Functional cardiac consequences of β-adrenergic stress-induced injury in themdxmouse model of Duchenne muscular dystrophy

Abstract

ABSTRACTCardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD), however, in themdxmouse model of DMD, the cardiac phenotype differs from that seen in DMD-associated cardiomyopathy. Although some have used pharmacologic stress to enhance the cardiac phenotype in themdxmodel, many methods lead to high mortality, variable cardiac outcomes, and do not recapitulate the structural and functional cardiac changes seen in human disease. Here, we describe a simple and effective method to enhance the cardiac phenotype model inmdxmice using advanced 2D and 4D high-frequency ultrasound to monitor cardiac dysfunction progressionin vivo. For our study,mdxand wild-type (WT) mice received daily low-dose (2 mg/kg/day) isoproterenol injections for 10 days. Histopathologic assessment showed that isoproterenol treatment increased myocyte injury, elevated serum cardiac troponin I levels, and enhanced fibrosis inmdxmice. Ultrasound revealed reduced ventricular function, decreased wall thickness, increased volumes, and diminished cardiac reserve in mdx mice compared to wild-type. Our findings highlight the utility of low-dose isoproterenol inmdxmice as a valuable model for exploring therapies targeting DMD-associated cardiac complications.SUMMARY STATEMENTThis work introduces an improved method to model heart failure in mouse models of Duchenne muscular dystrophy and comprehensively describes underlying cellular and physiologic mechanisms using advanced imaging techniques.