This work was supported in part by the Ministerio de Econom&#237;a y Competitividad, Spain (DEP2012-39262 to EI-G and DEP2015-69980-P to BF-G). Thanks to Frank Mcleod Henderson Higgins from McLeod&#180;s English Centre in Asturias, Spain, for language assistance.

The methods presented in this protocol have been evaluated and approved by the animal research technical committee (reference PROAE 04/2018, Principado de Asturias, Spain).
1. Planning
<ol>
	<li>Carefully select animals for the study based on the characteristics of interest (genetically modified, pathology models, age, etc.) and apply specific adaptations to the protocol (climbing without weights, reducing the number of rungs to climb, and inclination).</li>
	<li>Identify the strength modality to be assessed or trained: maximal strength, endurance-resistance, speed, etc. depending on the objectives of the study.</li>
	<li>Adjust the parameters carefully when functional assessment or training is framed, considering whether it focuses on the results of these tests or whether they are complementary to other types of clinical, functional, histological, or molecular determinations.</li>
	<li>Plan all issues related to training, particularly the timetable, duration of the training period, and frequency of sessions, and draw a training table.
	<ol>
		<li>Specify the warm-up steps and the inclination of the ladder, which will be the same throughout the training. Specify sets, repetitions, load (based on the results of the resistance tests done prior to the training period), and rest in between, paying attention to load increases based on the previous session.</li>
		<li>Modify the plan, as with human training, depending on the welfare of the animal. Modifications include decreasing repetitions, increasing rest time between sets or repetitions, and decreasing load to avoid overtraining and injury.</li>
	</ol>
	</li>
	<li>Upon completion, submit the design for evaluation and approval by the animal ethics research committee.</li>
</ol>
2. Devices and materials for resistance exercise
<ol>
	<li>Devices: Static and dynamic ladders 
	NOTE: Two types of ladders, so-called static and dynamic ladders (see Figure 1), can be used for resistance training and evaluation (see Table of Materials).
	<ol>
		<li>Use a vertical ladder with at least 30 steel wire steps of 1.5 mm diameter, separated by 15 mm, and a resting area of at least 20 x 20 cm on the top of the ladder. The slope of the ladder must be adjustable from 80&#176; to 110&#176; with the horizontal plane (Figure 1C). Delimit two lanes to prevent non-linear climbing.</li>
		<li>Use a dynamic ladder similar to the static ladder, with a plastic filament barrier at the top, that can be opened to control access to the resting area, and a plastic filament barrier at the bottom, to prevent the animals from climbing down. The angle of inclination of the ladder must be adjustable between 80&#176; and 100&#176;, the most common being 85&#176;. 
		&#8203;NOTE: The ladder can circulate by means of an upper and a lower shaft with a diameter of 8 cm. Lower shaft is driven by an electric motor which makes the steps descend at the front and ascend at the rear, creating an endless ladder. It is equipped with a reduction gear and a speed regulator for lowering the speed from 11.6 cm/s to 3.3 cm/s, and the most common speed is 5.6 cm/s.</li>
	</ol>
	</li>
</ol>
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/63098/63098fig01.jpg" /> 
Figure 1: Resistancetraining devices: static and dynamic ladders. (A) Mouse training with external weight on a static ladder. (B) Two mice training with weight on a dynamic ladder. (C) Schematic representation of ladder angles for training and evaluation. <a href="https://www.jove.com/files/ftp_upload/63098/63098fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<ol start="2">
	<li>Materials
	<ol>
		<li>Prepare the following materials: weights, wire for holding weights, steel gator clip, and clinical adhesive tape. 
		NOTE: The weights are steel cylinders of different mass (5, 10, 15, 20, 25, and 50 g), with a 5 mm diameter hole in the center to string them on a&#160;wire (Table of Materials). The wire to hold the weights is made of steel with a diameter of 1-1.5 mm and a length of 5-10 cm, depending on the number of weights to be loaded.</li>
		<li>Cut a piece of elastic adhesive bandage (Table of Materials) of approximately 3.0-3.5 cm x 1.0-1.5 cm size and attach it around the animal&#39;s tail to hold the weights. Be sure not to over-tighten as it may lead to blood flow restriction. 
		NOTE: At first, the animals&#39; behavior will be&#160;fighting against the tape and bitting it, but after a couple of days, they will tolerate it, grooming as usual and showing no signs of stress.</li>
		<li>Insert the desired weights in the wire and hook the gator clip (Table of Materials: Steel gator clip and wire for holding weights).</li>
		<li>Clamp the gator to the clinical tape attached to the animal&#39;s tail.</li>
		<li>Immediately after climbing the required rungs, remove the clamp and allow the animal to rest with the clinical tape on the tail, but without the weight (Figure 1).</li>
	</ol>
	</li>
</ol>
3. Acclimatization
NOTE: Proper acclimatization is essential to avoid exercise rejection and to minimize stress. Acclimatization is a crucial stage before resistance evaluation tests or training protocols are performed. Adequate time should be spent to achieve behavioral signs of comfort in the animals. Details of daily acclimatization with the static and dynamic ladders are shown in Table 1 and&#160;Table 2, respectively.
<ol start="1">
