Endpoint measures in the mdx mouse relevant for muscular dystrophy pre-clinical studies

Kobayashi, Yvonne M.; Rader, Erik P.; Crawford, Robert W.; Campbell, Kevin P.

doi:10.1016/j.nmd.2011.08.001

Cited by 32 publications

(33 citation statements)

References 35 publications

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“…Overall, the open field activity measure has major advantages: a) it is a comprehensive assessment of both locomotor and behavioral activity, which is strongly, but not always correlated with locomotive function; b) it is an easy measure to perform; c) it requires no animal handling during testing; d) it is a noninvasive measure that can be performed more than once throughout the duration of a study; e) no special training is needed to perform the test; f) multiple animals can be tested at one time; and g) it is a clinically relevant outcome measure 5,16 . However, when testing therapeutics, keep in mind that other factors can affect an animal's behavior, and in turn open field activity measurements.…”

Section: Discussionmentioning

confidence: 99%

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Behavioral and Locomotor Measurements Using an Open Field Activity Monitoring System for Skeletal Muscle Diseases

Tatem

Quinn

Phadke

et al. 2014

JoVE

135

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The open field activity monitoring system comprehensively assesses locomotor and behavioral activity levels of mice. It is a useful tool for assessing locomotive impairment in animal models of neuromuscular disease and efficacy of therapeutic drugs that may improve locomotion and/or muscle function. The open field activity measurement provides a different measure than muscle strength, which is commonly assessed by grip strength measurements. It can also show how drugs may affect other body systems as well when used with additional outcome measures. In addition, measures such as total distance traveled mirror the 6 min walk test, a clinical trial outcome measure. However, open field activity monitoring is also associated with significant challenges: Open field activity measurements vary according to animal strain, age, sex, and circadian rhythm. In addition, room temperature, humidity, lighting, noise, and even odor can affect assessment outcomes. Overall, this manuscript provides a well-tested and standardized open field activity SOP for preclinical trials in animal models of neuromuscular diseases. We provide a discussion of important considerations, typical results, data analysis, and detail the strengths and weaknesses of open field testing. In addition, we provide recommendations for optimal study design when using open field activity in a preclinical trial.

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Section: Discussionmentioning

confidence: 99%

“…In addition, the open field activity measure, total distance traveled, mirrors the 6 min walk test, a clinical trial outcome measure, which focuses on submaximal exercise performance and quality of life 15,16 . Overall this makes the open field activity test a beneficial secondary or auxiliary outcome measure to use in preclinical trials.…”

Section: Introductionmentioning

confidence: 99%

Behavioral and Locomotor Measurements Using an Open Field Activity Monitoring System for Skeletal Muscle Diseases

Tatem

Quinn

Phadke

et al. 2014

JoVE

135

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“…The Dmd mdx-5Cv Tg(Cmk-Mir486) mice showed marked improvements in both total running distances and time to exhaustion compared with Dmd mdx-5Cv littermates (Figure 3, A and B). Previous studies have shown that Dmd mdx mice have reduced overall and vertical activity before and after forced exercise (45,46). We measured the total activity of all 4 mouse genotype cohorts before and after forced downhill treadmill exercise.…”

Section: Figurementioning

confidence: 99%

“…The mouse 6-minute activity assays were performed following a protocol previously described, with slight modifications (45,46). The mice were run for 5 minutes at 3 m/min, followed by an increase to 10 m/min for 10 minutes.…”

Section: Dock3 Is An Essential Regulator Of Pten/akt and Rac1 Signalimentioning

confidence: 99%

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

Alexander¹,

Casar²,

Matsuki³

et al. 2014

J. Clin. Invest.

119

117

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Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, which resultsin dysfunctional signaling pathways within muscle. Previously, we identified microRNA-486 (miR-486) as a muscle-enriched microRNA that is markedly reduced in the muscles of dystrophin-deficient mice (Dmd mdx-5Cv mice) and in DMD patient muscles. Here, we determined that muscle-specific transgenic overexpression of miR-486 in muscle of Dmd mdx-5Cv mice results in reduced serum creatine kinase levels, improved sarcolemmal integrity, fewer centralized myonuclei, increased myofiber size, and improved muscle physiology and performance. Additionally, we identified dedicator of cytokinesis 3 (DOCK3) as a miR-486 target in skeletal muscle and determined that DOCK3 expression is induced in dystrophic muscles. DOCK3 overexpression in human myotubes modulated PTEN/AKT signaling, which regulates muscle hypertrophy and growth, and induced apoptosis. Furthermore, several components of the PTEN/AKT pathway were markedly modulated by miR-486 in dystrophin-deficient muscle. Skeletal muscle-specific miR-486 overexpression in Dmd mdx-5Cv animals decreased levels of DOCK3, reduced PTEN expression, and subsequently increased levels of phosphorylated AKT, which resulted in an overall beneficial effect. Together, these studies demonstrate that stable overexpression of miR-486 ameliorates the disease progression of dystrophin-deficient skeletal muscle.

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“…Modifications of this measure have been used to assess outcomes in animal models of Duchenne, including mdx mice 7 and golden retriever muscular dystrophy (GRMD) dogs 8 . In this study, we record voluntary open field movement in the 6 minutes immediately following a mild exercise challenge.…”

Section: Introductionmentioning

confidence: 99%

A Simple and Low-cost Assay for Measuring Ambulation in Mouse Models of Muscular Dystrophy

Gibbs

Crosbie-Watson

2017

JoVE

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Measuring functional outcomes in the treatment of muscular dystrophy is an essential aspect of preclinical testing. The assessment of voluntary ambulation in mouse models is a non-invasive and reproducible activity assay that is directly analogous to measures of patient ambulation such as the six-minute walk test and related mobility scores. Many common methods for testing mouse ambulation speed and distance are based on the open field test, where an animal's free movement within an arena is measured over time. One major downside to this approach is that commercial software and equipment for high-resolution motion tracking is expensive and may require transferring mice to specialized facilities for testing. Here, we describe a low-cost video-based system for measuring mouse ambulation that utilizes free and open-source software. Using this protocol, we demonstrate that voluntary ambulation in the dystrophin-null mdx mouse model for Duchenne muscular dystrophy is decreased relative to wild-type mouse activity. In mdx mice expressing the utrophin transgene, these activity deficits are not observed and the total distance travelled is indistinguishable from wild-type mice. This method is effective for measuring changes in voluntary ambulation associated with dystrophic pathology, and provides a versatile platform that can be readily adapted to diverse research settings.

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Endpoint measures in the mdx mouse relevant for muscular dystrophy pre-clinical studies

Cited by 32 publications

References 35 publications

Behavioral and Locomotor Measurements Using an Open Field Activity Monitoring System for Skeletal Muscle Diseases

Behavioral and Locomotor Measurements Using an Open Field Activity Monitoring System for Skeletal Muscle Diseases

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

A Simple and Low-cost Assay for Measuring Ambulation in Mouse Models of Muscular Dystrophy

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