Résumé :
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It is well known that the disease course in Duchenne muscular dystrophy (DMD) patients is heterogeneous, varying from patient to patient. Such heterogeneity is also seen in the Golden Retriever Muscular Dystrophy (GRMD) dogs. This is a drawback when evaluating the functional effect of a treatment. Identifying predictive markers of the clinical evolution would allow a better management of the model during therapeutic trials, and could contribute to identify or support therapeutic targets.This study aimed to identify biomarkers, able to predict the evolution of disease in the GRMD dogs towards one of the two clearly distinct clinical forms: the severe form (SF, loss of ambulation before the age of 6 months), and the moderate form (MF, no loss of ambulation). The proportion of circulating T-lymphocytes expressing high membrane levels of CD49d (the a-chain of the integrin VLA-4, previously defined by our group as a a progression biomarker of human DMD), was assessed in seventeen 2 months-old GRMD dogs (5 SF, 12 MF). Clinical and functional tests (motor score (10 SF, 14 MF), and gait analysis using accelerometry at 2 months (9 SF, 10 MF), force measurement at 4 months (5 SF, 11 MF) were also assessed to predict the two clinical forms of disease progression.The proportion of circulating CD4+VLA4hi T-lymphocytes was significantly increased (p=0.002) in SF dogs. The value of 12.16% could be defined as a predictive threshold for SF, with a specificity (Sp) of 83% and a sensitivity (Se) of 58%. Additionally, two months-old SF dogs were not able to maintain as frequent locomotor cycles as MF dogs (p=0.007). A stride frequency lower than 2.3 s-1 was shown to be able to predict SF, with a Sp of 90% and a Se of 78%. Four months-old SF dogs had delayed post-tetanic relaxation, in comparison to MF dogs (p=0.003). This particular contractile behaviour probably reflects a more impaired ionic homeostasis in SF dogs. Accordingly, 100 ms post-tetanic relaxation level lower than 43.2%, was able to predict SF with a Sp of 91% and a Se of 100%.These results underlie the pathophysiological implication of inflammation and ionic homeostasis impairment in this canine homologue of DMD. These predictive markers offer satisfying levels of specificity and sensitivity, which could be increased by combining the different markers, to reliably predict SF or MF. This combined strategy may be useful for better conducting therapeutic trials according to the predicted evolution of dogs, thus reducing the interfering drawback of clinical heterogeneity.
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