	<li>Accustom the animals to stay in the resting area at the top of the ladder (static or dynamic). Leave the animals in this place in groups of four, with bedding from their cage, for 15 min every day. Usually, after 3-5 days, the animals will show no signs of stress.</li>
	<li>Teach animals to climb up, not down, the ladder. Using the static ladder, place the mice on a rung close to the top, from where they can see the resting area.&#160;They will instinctively go to it. Then, teach them progressively to climb up from five rungs (3x) the first day, to 10 rungs (3x) the following day, up to 15 rungs (3x) (Table 1). 
	Use the same procedure with the dynamic ladder, first without movement, and then with the ladder moving at 5.4 cm/s and 6.6 cm/s and the animals climbing up for 2 min, completing five series (Table 2).</li>
	<li>Adapt the animals to carry weights, starting from the third day of acclimatization. Stick a piece of clinical tape to the base of the tail which will be used to hold weights.</li>
	<li>From the seventh day of acclimatization, attach small weights (5-10 g) to the clinical tape with a gator clip. Avoid performing too many series, so the adaptation is not transformed into training. 
	NOTE: Acclimatization of the control group is mandatory in case this group performs the resistance test. After this period, perform a ladder-climbing reminder once a week, with tape but without weights.</li>
</ol>
4. Resistance evaluation
<ol start="1">
	<li>Incremental tests to assess maximal strength 
	NOTE: This test intends to determine the maximal resistance measured as the maximum weight at which the animals can climb 10 rungs on the static ladder, which defines the 10-repetition maximum (10 RM)4. This protocol was adapted from previous studies (reviewed in Kregel et al.15).
	<ol>
		<li>For warming-up perform three series of 10-repetitions, 10 steps/repetition, without external load. For the first series set the slope at 90&#176;, and thereafter at 85&#176;. Allow a rest period of 60 s between series.</li>
		<li>Set the slope at 85&#176; (to prevent the weights from grazing or hooking on the rungs of the ladder).</li>
		<li>Attach the tape around the animal&#39;s tail to hold the weights and prepare the weights as previously explained.</li>
		<li>Start the test with an external load of 10 g and perform one series of 10 steps.</li>
		<li>Remove the weight and allow a rest period of 120 s in the resting area.</li>
		<li>Perform successive series of 10 steps increasing the external load by 5 g until exhaustion. Allow the resting period (120 s) between series.</li>
		<li>If one animal fails to climb 10 steps with a particular weight load, allow for another attempt with the same load after 120 s of rest. If it succeeds to climb with the load, it continues the test with the next load. If it fails again, record the weight load of the last completed series as its&#160;maximal weight load.</li>
		<li>The test result can be expressed as absolute external weight (g), as maximum load in relation to body weight (%), or as the mass lifted per gram of body weight, as per the discretion of the researcher. 
		NOTE: The previous protocol&#160;represents a model on which numerous modifications are possible for example, to assess the maximal resistance of genetically modified mice with neuromuscular disabilities. These animals are not able to climb with external loads and have difficulties climbing 10 rungs with the ladder set at 90&#176; of slope (unpublished data). The protocol consisted of climbing five steps without external load, starting with a slope of 110&#176;. The slope decreased 5&#176; in each series until 85&#176; with 120 s rest after each series. In this case, maximal resistance was expressed as the accumulated number of steps climbed (without considering repetitions after failures). The wild-type control group, after reaching the 85&#176; slope, will&#160;continue with the test by adding external weight to the tail, following previous protocol, until exhaustion.</li>
	</ol>
	</li>
	<li>Maximal endurance-resistance test with the static ladder
	<ol>
		<li>For warming-up perform three series of 10-repetitions, 10 steps/repetition, without external load. For the first series, set the slope at 90&#176;, and thereafter at 85&#176;. Allow a rest period of 60 s between series.</li>
		<li>Set the slope at 85&#176;.</li>
		<li>Clip the weight on the clinical tape placed around the tail of the mouse. 
		NOTE: Depending on the age and the characteristics of the animals, the external load can be the maximum weight obtained in a previous incremental test, a percentage of it (e.g., 50%), or a percentage of body weight (e.g., 100%-200%). If this test is performed after a period of training, it is recommended to use the same load as in the initial test to assess the changes.</li>
		<li>Perform consecutive series of 10 steps until exhaustion. No resting time is allowed after each series.</li>
		<li>The test result is the number of climbed rungs.</li>
	</ol>
	</li>
	<li>Maximal endurance-resistance test with the dynamic ladder 
	NOTE: The use of the dynamic ladder allows the researcher to control the climbing speed.
	<ol>
		<li>Set the slope at 85&#176;.</li>
		<li>Set the speed at 4.2 cm/s.</li>
		<li>For warming-up perform three series of 100 steps, without external load. Allow a rest period of 60 s between series.</li>
		<li>Clip the weight on the clinical tape placed around the mouse tail. 
