Age-dependent Dystrophin Loss and Genetic Reconstitution Establish a Molecular Link Between Dystrophin and Heart Performance During Aging

Abstract

The aging-related decline in cardiac function is an important public health problem. The molecular basis of age-dependent loss of cardiac function is largely unknown and there are no effective therapies addressing this important form of heart disease. This study evaluates the role of the cytoskeletal protein dystrophin in the process of normal cardiac aging. Here, we show that the cytoskeletal protein dystrophin in the hearts of old mice is significantly decreased to a level of 36% that of young mice, whereas other key members of the dystrophin complex are unchanged. Age-dependent decreased ejection fraction was rescued by systemic delivery of an adeno-associated viral vector harboring a functional micro-dystrophin cassette (48.9 ± 2.5% in untreated aged vs. 61.6 ± 7.4% in treated aged mice, compared to 67.1 ± 2.6% in young mice). These data provide the first direct evidence that decreased dystrophin levels are an important modulator of cardiac function in the aged heart.