Australian Labradoodle Dystrophinopathy: A Novel Canine Model for the Study of Duchenne Muscular Dystrophy Cardiomyopathy

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that results in progressive damage to both skeletal and cardiac myocytes. As a result of improved ventilatory care, mortality in affected patients is increasingly attributed to cardiomyopathy. We have identified a novel dystrophin mutation in exon 21 in Australian Labradoodles. Affected dogs have poor weight gain and weight loss with gait abnormalities, exercise intolerance, skeletal muscle atrophy, macroglossa, ptyalism, dysphagia, kyphosis, and a plantigrade stance developing by 6 months of age. Concurrent echocardiographic and electrocardiographic abnormalities include hyperechoic foci in the left ventricular papillary muscles, septal hypokinesis, decreased left ventricular systolic and diastolic volume and internal diameter, and atrioventricular (AV) block. Skeletal muscle pathology in affected dogs is similar to what has been described in people with DMD and includes myocyte degeneration, necrosis, and regeneration, fibrofatty infiltration, lymphohistiocytic inflammation, and mineralization. Histopathologic findings in the heart were observed in the dog with the AV block and consisted of a focal area of mineralization adjacent to the sinoatrial node. Cardiac transcriptome sequencing on left ventricular myocardial samples found 29,740 genes expressed and 1267 differentially expressed genes. Expression patterns from affected dogs were generally distinct from controls and there was a high correlation between samples. The ten gene transcripts with the greatest up regulation (in descending order of fold change) included BDNF, MYL4, PENK, BSPRY, PRR32, NPPA, LOC490471, LYZF2, CDH10, and FGF6. We also found that the most down-regulated transcripts (in ascending order of fold change) included LOC612108, ST8SIA2, FOXR1, P2RX6, LOC610380, DAO, CNR2, SDC1, LRRC55, and TMEM171). The majority of the above-mentioned genes have known roles in cardiac compensatory changes secondary to dystrophinopathic-associated damage, including survival, remodeling, contractility, conduction, and immunoregulation. Differential expression of genes was also observed in pathways associated with cardiac oxidative stress, apoptosis, and contractility. These findings are significant because they support the use of the Australian Labradoodle as a novel animal model for the study of DMD cardiomyopathy, they elucidate pathways and differential gene expression involved in Labradoodle dystrophinopathic cardiomyopathy, and they may aid in the development of therapeutic targets to treat dystrophinopathy-associated cardiac disease.