		NOTE: Depending on the age and the characteristics of the animals, the external load can be the maximum weight obtained in a previous incremental test, a percentage of it (e.g., 50%), or a percentage of body weight (e.g., 100%-200%). If this test is performed after a period of training, it is recommended to use the same load as in the initial test to assess the changes.</li>
		<li>Start at 4.2 cm/s and increase the speed by 1.2 cm/s every 60 s until exhaustion. 
		&#8203;NOTE: The test result is the exercise time, the number of rungs climbed, or the maximum speed.&#160;</li>
	</ol>
	</li>
</ol>
5. Resistance training with static ladder
NOTE: Before starting the training period, acclimatization (Table 1) and training planning are necessary. To reduce anxiety, adapt and train the mice in groups of four animals sharing the same cage.
<ol>
	<li>For everyday warming-up perform three series of 10 repetitions, 10 steps/repetition, without external load. For the first series set the slope at 90&#176;, and thereafter at 85&#176;. Allow a rest period of 60 s between series.</li>
	<li>The training session starts in the resting area. Clip the gator with the weight on the clinical tape.</li>
	<li>Gently place the mouse 10-20 rungs below the resting place. Allow the mouse to grip the rung and climb to the resting area. 
	Repeat this process&#160;until the number of rungs in this series (e.g.,10 rungs x 10 series) is completed.</li>
	<li>Remove the weight from the mouse tail and wait for 120 s until the next series.</li>
	<li>Increase the number of steps and the maximum weight loads of the series throughout the training period, while maintaining the weekly schedule. 
	&#8203;NOTE: An example of the variation of loads during a week planning is shown in Table 3. Shortly, Tuesday and Friday with high weight load (40-50 g) and a low number of steps (500-400); Monday and Thursday with intermediate weight load (25-35 g) and an intermediate number of steps (800-600); and Wednesday without weight load but a high number of steps (2,000). This design facilitates recovery from previous training sessions and avoids injuries and overtraining. Examples of 3 weeks of training with multiple designs using the static ladder are shown in Table 4 (at the beginning, in the middle, and at the end of the training period, respectively)4.</li>
</ol>
6. Resistance training with dynamic ladder
NOTE: After acclimatization, the training on the dynamic ladder is quite like the static one (Table 2). Training is performed on 2-4 mice at a time.
<ol>
	<li>Set the slope to 85&#176;, close the door to the resting area, and start the ladder at the desired speed (e.g., 5.4 cm/s).</li>
	<li>For warming-up perform three series of 100 steps, without external load. Allow a rest period of 60 s between series.</li>
	<li>Before the training sessions starts, when the mouse is in the resting area, clip the gator with the weight on the clinical tape. Alternatively, the weight can be attached when the mouse is already on the ladder.</li>
	<li>Gently place the mouse at the top of the moving staircase with the weight on the tail. Allow the mice to grip the rung and climb.</li>
	<li>When the number of rungs in this series is reached (e.g., 100), remove the weights. Then the door is opened so that the animal can go to the resting area. The rest time is 120 s before the next series. 
	NOTE: The number of steps climbed is counted as a function of the climbing time at the set speed.</li>
	<li>Repeat this procedure until the training session is completed. The detailed daily training program is shown in Table 5.</li>
</ol>
7. Evaluation of the crossover effect of resistance training on endurance performance
NOTE: For this, an incremental treadmill test is performed4, after 24 h of rest.
<ol>
	<li>After a warm-up of 3 min at 10 cm/s, start the incremental test at 10 cm/s and 10&#176; angle of inclination.</li>
	<li>Increase the speed by 3.33 cm/s every 3 min until exhaustion. 
	NOTE: No electric shocks are used, so a painter&#39;s brush is placed at the back of the treadmill to prevent the mice from running off it.</li>
</ol>
8. Animal behavior during procedures
NOTE: Continuous monitoring of the adaptation of mice to training should be performed to detect extreme fatigue, overtraining, or injury.
<ol>
	<li>Observe signs of animal welfare, in particular grooming and refusal to training. The normal behavior of the mouse, after a series of intense training, is to remain inactive for about one minute due to fatigue. After that, they start grooming, exploring, or trying to remove the tape on the tail.</li>
	<li>In the case of a mouse refusing to train a series, try giving longer rests or even not performing that&#160;series to prevent inhibition.</li>
	<li>Occasionally, when carrying out lightweight exercises, gently push the animal&#39;s tail, to encourage it to finish the series. The animals stop climbing because it is not a demanding task. Conversely, when animals are carrying a heavy load, gently shift the animal&#39;s weight to ease the load and encourage it to finish the series, and then allow the animal to rest until the next training session. The animals may stop or even attempt to descend because of the heavy load.</li>
</ol>
9. Safety procedures
<ol>
	<li>Security procedures for researchers: Conduct research in the animal facility laboratory and use shoe covers, coveralls, gloves, caps, and masks. There are no additional requirements other than those specific to animal research.</li>
	<li>Security for animals: During the exercise sessions continuous attention must be paid to the animals, due to potential risks, such as falls or jumps. Place a hand under the weights to catch and hold the mice in case of fall due to exhaustion, since its ability to hold on to the rungs properly will be limited.</li>
</ol>

