Duchenne muscular dystrophy (DMD) is a fatal disease of striated muscle deterioration caused by lack of the cytoskeletal
protein dystrophin.
Dystrophin deficiency causes muscle membrane instability, skeletal muscle wasting,
cardiomyopathy, and
heart failure. Advances in palliative respiratory care have increased the incidence of
heart disease in DMD patients, for which there is no cure or effective
therapy. Here we have shown that chronic infusion of membrane-sealing
poloxamer to severely affected dystrophic dogs reduced myocardial
fibrosis, blocked increased serum cardiac
troponin I (cTnI) and brain type
natriuretic peptide (BNP), and fully prevented
left-ventricular remodeling. Mechanistically, we observed a markedly greater primary defect of reduced cell compliance in dystrophic canine myocytes than in the mildly affected mdx mouse myocytes, and this was associated with a lack of
utrophin upregulation in the dystrophic canine cardiac myocytes. Interestingly, after chronic
poloxamer treatment, the poor compliance of isolated canine myocytes remained evident, but this could be restored to normal upon direct application of
poloxamer. Collectively, these findings indicate that
dystrophin and
utrophin are critical to membrane stability-dependent cardiac myocyte mechanical compliance and that
poloxamer confers a highly effective membrane-stabilizing chemical surrogate in
dystrophin/
utrophin deficiency. We propose that membrane sealant
therapy is a potential treatment modality for DMD
heart disease and possibly other disorders with membrane defect etiologies.