Chronic Administration of a Leupeptin-Derived Calpain Inhibitor Fails to Ameliorate Severe Muscle Pathology in a Canine Model of Duchenne Muscular Dystrophy

Childers, Martin K.; Bogan, Janet R.; Bogan, Daniel J.; Greiner, Hansel M.; Holder, M.N.; Grange, Robert W.; Kornegay, Joe N.

doi:10.3389/fphar.2011.00089

Cited by 20 publications

(20 citation statements)

References 46 publications

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“…Histopathologic / functional correlation would be required to validate these markers and is ongoing, using functional indices of isometric distal limb force [37] and repeated eccentric contractions; muscle weight; and histopathological measures of myofiber and endomysial space (non-contractile tissue) per unit area [38, 39]. .…”

Section: Ivdiscussionmentioning

confidence: 99%

A computerized MRI biomarker quantification scheme for a canine model of Duchenne muscular dystrophy

et al. 2013

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Purpose Golden retriever muscular dystrophy (GRMD) is a widely used canine model of Duchenne muscular dystrophy (DMD). Recent studies have shown that magnetic resonance imaging (MRI) can be used to non-invasively detect consistent changes in both DMD and GRMD. In this paper, we propose a semi-automated system to quantify MRI biomarkers of GRMD. Methods Our system was applied to a database of 45 MRI scans from 8 normal and 10 GRMD dogs in a longitudinal natural history study. We first segmented six proximal pelvic limb muscles using two competing schemes: 1) standard, limited muscle range segmentation and 2) semi-automatic full muscle segmentation. We then performed pre-processing, including: intensity inhomogeneity correction, spatial registration of different image sequences, intensity calibration of T2-weighted (T2w) and T2-weighted fat suppressed (T2fs) images, and calculation of MRI biomarker maps. Finally, for each of the segmented muscles, we automatically measured MRI biomarkers of muscle volume and intensity statistics over MRI biomarker maps, and statistical image texture features. Results The muscle volume and the mean intensities in T2 value, fat, and water maps showed group differences between normal and GRMD dogs. For the statistical texture biomarkers, both the histogram and run-length matrix features showed obvious group differences between normal and GRMD dogs. The full muscle segmentation shows significantly less error and variability in the proposed biomarkers when compared to the standard, limited muscle range segmentation. Conclusion The experimental results demonstrated that this quantification tool can reliably quantify MRI biomarkers in GRMD dogs, suggesting that it would also be useful for quantifying disease progression and measuring therapeutic effect in DMD patients.

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Section: Ivdiscussionmentioning

confidence: 99%

A computerized MRI biomarker quantification scheme for a canine model of Duchenne muscular dystrophy

et al. 2013

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“…, Childers et al . ). Considering that multiple sarcomeric and cytoskeletal proteins, kinases and transcription factors are calpain substrates (Goll et al .…”

Section: Calpainsmentioning

confidence: 97%

“…(Childers et al . ) when they found that C101 failed to decrease calpain activity or decrease disease severity following eight weeks of treatment in golden retriever muscular dystrophy (GRMD) dogs. Additionally, 6 months of leupeptin administration did not lead to histological or functional benefits in mdx mice (Selsby et al .…”

Section: Calpainsmentioning

confidence: 99%

The physiological response of protease inhibition in dystrophic muscle

Hollinger

Selsby

2013

Acta Physiologica

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Duchenne muscular dystrophy (DMD) is caused by the production of a non-functional dystrophin gene product and a failure to accumulate functional dystrophin protein in muscle cells. This leads to membrane instability, loss of Ca(2+) homoeostasis and widespread cellular injury. Associated with these changes are increased protease activities in a variety of proteolytic systems. As such, there have been numerous investigations directed towards determining the therapeutic potential of protease inhibition. In this review, evidence from genetic and/or pharmacological inhibition of proteases as a treatment strategy for DMD is systematically evaluated. Specifically, we review the potential roles of calpain, proteasome, caspase, matrix metalloproteinase and serine protease inhibition as therapeutic approaches for DMD. We conclude that despite early results to the contrary, inhibition of calpain proteases is unlikely to be successful. Conversely, evidence suggests that inhibition of proteasome, matrix metalloproteinases and serine proteases does appear to decrease disease severity. An important caveat to these conclusions, however, is that the fundamental cause of DMD, dystrophin deficiency, is not corrected by this strategy. Hence, this should not be viewed as a cure, but rather, protease inhibitors should be considered for inclusion in a therapeutic cocktail. Physiological Relevance. Selective modulation of protease activity has the potential to profoundly change intracellular physiology resulting in a possible treatment for DMD. However, alteration of protease activities could also lead to worsening of disease progression by promoting the accumulation of substrates in the cell. The balance of benefit and potential damage caused by protease inhibition in human DMD patients is largely unexplored.

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“…Unfortunately, long-term intravenous administration of NBD was found to induce untoward infusion reactions even in normal dogs. In addition to anti-inflammatory drugs, CXMD dogs have also been used to test calpain inhibitor (172), proteasome inhibitor (173), bradykinin (174,175), and laminin-111 protein therapy (176). Proteasome inhibitor reduced muscle inflammation and partially restored dystrophin-associated glycoprotein complex.…”

Section: Therapeutic Testing In the Canine Model And Impact On Patienmentioning

confidence: 99%

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases

et al. 2020

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Mouse models of human disease remain the bread and butter of modern biology and therapeutic discovery. Nonetheless, more often than not mouse models do not reproduce the pathophysiology of the human conditions they are designed to mimic. Naturally occurring large animal models have predominantly been found in companion animals or livestock because of their emotional or economic value to modern society and, unlike mice, often recapitulate the human disease state. In particular, numerous models have been discovered in dogs and have a fundamental role in bridging proof of concept studies in mice to human clinical trials. The present article is a review that highlights current canine models of human diseases, including Alzheimer's disease, degenerative myelopathy, neuronal ceroid lipofuscinosis, globoid cell leukodystrophy, Duchenne muscular dystrophy, mucopolysaccharidosis, and fucosidosis. The goal of the review is to discuss canine and human neurodegenerative pathophysiologic similarities, introduce the animal models, and shed light on the ability of canine models to facilitate current and future treatment trials.

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Chronic Administration of a Leupeptin-Derived Calpain Inhibitor Fails to Ameliorate Severe Muscle Pathology in a Canine Model of Duchenne Muscular Dystrophy

Cited by 20 publications

References 46 publications

A computerized MRI biomarker quantification scheme for a canine model of Duchenne muscular dystrophy

A computerized MRI biomarker quantification scheme for a canine model of Duchenne muscular dystrophy

The physiological response of protease inhibition in dystrophic muscle

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases

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