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<li>Kruger, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Functional+and+muscular+adaptations+in+an+experimental+model+for+isometric+strength+training+in+mice%5BTitle%5D)+AND+%22PLoS+One%22%5BJournal%5D)">Functional and muscular adaptations in an experimental model for isometric strength training in mice.</a> PLoS One. 8 (11), 79069(2013).</li>
<li>Hendrickse, P. W., Krusnauskas, R., Hodson-Tole, E., Venckunas, T., Degens, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Endurance+exercise+plus+overload+induces+fatigue+resistance+and+similar+hypertrophy+in+mice+irrespective+of+muscle+mass%5BTitle%5D)+AND+%22Experimental+Physiology%22%5BJournal%5D)">Endurance exercise plus overload induces fatigue resistance and similar hypertrophy in mice irrespective of muscle mass.</a> Experimental Physiology. 105 (12), 2110-2122 (2020).</li>
<li>Knab, A. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Repeatability+of+exercise+behaviors+in+mice%5BTitle%5D)+AND+%22Physiology+%26+Behavior%22%5BJournal%5D)">Repeatability of exercise behaviors in mice.</a> Physiology & Behavior. 98 (4), 433-440 (2009).</li>
<li>Konhilas, J. P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Loaded+wheel+running+and+muscle+adaptation+in+the+mouse%5BTitle%5D)+AND+%22American+Journal+of+Physiology-Heart+and+Circulatory+Physiology%22%5BJournal%5D)">Loaded wheel running and muscle adaptation in the mouse.</a> American Journal of Physiology-Heart and Circulatory Physiology. 289 (1), 455-465 (2005).</li>
<li>Reiter, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Functional+measures+of+grip+strength+and+gait+remain+altered+long-term+in+a+rat+model+of+post-traumatic+elbow+contracture%5BTitle%5D)+AND+%22The+Journal+of+Biomechanical+Engineering%22%5BJournal%5D)">Functional measures of grip strength and gait remain altered long-term in a rat model of post-traumatic elbow contracture.</a> The Journal of Biomechanical Engineering. , (2019).</li>
<li>Stieglitz, T., Schuettler, M., Schneider, A., Valderrama, E., Navarro, X. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Noninvasive+measurement+of+torque+development+in+the+rat+foot%3A+measurement+setup+and+results+from+stimulation+of+the+sciatic+nerve+with+polyimide-based+cuff+electrodes%5BTitle%5D)+AND+%22IEEE+Transactions+on+Neural+Systems+and+Rehabilitation+Engineering%22%5BJournal%5D)">Noninvasive measurement of torque development in the rat foot: measurement setup and results from stimulation of the sciatic nerve with polyimide-based cuff electrodes.</a> IEEE Transactions on Neural Systems and Rehabilitation Engineering. 11 (4), 427-437 (2003).</li>
<li>Seo, D. Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Humanized+animal+exercise+model+for+clinical+implication%5BTitle%5D)+AND+%22Pfl%C3%BCgers+Archiv%22%5BJournal%5D)">Humanized animal exercise model for clinical implication.</a> Pflügers Archiv. 466 (9), 1673-1687 (2014).</li>
<li>Tanaka, H., Swensen, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Impact+of+resistance+training+on+endurance+performance.+A+new+form+of+cross-training%5BTitle%5D)+AND+%22Sports+Medicine%22%5BJournal%5D)">Impact of resistance training on endurance performance. A new form of cross-training.</a> Sports Medicine. 25 (3), 191-200 (1998).</li>
<li>Hakkinen, K., Mero, A., Kauhanen, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Specificity+of+endurance%2C+sprint+and+strength+training+on+physical+performance+capacity+in+young+athletes%5BTitle%5D)+AND+%22The+Journal+of+Sports+Medicine+and+Physical+Fitness%22%5BJournal%5D)">Specificity of endurance, sprint and strength training on physical performance capacity in young athletes.</a> The Journal of Sports Medicine and Physical Fitness. 29 (1), 27-35 (1989).</li>
<li>Vellers, H. L., Kleeberger, S. R., Lightfoot, J. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Inter-individual+variation+in+adaptations+to+endurance+and+resistance+exercise+training%3A+genetic+approaches+towards+understanding+a+complex+phenotype%5BTitle%5D)+AND+%22Mammalian+Genome%22%5BJournal%5D)">Inter-individual variation in adaptations to endurance and resistance exercise training: genetic approaches towards understanding a complex phenotype.</a> Mammalian Genome. 29 (1), 48-62 (2018).</li>
</ol>

