We thank Dr. Nicolai Konow for providing the data used in this study. Funded by NSF IOS-2016049 and NSF DBI-2021832.

&quot;Avatar&quot;- Optimized Ex Vivo Work Loop Experiment to Emulate In Vivo Muscle Force

<ol>
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All authors acknowledge there is no conflict of interest.

While organisms move seamlessly across landscapes, the underlying loads and strains that the muscles experience vary drastically1,6,23. During both in vivo locomotion1,24 and in &#34;avatar&#34; experiments, muscles are stimulated submaximally under cyclical, non-steady conditions. The isometric force-length and isotonic force-velocity relationships are not well...

Moving animals achieve impressive athletic feats of endurance, speed, and agility in complex environments. Animal locomotion is particularly impressive in contrast to human-engineered machines-the stability and agility of current-legged robots, prostheses, and exoskeletons remain poor compared to animals. Legged locomotion in natural terrain requires precise control and rapid adjustments to alter the speed and maneuver environmental features that act as unexpected perturbations1,2,3,4. Yet, understanding non-steady locomotion is inherently challenging because the dynamics depend on complex interactions between the physical environment, musculoskeletal mechanics, and sensorimotor control1,2. Legged locomotion requires responding to unexpected perturbations with rapid multi-modal processing of sensory information and coordinated actuation of limbs and joints1,5. Ultimately, movement is made possible by muscles producing force via intrinsic mechanical properties of the musculoskeletal system as well as from neural control1,5,6,7. An outstanding question of neuromechanics is how these factors interact to produce coordinated movement in response to unexpected perturbations. The following technique utilizes muscle&#39;s intrinsic mechanical response to deformation using in vivo strain trajectories during controllable ex vivo experiments with an &#34;avatar&#34; muscle.
The muscle work loop technique has provided an important framework for understanding intrinsic muscle mechanics during cyclical movements8,9,10. The traditional work loop technique drives muscles through predefined, typically sinusoidal, strain trajectories using frequencies and activation patterns measured during in vivo experiments2,8,9,11. Using sinusoidal length trajectories can realistically estimate work and power output during flight12 and swimming2 under conditions where animals do not undergo rapid changes in strain trajectories due to interaction with the environment and musculoskeletal kinematics. However, in vivo muscle strain trajectories during legged locomotion arise dynamically from interactions among neural activation, musculoskeletal kinematics, and loads applied by the environment5,7,13,14. A more realistic work loop technique is needed to emulate loads, strain trajectories, and force production that corresponds to in vivo muscle-tendon dynamics and provides insight into how intrinsic muscle mechanics and neural control interact to produce coordinated movement in the face of perturbations.
Here, we present a novel way to emulate in vivo muscle forces during treadmill locomotion by using an &#34;avatar&#34; muscle from a laboratory rodent during controlled ex vivo experiments with in vivo strain trajectories that represent time-varying in vivo loads. Using the measured in vivo strain trajectories from a target muscle on muscles from a laboratory animal during controlled ex vivo experiments will emulate loads experienced during locomotion. In the experiments described here, the ex vivo mouse extensor digitorum longus (EDL) muscle is used as an &#34;avatar&#34; for the in vivo rat medial gastrocnemius (MG) muscle during walking, trotting, and galloping on a treadmill13. This approach is similar to the work-loop technique, except that in vivo strain trajectories are scaled appropriately and imposed on ex vivo mouse muscles attached to a servo motor. While mouse EDL muscles differ in size, fiber type, and architecture compared to the rat MG, it is possible to control for these differences. The &#34;avatar&#34; technique allows one to: (1) emulate in vivo strain, activation, stride frequency, and work-loop patterns; (2) vary these patterns to match in vivo force responses most accurately; and (3) vary specific features of strain and/or activation in controlled combinations to test mechanistic hypotheses.

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			<td>Braided Non-Absorbable Silk Suture 4-0&#160;</td>
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			<td>Sigma-Aldrich</td>
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			<td>Sigma-Aldrich</td>
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			<td>S88 Stimulator</td>
			<td>Grass</td>
			<td>M643H05</td>
			<td>Available for purchase on Ebay</td>
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			<td>Sigma-Aldrich</td>
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			<td>Wild Type Mice</td>
			<td>Jackson Laboratory</td>
			<td>B6C3Fe a/a Ttn mdm/J</td>
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"avatar", a modified ex vivo work loop experiments using in vivo strain and activation

Movement behaviors are emergent features of dynamic systems that result from muscle force production and work output. The interplay between neural and mechanical systems occurs at all levels of biological organization concurrently, from the tuning of leg muscle properties while running to the dynamics of the limbs interacting with the ground. Understanding the conditions under which animals shift their neural control strategies toward intrinsic muscle mechanics (&#39;preflexes&#39;) in the control hierarchy would allow muscle models to predict in vivo muscle force and work more accurately. To understand in vivo muscle mechanics, ex vivo investigation of muscle force and work under dynamically varying strain and loading conditions similar to in vivo locomotion is required. In vivo strain trajectories typically exhibit abrupt changes (i.e., strain and velocity transients) that arise from interactions among neural activation, musculoskeletal kinematics, and loads applied by the environment. The principal goal of our &#34;avatar&#34; technique is to investigate how muscles function during abrupt changes in strain rate and loading when the contribution of intrinsic mechanical properties to muscle force production may be highest. In the &#34;avatar&#34; technique, the traditional work-loop approach is modified using measured in vivo strain trajectories and electromyographic (EMG) signals from animals during dynamic movements to drive ex vivo muscles through multiple stretch-shortening cycles. This approach is similar to the work-loop technique, except that in vivo strain trajectories are scaled appropriately and imposed on ex vivo mouse muscles attached to a servo motor. This technique allows one to: (1) emulate in vivo strain, activation, stride frequency, and work-loop patterns; (2) vary these patterns to match in vivo force responses most accurately; and (3) vary specific features of strain and/or activation in controlled combinations to test mechanistic hypotheses.

Author Spotlight: Bridging the Gap Between In Vivo and Ex Vivo Studies with the &quot;Avatar&quot; Technique to Advance Muscle Mechanics Research 

"Avatar", a Modified Ex vivo Work Loop Experiments Using In vivo Strain and Activation

The goal of the &#34;avatar&#34; experiments is to replicate in vivo force production and work output as closely as possible during ex vivo work loop experiments. This study chose to use mouse EDL as an &#34;avatar&#34; for rat MG because mouse EDL and rat MG are both comprised of mostly of fast-twitch muscles20,21. Both muscles are primary movers of the ankle joint (EDL ankle dorsiflexor, MG ankle plantarflexor) with similar pennation angles (m...

Watch this Scientific Journal Video about Bridging the Gap Between In Vivo and Ex Vivo Studies with the "Avatar" Technique to Advance Muscle Mechanics Research at JoVE.com

This article details the methodology for emulating in vivo muscle force production during ex vivo work loop experiments using an "avatar" muscle from a laboratory rodent to assess the contributions of strain transients and activation to the muscle force response.

Movement behaviors are emergent features of dynamic systems that result from muscle force production and work output. The interplay between neural and ...

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530 Views.  Northern Arizona University. This article details the methodology for emulating in vivo muscle force production during ex vivo work loop experiments using an "avatar" muscle from a laboratory rodent to assess the contributions of strain transients and activation to the muscle force response. 