MDX Mouse as Therapeutic Model System: Development and Implementation of Phenotypic Monitoring

Hudecki, Michael S.; Pollina, Catherine M.

doi:10.1007/978-1-4684-5865-7_29

Cited by 12 publications

(15 citation statements)

References 19 publications

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“…Hudecki et al used small animal activity chambers that recorded spontaneous physical movements as “events” in mdx mice. 25 They found decreased activity in mdx mice over time, but this was no different from findings in age-matched controls. They did see a significant elevation in activity in mdx mice treated with dexamethasone and imipramine.…”

Section: Discussionmentioning

confidence: 90%

“…2,3,9,25,39 These parameters are also used to successfully evaluate drug interventions, and can validate results from longitudinal non-invasive muscle function testing at completion of the trial. 2,4,8,9,11,15,20,21,26,33,39,45 Collagen-sensitive stains can be used to quantitate the amount of fibrosis in cardiac and skeletal muscles, as shown in Figure 2, and Evans blue dye uptake can also be used to assess muscle cell membrane integrity.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to DMD patients, mdx mice have increased levels of serum CK. 2,3,9,17,25 However, because mdx mice undergo an initial period of degeneration/regeneration and maintain a mild phenotype, correlation of CK levels with function and histological parameters is difficult. Some studies have shown improved functional/histological parameters with no changes in increased CK levels.…”

Section: Discussionmentioning

confidence: 99%

“…2,17 CK levels were shown to increase with age, exercise, and male gender. 9,25,45 CK values tended to have large variations within studies and could vary dramatically across studies. It is critical in the methodology to avoid artificial increases.…”

Section: Discussionmentioning

confidence: 99%

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Preclinical drug trials in the mdx mouse: Assessment of reliable and sensitive outcome measures

et al. 2009

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The availability of animal models for Duchenne muscular dystrophy has led to extensive preclinical research on potential therapeutics. Few studies have focused on reliability and sensitivity of endpoints for mdx mouse drug trials. Therefore, we sought to compare a wide variety of reported and novel endpoint measures in exercised mdx and normal control mice at 10, 20, and 40 weeks of age. Statistical analysis as well as power calculations for expected effect sizes in mdx preclinical drug trials across different ages showed that body weight, normalized grip strength, horizontal activity, rest time, cardiac function measurements, blood pressure, total central/peripheral nuclei per fiber, and serum creatine kinase are the most effective measurements for detecting drug-induced changes. These data provide an experimental basis upon which standardization of preclinical drug testing can be developed.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Preclinical drug trials in the mdx mouse: Assessment of reliable and sensitive outcome measures

et al. 2009

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“…With swimming exercise, the most commonly used parameter of exercise capacity is duration of exercise before exhaustion (15,31,36,61). With treadmill exercise, both duration of exercise and total distance have been utilized to determine exercise capacity (21,22,40,42,46,56). With aid of a photometric detection device located at the end of the treadmill belt, the number of "beam breaks" has also been used to determine exercise capacity.…”