The corresponding author ensures that all authors have no conflicts of interest.

Training is an intervention with multiple applications in research, apart from the study of exercise itself. Thus, the analysis of its effect on ageing20&#160;or certain pathological conditions and physical therapy21&#160;has received much attention in recent years. In addition, numerous authors have analyzed the effect of pharmacological22&#160;or dietary21&#160;interventions on physical fitness. In this context, interest has...

Physical exercise is a determinant lifestyle factor for promoting health and decreasing the incidence of the most prevalent chronic diseases as well as some types of cancer in humans1.
Resistance exercise has raised interest because of its overwhelming relevance for health throughout life2, especially due to its benefits in counteracting age-related diseases that affect the locomotor system, such as sarcopenia, osteoporosis, etc3. Moreover, resistance exercise also affects tissues and organs not directly involved in the execution of movement, such as the brain4. This relevance in recent years has encouraged the development of resistance exercise models in animals to study the underlying tissular and molecular mechanisms, when it is not possible in humans or when the animals provide better insight and are a more controlled model.
Unlike resistance exercise in humans, for animal models&#160;researchers usually rely on forced procedures. However, aversive stimuli must be avoided in this context, mainly to preserve animal welfare, reduce stress, and decrease the severity of the experimental procedures5. It should be noted that animals enjoy exercise even in the wild6. For these reasons, it is necessary to improve adaptation to the experiment through prolonged stepwise acclimatization.
The devices, materials, and protocols used for resistance training and assessment in experimental animals must allow the precise control and modulation of numerous variables: load, volume, speed, and frequency7. They should also allow different types of muscle contractions to be performed: concentric, eccentric, or isometric. Considering the above, the protocols used should be able to specifically evaluate or train for different applications of strength: maximal strength, hypertrophy, speed, and endurance.
There are several methods of strength training, such as jumping in water8,9, weighted swimming in water10, or muscle electrostimulation11. However, static and dynamic ladders are versatile devices that are widely used12,13,14.
Resistance assessment in experimental animal models provides valuable information for many research settings, such as describing the phenotypic characteristics of genetically modified animals, evaluating the effect of different intervention protocols (dietary components supplementation, drug treatments, microbiota transplantation, etc.), or assessing the effect of training protocols. Training models provide insight into the physiology of adaptation to strength exercise, which helps to better understand the effect of exercise on health status and pathophysiology.
Consequently, there is no universal protocol for resistance training or the functional assessment of strength in animal models, so versatile protocols are needed.
The aim of this study is to identify the most relevant factors to be considered when designing and applying a protocol for resistance training and evaluation using static and dynamic ladders in animal models, as well as provide specific examples.

<table><tbody><tr><td>Dynamic ladder</td><td>in-house production</td><td></td><td></td></tr><tr><td>Elastic adhesive bandage 6 cm x 2.5 m</td><td>BSN medical</td><td>4005556</td><td></td></tr><tr><td>Gator Clip Steel NON-INSUL 10A</td><td>Digikey electronics</td><td>BC60ANP</td><td></td></tr><tr><td>Static ladder</td><td>in-house production</td><td></td><td></td></tr><tr><td>Weights</td><td>in-house production</td><td></td><td></td></tr><tr><td>Wire for holding weigths</td><td>in-house production</td><td></td><td></td></tr></tbody></table>

versatility of protocols for resistance training and assessment using static and dynamic ladders in animal models

Resistance training is a physical exercise model with profound benefits for health throughout life. The use of resistance exercise animal models is a way to gain insight into the underlying molecular mechanisms that orchestrate these adaptations. The aim of this article is to describe exercise models and training protocols designed for strength training and evaluation of resistance in animal models and provide examples. In this article, strength training and resistance evaluation are based on ladder climbing activity, using static and dynamic ladders. These devices allow a variety of training models as well as provide precise control of the main variables which determine resistance exercise: volume, load, velocity, and frequency. Furthermore, unlike resistance exercise in humans, this is a forced exercise. Thus, aversive stimuli must be avoided in this intervention to preserve animal welfare. Prior to implementation, a detailed design is necessary, along with an acclimatization and learning period. Acclimatization to training devices, such as ladders, weights, and clinical tape, as well as to the manipulations required, is necessary to avoid exercise rejection and to minimize stress. At the same time, the animals are taught to climb up the ladder, not down, to the resting area on the top of the ladder. Resistance evaluation can characterize physical strength and permit adjusting and quantifying the training load and the response to training. Furthermore, different types of strength can be evaluated. Regarding training programs, with appropriate design and device use, they can be sufficiently versatile to modulate different types of strength. Furthermore, they should be flexible enough to be modified depending on the adaptive and behavioral response of the animals or the presence of injuries. In conclusion, resistance training and assessment using ladders and weights are versatile methods in animal research.

Results with static ladder 
The progressive resistance training protocol used and described by Codina-Martinez et al.4 (Table 4) was tested in a preliminary study consisting of 7 weeks of training on a static ladder with 6-months-old wild-type C57BL6J mice (n = 4). In this preliminary study, incremental tests to assess maximal strength were performed before and after the training period. We observed a 46.4% increase in maximal strength, meaning that at the en...

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Versatility of Protocols for Resistance Training and Assessment Using Static and Dynamic Ladders in Animal Models

The present protocol describes resistance training and testing using static and dynamic ladders in animal models.

Resistance training is a physical exercise model with profound benefits for health throughout life. The use of resistance exercise animal models is a way ...

versatility-protocols-for-resistance-training-assessment-using-static

Research

JoVE Journal

Biology

2.5K Views.  University of Oviedo. Dit weerstandstrainingsprotocol is belangrijk omdat het kan worden toegepast in dieronderzoek om de effecten van krachttraining op de gezondheid op te helderen. Het grote voordeel van deze methode is dat deze kan worden toegepast voor verschillende krachttrainingsmodellen en krachtbeoordelingen. Deze techniek geeft inzicht in fysieke fitheid, met name kracht, en kan worden toegepast om systemische ziekten en het effect van behandelingen op spierprestaties te bestuderen.Het maakt het mo...

