FNDC4 Prevents Aging-Related Cardiac Dysfunction: By Restoring AMPKα/PPARα-Dependent Mitochondrial Function

Area of Science:

• Cardiovascular Biology
• Mitochondrial Medicine
• Aging Research

Background:

• Mitochondrial dysfunction is a hallmark of aging hearts, impacting cardiac homeostasis and oxidative metabolism.
• Fibronectin type III domain-containing 4 (FNDC4) is implicated in mitochondrial biogenesis and metabolic regulation.
• Reduced FNDC4 levels are observed in aging hearts and correlate with impaired cardiac function.

Purpose of the Study:

• To investigate the role of FNDC4 in age-related cardiac dysfunction.
• To elucidate the molecular mechanisms by which FNDC4 influences cardiac aging.
• To determine the therapeutic potential of FNDC4 in mitigating cardiac aging.

Main Methods:

• Comparative analysis of FNDC4 levels in young and aging mice.
• Generation of cardiac-specific FNDC4 overexpression and knockdown mouse models.
• Assessment of cardiac function and remodeling using established physiological and histological techniques.
• Transcriptome and metabolomic analyses to identify FNDC4-regulated pathways.

Main Results:

• Aging mice showed significantly decreased cardiac and plasma FNDC4 levels.
• Cardiac-specific FNDC4 overexpression ameliorated aging-related cardiac remodeling and dysfunction.
• Cardiac-specific FNDC4 knockdown exacerbated aging-related cardiac pathology.
• FNDC4 activation of the AMP-activated protein kinase α/peroxisome proliferator-activated receptor α signaling pathway was identified.
• This pathway improved mitochondrial dysfunction and reduced lipotoxicity in aging hearts.

Conclusions:

• FNDC4 plays a protective role against age-related cardiac dysfunction.
• FNDC4 mitigates cardiac aging by enhancing mitochondrial function and metabolic balance via the AMPKα/PPARα pathway.
• Targeting FNDC4 represents a potential therapeutic strategy for age-related heart disease.