Malignant cardiac phenotype after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous R349P desmin knock-in mice

Abstract

Mutations of the human desmin gene on chromosome 2q35 cause autosomal-dominant and -recessive myopathies and ardiomyopathies. For pathophysiological and therapeutic studies, we generated a R349P desmin knock-in mouse strain, which serves as patient-mimicking disease model for desminopathies. Here, we investigated the influence of pressure overload on cardiac function in heterozygous R349P desmin knock-in mice. Young, non-operated heterozygous R349P desmin knock-in mice do not show obvious signs of cardiomyopathy. When subjected to pressure overload by TAC operation, these mice develop marked signs of cardiomyopathy with accompanying arrhythmias and atrioventricular blocks. The cardiac disease manifestations are associated with reductions in mitochondrial respiratory chain complex activities and mitochondrial DNA copy numbers. Preventive avoidance of pressure overload, i.e. arterial hypertension, to the heart may thus represent a crucial therapeutic measure. Heterozygous R349P desmin knock-in mice and their wild-type siblings were used. Transverse aortic constriction (TAC) operation was performed to induce pressure overload. Cardiac function was analyzed by left heart catheterization, electrophysiological investigation, and echocardiography. Moreover, mitochondrial respiratory complex activities, mtDNA copy number, and mtDNA integrity were investigated.