Project description:Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene and loss of the protein dystrophin. The absence of dystrophin leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Despite extensive attempts to develop definitive therapies for DMD, the standard of care remains prednisone, which has only palliative benefits. Animal models, mainly the mdx mouse and golden retriever muscular dystrophy (GRMD) dog, have played a key role in studies of DMD pathogenesis and treatment development. Because the GRMD clinical syndrome is more severe than in mice, better aligning with the progressive course of DMD, canine studies may translate better to humans. The original founder dog for all GRMD colonies worldwide was identified in the early 1980s before the discovery of the DMD gene and dystrophin. Accordingly, analogies to DMD were initially drawn based on similar clinical features, ranging from the X-linked pattern of inheritance to overlapping histopathologic lesions. Confirmation of genetic homology between DMD and GRMD came with identification of the underlying GRMD mutation, a single nucleotide change that leads to exon skipping and an out-of-frame DMD transcript. GRMD colonies have subsequently been established to conduct pathogenetic and preclinical treatment studies. Simultaneous with the onset of GRMD treatment trials, phenotypic biomarkers were developed, allowing definitive characterization of treatment effect. Importantly, GRMD studies have not always substantiated findings from mdx mice and have sometimes identified serious treatment side effects. While the GRMD model may be more clinically relevant than the mdx mouse, usage has been limited by practical considerations related to expense and the number of dogs available. This further complicates ongoing broader concerns about the poor rate of translation of animal model preclinical studies to humans with analogous diseases. Accordingly, in performing GRMD trials, special attention must be paid to experimental design to align with the approach used in DMD clinical trials. This review provides context for the GRMD model, beginning with its original description and extending to its use in preclinical trials.

Project description:Like Duchenne muscular dystrophy (DMD), the Golden Retriever Muscular Dystrophy (GRMD) dog model of DMD exhibits is characterized by muscle necrosis, progressive paralysis, and pseudohypertrophy in specific skeletal muscles. This severe GRMD phenotype included atrophy of the biceps femoris (BF) and compared to unaffected normal dogs, while the long digital extensor (LDE) of the pelvic limb, serving as a hip flex and stifle extensor, is unaffected. A recent microarray analysis of GRMD identified alterations in genes associated with lipid metabolism and energy production. We, therefore, undertook a non-targeted metabolomics analysis of the GRMD BF (affected) and LDE (unaffected) using GC-MS to identify underlying metabolic defects specific for affected GRMD skeletal muscle. Of the 134 metabolites identified in BF, eight were significantly altered in GRMD BF compared to control BF (Glutamic Acid (2.48 fold vs. controls); Oleic Acid (1.76 fold vs. controls); Proline (1.73 fold vs. controls); Myoinositol-2- Phosphate (0.44 fold vs. controls); Fumaric Acid (0.40 fold vs. controls); Carnosine (0.40 fold vs. controls); Lactamide (0.33 fold vs. controls); and Stearamide (0.23 fold vs. controls). Pathway analysis of the T-test significant metabolites identified BF muscle metabolites significantly enriched for Arginine and proline metabolism (p=5.8E-4, FDR=0.04) and Alanine, aspartate, and glutamate metabolism (p=1.3E-3, FDR=0.05). The GRMD LDE previously reported to be unaffected, in contrast, had only one significantly altered metabolite (3-Phosphoglyceric Acid (0.35 Fold vs. controls)).The identification of elevated BF Oleic acid (a long-chain fatty acid) is consistent with recent microarray studies identifying altered lipid metabolism genes, while alterations in Arginine and Proline metabolism are consistent with recent studies identifying elevated L-arginine in DMD patient sera as a biomarker of disease (alterations in DMD or GRMD muscle itself have not previously been reported).Together, these studies demonstrate muscle-specific alterations in GRMD-affected muscle, which illustrate previously unidentified metabolic changes.

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Golden retriever pyometra project

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