Section: Respiratory Exchange Ratio and Anaerobic Thresholdmentioning

confidence: 99%

Exercise assessment of transgenic models of human cardiovascular disease

Bernstein

2003

Physiological Genomics

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Bernstein, Daniel. Exercise assessment of transgenic models of human cardiovascular disease. Physiol Genomics 13: 217-226, 2003; 10.1152/ physiolgenomics.00188.2002.-Exercise provides one of the most severe, yet physiological, stresses to the intact cardiovascular system and is a major determinant of the utilization of metabolic substrates. The adaptations to exercise are the result of a coordinated response of multiple organ systems, including cardiovascular, pulmonary, endocrine-metabolic, immunologic, and skeletal muscle. With the proliferation of genetically altered murine models of cardiovascular disease, the importance of developing methods of accurate physiological phenotyping is critical. There are numerous examples of transgenic models in which the baseline cardiovascular phenotype is unchanged or minimally changed from the wild type, only to become manifest during the stress of exercise testing. In this review, we cover the basics of the murine cardiovascular response to exercise and the importance of attending to strain differences, compare different exercise methodologies (constant workload treadmill, incremental workload treadmill, swimming) and hemodynamic monitoring systems, and examine the murine response to exercise conditioning. Several examples where exercise studies have contributed to the elucidation of cardiovascular phenotypes are reviewed: the ␤-adrenergic receptor knockouts, phospholamban knockout, dystrophin knockout (mdx), and the mutant ␣-myosin heavy chain (R403Q) transgenic.␤-adrenergic receptor knockout; skeletal muscle; phospholamban knockout; dystrophin knockout; mutant ␣-myosin heavy chain transgenic OVER THE PAST DECADE, there has been a proliferation of genetically modified animal models of human cardiovascular disease. Despite adaptation of transgenic technology to larger mammals, the mouse remains the most commonly used species for transgenic studies and continues to be the only species in which targeted genetic deletions are possible. The addition of technologies allowing tissue-specific knockouts as well as the ability to turn gene expression on and off again at will enhances our ability to study genetic regulation of the cardiovascular system. Some phenotypes, however, may be extremely subtle. Thus thorough evaluation of genetically altered murine models requires the ability to study all components of murine cardiovascular physiology. The development of techniques allowing the evaluation of mice in an awake, unrestrained state has advanced the study of true resting cardiovascular dynamics and has also allowed the introduction of exercise testing to study cardiovascular response during stressed states. Exercise studies provide valuable information about how the cardiovascular system responds under maximally stimulated conditions, with the possibility of uncovering phenotypes not observed at rest. Given the expense and time involved in creating genetically altered murine models of human cardiovascular disease, it is not unreasonable to suggest that most if not all models s...

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RANK and RANKL expression as markers of dendritic cell–t cell interactions in paired samples of rheumatoid synovium and lymph nodes

Page¹,

Miossec²

2005

Arthritis & Rheumatism

113

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Objective. The RANK/RANKL pathway is critical in bone destruction in conditions such as rheumatoid arthritis (RA). Since RANK/RANKL-deficient mice show major lymph node (LN) abnormalities, undertook this study to investigate the expression of RANK/ RANKL in paired samples of synovium and LNs from RA patients.Methods. Using immunohistochemistry, RANK/ RANKL expression by dendritic cell (DC) and T cell subsets was studied in this unique set of samples and in RA synoviocytes stimulated with interleukin-1␤ (IL-1␤), tumor necrosis factor ␣ (TNF␣), and IL-17.Results. In RA synovium, RANKL؉ cells were detected in the lining layer and the lymphocytic infiltrates, whereas RANK expression was restricted to the perivascular infiltrates. In LNs, RANK؉ and RANKL؉ cells were diffusely expressed in the T cell zone and in germinal centers. Double staining of paired RA synovium and LN sections showed that some immature CD1a؉ DCs expressed RANK and RANKL, while some mature DC-LAMP؉ DCs expressed only RANK. Some CD3؉, CD4؉, interferon-␥؉, and IL-17؉ cells expressed RANKL, while none expressed RANK. Treatment of synoviocytes with TNF␣ or IL-1␤ in combination with IL-17 was particularly potent at inducing RANKL expression.Conclusion. This study shows the involvement of RANK/RANKL in DC-T cell interactions during an inflammatory process. RANK expression appears to be limited to the sites of immune reaction, both in the synovium and in LNs. Therapeutic control of these targets may have both positive and negative consequences for the immune system.

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MDX Mouse as Therapeutic Model System: Development and Implementation of Phenotypic Monitoring

Cited by 12 publications

References 19 publications

Preclinical drug trials in the mdx mouse: Assessment of reliable and sensitive outcome measures

Preclinical drug trials in the mdx mouse: Assessment of reliable and sensitive outcome measures

Exercise assessment of transgenic models of human cardiovascular disease

RANK and RANKL expression as markers of dendritic cell–t cell interactions in paired samples of rheumatoid synovium and lymph nodes

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