Video: Versatility of Protocols for Resistance Training and Assessment Using Static and Dynamic Ladders in Animal Models

Getting to Compliance in Forced Exercise in Rodents: A Critical Standard to Evaluate Exercise Impact in Aging-related Disorders and Disease

There is a major increase in the awareness of the positive impact of exercise on improving several disease states with neurobiological basis; these include improving cognitive function and physical performance. As a result, there is an increase in the number of animal studies employing exercise. It is argued that one intrinsic value of forced exercise is that the investigator has control over the factors that can influence the impact of exercise on behavioral outcomes, notably exercise frequency, duration, and intensity of the exercise regimen. However, compliance in forced exercise regimens may be an issue, particularly if potential confounds of employing foot-shock are to be avoided. It is also important to consider that since most cognitive and locomotor impairments strike in the aged individual, determining impact of exercise on these impairments should consider using aged rodents with a highest possible level of compliance to ensure minimal need for test subjects. Here, the pertinent steps and considerations necessary to achieve nearly 100% compliance to treadmill exercise in an aged rodent model will be presented and discussed. Notwithstanding the particular exercise regimen being employed by the investigator, our protocol should be of use to investigators that are particularly interested in the potential impact of forced exercise on aging-related impairments, including aging-related Parkinsonism and Parkinson&#8217;s disease.

Exercise may alleviate behavioral impairments associated with neurodegenerative diseases. Studies of the mechanisms underlying exercise-mediated effects have increased in disease models, but the neurobiological background accompanying these diseases, specifically aging, is likely not considered. Here, we illustrate measures to increase the likelihood of a successful exercise paradigm in aged rats.

There is a major increase in the awareness of the positive impact of exercise on improving several disease states with neurobiological basis; these ...

Behavior

A Novel Single Animal Motor Function Tracking System Using Simple, Readily Available Software

We have recently demonstrated that implanting intracortical microelectrodes in the motor corteces of rats&#160;results in immediate and lasting motor deficits. Motor impairments were manually quantified through an open field grid test to measure the gross motor function and through a ladder test to measure the fine motor function. Here, we discuss a technique for the automated quantification of the video-recorded tests using our custom Capadona Behavioral Video Analysis System: Grid and Ladder Test, or BVAS. Leveraging simple and readily available coding software (see the Table of Materials), this program allows for the tracking of a single animal on both the open field grid and the ladder tests. In open field grid tracking, the code thresholds the video for intensity, tracks the position of the rat over the 3 min duration of the grid test, and analyzes the path. It then computes and returns measurements for the total distance traveled, the maximum velocity achieved, the number of left- and right-handed turns, and the total number of grid lines crossed by the rat. In ladder tracking, the code again thresholds the video for intensity, tracks the movement of the rat across the ladder, and returns calculated measurements including the time it took the rat to cross the ladder, the number of paw slips occurring below the plane of the ladder rungs, and the incidence of failures due to stagnation or reversals. We envision that the BVAS developed here can be employed for the analysis of motor function in a variety of applications, including many injury or disease models.

The current study aimed to automate the quantification of motor deficits in rats. The initial evaluation model assesses motor loss resulting from an intracortical microelectrode implantation in the motor cortex. We report on the development and use of a tracking algorithm using easily adaptable, simple, and readily available coding software.

We have recently demonstrated that implanting intracortical microelectrodes in the motor corteces of rats&#160;results in immediate and lasting motor ...

The Ladder Rung Walking Task: A Scoring System and its Practical Application.

Progress in the development of animal models for/stroke, spinal cord injury, and other neurodegenerative disease requires tests of high sensitivity to elaborate distinct aspects of motor function and to determine even subtle loss of movement capacity. To enhance efficacy and resolution of testing, tests should permit qualitative and quantitative measures of motor function and be sensitive to changes in performance during recovery periods. The present study describes a new task to assess skilled walking in the rat to measure both forelimb and hindlimb function at the same time. Animals are required to walk along a horizontal ladder on which the spacing of the rungs is variable and is periodically changed. Changes in rung spacing prevent animals from learning the absolute and relative location of the rungs and so minimize the ability of the animals to compensate for impairments through learning. In addition, changing the spacing between the rungs allows the test to be used repeatedly in long-term studies. Methods are described for both quantitative and qualitative description of both fore- and hindlimb performance, including limb placing, stepping, co-ordination. Furthermore, use of compensatory strategies is indicated by missteps or compensatory steps in response to another limb&#x2019;s misplacement. 

The ladder rung walking task is a new test to assess skilled walking and measure both forelimb and hindlimb placing, stepping, and inter-limb co-ordination.

Progress in the development of animal models for/stroke, spinal cord injury, and other neurodegenerative disease requires tests of high sensitivity to ...

