Differential Effectiveness of Poloxamer 188 in Dystrophic Cardiomyopathy Reveals Complex Pathophysiology

Abstract

AbstractSynthetic membrane stabilizers, such as poloxamer 188 (P188), have great promise in the treatment of Duchenne muscular dystrophy and other diseases associated with disrupted membranes. The aim of this study was to assess the efficacy of P188 to limit myocardial damage in models of muscular dystrophy subjected to highly injurious stress. These studies use male and female mdx and β-sarcoglycan null (β-SG-/-) mice subjected to an isoproterenol stress protocol in the presence or absence of P188. We show that P188 provides a significant level of protection to male mdx hearts from the isoproterenol induced injury. Surprisingly, we find that P188 has no protective actions in female mdx mice or in β-SG-/-mice of either sex. These results suggest that the mechanism of action of P188 is more complicated than previously thought. The presence of sex differences in the absence of dystrophin is not consistent with a model of P188 working by biophysical restoration of membrane integrity. Furthermore, the absence of protective effects of P188 in β-SG-/-myocardium indicates that there are important differences in the mechanisms of membrane damage in hearts lacking dystrophin and hearts lacking the sarcoglycan complex. Developing a better understanding of these differences will be important in the development of therapies for dystrophic cardiomyopathy and other forms of heart disease.