Cardiac-specific overexpression of serum response factor regulates age-associated decline in mitochondrial function

Abstract

Cardiac aging is an intrinsic process that leads to impaired heart function, along with cellular and molecular changes. Recent research highlights the important role of mitochondria in cardiac function, due to the heart's high energy demands. Serum response factor (SRF), a transcription factor involved in regulating actin and smooth muscle gene expression, is well known as a regulator of various aspects of cardiac function. However, its role in mitochondrial regulation and cardiac aging is poorly understood. Our laboratory generated a transgenic mouse model with cardiac-specific overexpression of SRF, which exhibits characteristics of diastolic dysfunction and accelerated cardiac aging in young adult transgenic mice. In this study, we tested how cardiac-specific overexpression of SRF affects age associated mitochondrial dysfunction in the heart. Our results showed that cardiac specific SRF overexpression reduced the lifespan of mice and induced cardiomyopathy. Histological analysis revealed cardiac hypertrophy and fibrosis in transgenic mice hearts. SRF overexpression led to significant alterations in mitochondrial structure and function, including reduced mitochondrial biogenesis and dysregulation of oxidative phosphorylation. These changes were accompanied by increased oxidative stress, a decline in antioxidant enzyme activity, and disrupted calcium handling. Moreover, cardiac-specific SRF overexpression activated the MAPK signaling pathway. Our findings were further corroborated by similar mitochondrial dysfunction observed in a human cardiomyocyte cells transfected with SRF plasmid. Taken together, these findings suggest that SRF plays a novel role in cardiac aging, thus establishing SRF as a potential therapeutic target for mitigating age-associated decline in mitochondrial function and preserving cardiac health in older adults.