Assessing Motor Performance in TH-Related Murine Models Using the Ladder Beam Test

A Versatile, Behavioral Method to Investigate Thyroid Hormone Effects on Cerebellar Function

Thyroid hormone (TH) action is essential during the development of the central nervous system, including the cerebellum. In case of TH deficiency in early life such as congenital hypothyroidism, patients display neurological disorders such as cognitive retardation and motor deficits. There are various studies using mouse models with tissue- or cell-specific TH deficiency to investigate the role of TH in the cerebellum. Compared to generalized congenital hypothyroid mice, cerebellar cell-specific TH-deficient mice display milder and subtler ataxic features, making the assessment of motor function difficult when using conventional tests such as the rotarod test. 
Due to the need for an alternative tool to assess motor function in TH-related animal models, we developed a versatile behavioral method called the "ladder beam test," in which we can design the various ladder tests depending on the severity of ataxia in model mice. We utilized transgenic mice expressing a dominant-negative TH receptor specifically in the cerebellar Purkinje cell, a sole output neuron in the cerebellar cortex modulating motor performance. The newly-built ladder beam test successfully detected robust impairments in motor performance in the transgenic mice at a greater level compared to the rotarod test. Disruption of motor learning was also detected in the ladder beam test but not in the rotarod test. The protocol with this novel behavioral apparatus can be applied to other animal models that may show mild ataxic phenotype to examine subtle changes in cerebellar function.

Author Spotlight: Accurately Assessing Thyroid Hormone-Driven Motor Alterations in Mouse

Here we present a protocol for a versatile behavior test developed recently, the ladder beam test. This test has the advantage of detecting subtle cerebellar ataxia caused by a defect of thyroid hormone action in the central nervous system over the conventional behavior tests assessing motor performance.

Thyroid hormone (TH) action is essential during the development of the central nervous system, including the cerebellum. In case of TH deficiency in early ...

Rodent Behavioral Testing to Assess Functional Deficits Caused by Microelectrode Implantation in the Rat Motor Cortex

Medical devices implanted in the brain hold tremendous potential. As part of a Brain Machine Interface (BMI) system, intracortical microelectrodes demonstrate the ability to record action potentials from individual or small groups of neurons. Such recorded signals have successfully been used to allow patients to interface with or control&#160;computers, robotic limbs, and their own limbs. However, previous animal studies have shown that a microelectrode implantation in the brain not only damages the surrounding tissue but can also result in functional deficits. Here, we discuss a series of behavioral tests to quantify potential motor impairments following the implantation of intracortical microelectrodes into the motor cortex of a rat. The methods for open field grid, ladder crossing, and grip strength testing provide valuable information regarding the potential complications resulting from a microelectrode implantation. The results of the behavioral testing are correlated with endpoint histology, providing additional information on the pathological outcomes and impacts of this procedure on the adjacent tissue.

We have shown that a microelectrode implantation in the motor cortex of rats causes immediate and lasting motor deficits. The methods proposed herein outline a microelectrode implantation surgery and three rodent behavioral tasks to elucidate potential changes in the fine or gross motor function due to implantation-caused damage to the motor cortex.

Medical devices implanted in the brain hold tremendous potential. As part of a Brain Machine Interface (BMI) system, intracortical microelectrodes ...

Bioengineering

A Training Program Using an Agility Ladder for Community-Dwelling Older Adults

Aging impairs physical and cognitive functions and limits daily activities. Agility training can improve or maintain physical functioning in older people. The purpose of this study is to report the physical fitness benefits of a training program for independent community-dwelling older adults using an agility ladder. Each training session lasted approximately 30 minutes, and the benefits were achieved with two sessions per week for 14 weeks. Training was timed and involved four different drills and varying levels of difficulty through time. The exercises were performed at the School of Physical Education of the University of Campinas, S&#227;o Paulo state, Brazil. The study participants (n = 16; mean age of 66.9 &#177; 5.0 years) were instructed to perform the exercises as quickly as possible without making mistakes and were assisted by a physical trainer when they made mistakes. Assessments were performed both before and after training using five functional tests (i.e., Illinois agility, five times sit-to-stand, timed up-and-go, walking usual speed, and one-leg stand). Although the study sample was not compared with a control group, the results indicate that training protocols using an agility ladder are easy and practical and improve physical function performance in older adults.

The aim of this study is to present an agility training program for older people. The feasibility of this program is described, and the training protocol demonstrated by video imaging.

Aging impairs physical and cognitive functions and limits daily activities. Agility training can improve or maintain physical functioning in older people. ...

Medicine

Multifactorial Assessment of Motor Behavior in Rats after Unilateral Sciatic Nerve Crush Injury

The induction of a peripheral nerve injury is a widely used method in neuroscience for the assessment of repair and pain mechanisms among others. In addition, in the research field of movement disorders, sciatic crush injury has been employed to trigger a dystonia-like phenotype in genetically predisposed DYT-TOR1A rodent models of dystonia. To achieve consistent, reproducible and comparable results after a sciatic nerve crush injury, a standardized method for inducing the nerve crush is essential, in addition to a standardized phenotypical characterization. Attention must be paid not only to the specific assortment of behavioral tests, but also to the technical requirements, the correct execution and consecutive data analysis. This protocol describes in detail how to perform a sciatic nerve crush injury and provides a behavioral test battery for the assessment of motor deficits in rats that includes the open field test, the CatWalk XT gait analysis, the beam walking task, and the ladder rung walking task.

We provide a protocol for the assessment of motor behavior via a behavioral test battery in rats after sciatic nerve crush injury.

