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

Area of Science:

• Cardiovascular Biology
• Mitochondrial Biology
• Aging Research

Background:

• Cardiac aging involves impaired heart function and cellular changes, with mitochondria playing a critical role due to high energy demands.
• Serum response factor (SRF) regulates cardiac function, but its role in mitochondrial regulation and cardiac aging remains unclear.

Purpose of the Study:

• To investigate the impact of cardiac-specific SRF overexpression on age-associated mitochondrial dysfunction in the heart.
• To explore SRF's novel role in cardiac aging and its potential as a therapeutic target.

Main Methods:

• Generated a cardiac-specific SRF-overexpressing transgenic mouse model.
• Performed histological analysis, assessed mitochondrial structure and function, oxidative stress markers, antioxidant enzyme activity, and calcium handling.
• Investigated SRF's effect in human cardiomyocyte cells transfected with SRF plasmid.

Main Results:

• Cardiac SRF overexpression reduced lifespan, induced cardiomyopathy, cardiac hypertrophy, and fibrosis in mice.
• Observed significant alterations in mitochondrial structure and function, including reduced biogenesis, dysregulated oxidative phosphorylation, increased oxidative stress, and disrupted calcium handling.
• Confirmed similar mitochondrial dysfunction in SRF-transfected human cardiomyocytes and identified MAPK signaling pathway activation.

Conclusions:

• Cardiac-specific SRF overexpression accelerates cardiac aging and mitochondrial dysfunction, highlighting SRF's novel role in this process.
• SRF is identified as a potential therapeutic target for mitigating age-associated mitochondrial decline and preserving cardiac health.