Fibroblasts Drive Metabolic Reprogramming in Pacemaker Cardiomyocytes

Area of Science:

• Cardiovascular Biology
• Cellular Metabolism
• Cardiac Electrophysiology

Background:

• The sinoatrial node (SAN) microenvironment, comprising pacemaker cardiomyocytes (PCs) and fibroblasts, is vital for heart rhythm.
• Altered SAN microenvironments can lead to cardiac rhythm failure.
• Understanding fibroblast-PC interactions is key to elucidating SAN rhythm generation.

Purpose of the Study:

• To investigate how fibroblasts interact with pacemaker cells and influence their metabolic reprogramming and rhythmic activity.
• To identify the molecular mechanisms by which fibroblasts regulate the functional integrity of the SAN.

Main Methods:

• Utilized Tbx18-induced PCs and fibroblasts for co-cultures and engineered tissues as in vitro models.
• Employed RNA-sequencing, metabolomics, and cellular/molecular techniques.
• Validated findings in vivo in rodents and human induced pluripotent stem cell-derived cardiomyocytes.

Main Results:

• Fibroblasts activate aerobic glycolysis and metabolic reprogramming in PCs, regulating their rhythmicity.
• This reprogramming is mediated by fibroblast-induced Aldoc (aldolase c) expression in PCs via an integrin-dependent signaling pathway.
• Disruption of fibroblast-PC interaction or Aldoc knockdown abolished electrical activity; engineered tissues recapitulated SAN microenvironment function.

Conclusions:

• Fibroblasts are critical regulators of SAN rhythmicity through Aldoc-mediated metabolic reprogramming.
• This study reveals the cellular machinery underlying vertebrate SAN function.
• Identifies a novel therapeutic target for cardiac rhythm disorders.