devastating impact on quality of life and is challenging to manage effectively. To blunt orthostatic fluid shifts, static calf compression garments are often prescribed to patients with syncope, but have questionable efficacy. Intermittent calf compression, which mimics the skeletal muscle pump to minimize pooling and filtration, holds promise for the management of syncope. We aimed to evaluate the effectiveness of intermittent calf compression for increasing orthostatic tolerance (OT; time to presyncope). We conducted a randomized single-blind crossover study, in which participants (n = 21) underwent three graded 60° head-up-tilt tests to presyncope with combined lower body negative pressure on separate days. Low frequency intermittent calf compression (ICLF; 4 s on and 11 s off) at 0–30 and 0–60 mmHg was applied during two tests and compared to a placebo condition where the garment was fitted, but no compression applied. We measured continuous leg circumference changes (strain gauge plethysmography), cardiovascular responses (finger plethysmography; Finometer Pro), end tidal gases (nasal cannula), and cerebral blood flow velocity (CBFv, transcranial Doppler). The 0–60 mmHg ICLF increased OT (33 ± 2.2 min) compared to both placebo (26 ± 2.4 min; p < 0.001) and 0–30 mmHg ICLF (25 ± 2.7 min; p < 0.001). Throughout testing 0–60 mmHg ICLF reduced orthostatic fluid shifts compared to both placebo and 0–30 mmHg ICLF (p < 0.001), with an associated improvement in stroke volume (p < 0.001), allowing blood pressure to be maintained at a reduced heart rate (p < 0.001). In addition, CBFv was higher with 0–60 mmHg ICLF than 0–30 mmHg ICLF and placebo (p < 0.001). Intermittent calf compression is a promising novel intervention for the management of orthostatic intolerance, which may provide affected individuals renewed independence and improved quality of life.

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Article
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Glaucoma-Related Differences in Gaze Behavior When Negotiating Obstacles

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2018-07-24
Abstract: 

Purpose: Safe navigation requires avoiding objects. Visual field loss may affect how one visually samples the environment, and may thus contribute to bumping into objects and falls. We tested the hypothesis that gaze strategies and the number of collisions differ between people with glaucoma and normally sighted controls when navigating around obstacles, particularly under multitasking situations.

Methods: Twenty persons with moderate–severe glaucoma and 20 normally sighted controls walked around a series of irregularly spaced vertical obstacles under the following three conditions: walking with obstacles only, walking and counting backward to simulate a conversation, and walking while performing a concurrent visual search task to simulate locating a landmark. We quantified gaze patterns and the number of obstacle contacts.

Results: Compared with controls, people with glaucoma directed gaze closer to their current position (P < 0.05). They also directed a larger proportion of fixations (in terms of number and duration) to obstacles (P < 0.05). Despite this finding, considerably more people with glaucoma contacted an obstacle (P < 0.05). Multitasking led to changes in gaze behavior in both groups, and this was accompanied by a large increase in obstacle contacts among those with glaucoma (P < 0.05).

Conclusions: Glaucoma alters gaze patterns when negotiating a series of obstacles and increases the likelihood of collisions. Multitasking in this situation exacerbates these changes.

Translational Relevance: Understanding glaucoma-related changes in gaze behavior during walking in cluttered environments may provide critical insight for orientation and mobility specialists and guide the design of gaze training interventions to improve mobility.

Document type: 
Article
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