The induction of a peripheral nerve injury is a widely used method in neuroscience for the assessment of repair and pain mechanisms among others. In ...

Neuroscience

Dosage-Adjusted Resistance Training in Mice with a Reduced Risk of Muscle Damage

Progressive resistance training (PRT), which involves performing muscle contractions against progressively greater external loads, can increase muscle mass and strength in healthy individuals and in patient populations. There is a need for precision rehabilitation tools to test the safety and effectiveness of PRT to maintain and/or restore muscle mass and strength in preclinical studies on small and large animal models. The PRT methodology and device described in this article can be used to perform dosage-adjusted resistance training (DART). The DART device can be used as a standalone dynamometer to objectively assess the concentric contractile torque generated by the ankle dorsiflexors in mice or can be added to a pre-existing isokinetic dynamometry system. The DART device can be fabricated with a standard 3D printer based on the instructions and open-source 3D print files provided in this work. The article also describes the workflow for a study to compare contraction-induced muscle damage caused by a single bout of DART to muscle damage caused by a comparable bout of isometric contractions (ISOM) in a mouse model of limb-girdle muscular dystrophy type 2B/R2 (BLAJ mice). The data from eight BLAJ mice (four animals for each condition) suggest that less than 10% of the tibialis anterior (TA) muscle was damaged from a single bout of DART or ISOM, with DART being less damaging than ISOM.

The present protocol describes a unique technique called dosage-adjusted resistance training (DART), which can be incorporated into precision rehabilitation studies performed in small animals, such as mice.

Progressive resistance training (PRT), which involves performing muscle contractions against progressively greater external loads, can increase muscle ...

Automated Assessment of Fine Motor Performance in Mice Using the Erasmus Ladder

Monitoring Fine and Associative Motor Learning in Mice Using the Erasmus Ladder

Behavior is shaped by actions, and actions necessitate motor skills such as strength, coordination, and learning. None of the behaviors essential for sustaining life would be possible without the ability to transition from one position to another. Unfortunately, motor skills can be compromised in a wide array of diseases. Therefore, investigating the mechanisms of motor functions at the cellular, molecular, and circuit levels, as well as understanding the symptoms, causes, and progression of motor disorders, is crucial for developing effective treatments. Mouse models are frequently employed for this purpose.
This article describes a protocol that allows the monitoring of various aspects of motor performance and learning in mice using an automated tool called the Erasmus Ladder. The assay involves two phases: an initial phase where mice are trained to navigate a horizontal ladder built of irregular rungs (&#34;fine motor learning&#34;), and a second phase where an obstacle is presented in the path of the moving animal. The perturbation can be unexpected (&#34;challenged motor learning&#34;) or preceded by an auditory tone (&#34;associative motor learning&#34;). The task is easy to conduct and is fully supported by automated software.
This report shows how different readouts from the test, when analyzed with sensitive statistical methods, allow fine monitoring of mouse motor skills using a small cohort of mice. We propose that the method will be highly sensitive to evaluate motor adaptations driven by environmental modifications as well as early-stage subtle motor deficits in mutant mice with compromised motor functions.

Author Spotlight: Unveiling Neural Mechanisms Through Automated Evaluation of Motor Learning and Myelin Plasticity Studies Using the Erasmus Ladder 

This article presents a protocol that allows a non-invasive and automated assessment of fine motor performance, as well as adaptive and associative motor learning upon challenges, using a device called the Erasmus Ladder. Task difficulty can be titrated to detect motor impairment ranging from major to subtle degrees.

Behavior is shaped by actions, and actions necessitate motor skills such as strength, coordination, and learning. None of the behaviors essential for ...

Exploring T2DM Exercise Interventions: A Static Training Device for Mice

Static Strength Training Method for Type 2 Diabetic Mice

The treatment of type 2 diabetes mellitus (T2DM) is a major difficulty in improving patient health. Exercise is one of the main interventions for T2DM. Static strength training is one of the key forms of traditional sports in China. Research shows that static strength training is an effective clinical method for T2DM intervention, but there is no experimental device suitable for static training in mice. One of the difficulties in moving from clinical to basic research is to design appropriate experimental devices. In order to further study the mechanism of static training intervention in T2DM, a simple method for making a static training device for mice is introduced in this paper. This device has the advantages of simple operation, cheap material, and high feasibility. Previous studies conducted under this protocol have shown that static training can effectively reduce blood glucose levels and improve the mitochondrial function of skeletal muscle cells in T2DM mice. The purpose of introducing this device is to promote research on the mechanism of traditional exercise in the intervention of T2DM and to lay a foundation for the quantitative intervention of exercise.

Author Spotlight: Advancing Diabetes Research with Static Exercise Training in Mice

This protocol provides a simple method of making static training equipment for mice. The device maintains the muscle isometric contraction of the limbs of mice so as to verify the intervention effect of traditional exercise on type 2 diabetes (T2DM) and provides new exercise therapy for the clinical treatment of T2DM.

The treatment of type 2 diabetes mellitus (T2DM) is a major difficulty in improving patient health. Exercise is one of the main interventions for T2DM. ...

Versatility of Protocols for Resistance Training and Assessment Using Static and Dynamic Ladders in Animal Models

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