The nutrient sensor CRTC and Sarcalumenin/thinman represent an alternate pathway in cardiac hypertrophy

Area of Science:

• Cardiology
• Molecular Biology
• Genetics

Background:

• Calcineurin (CaN) is known to regulate gluconeogenic genes and is implicated in cardiac hypertrophy.
• The role of CREB-regulated transcription co-activator (CRTC) in cardiac function, particularly in hypertrophy, remains largely unexplored.

Purpose of the Study:

• To investigate the cardiac-autonomous role of CRTC in cardiac hypertrophy.
• To elucidate the molecular mechanisms and signaling pathways involving CRTC in cardiac function.

Main Methods:

• Utilized Drosophila melanogaster as a model system to study CRTC mutants and cardiac-specific knockdown/overexpression.
• Performed RNA sequencing (RNA-seq) on CRTC-manipulated Drosophila hearts.
• Investigated CRTC knockdown in zebrafish and human induced cardiomyocytes.

Main Results:

• CRTC mutants and knockdown in Drosophila hearts showed cardiac restriction, myofibrillar disorganization, fibrosis, and tachycardia.
• Cardiac-specific CRTC overexpression in Drosophila led to hypertrophy.
• CaN-induced hypertrophy was reduced in CRTC mutants, indicating CRTC's mediating role.
• RNA-seq identified metabolic gene dysregulation and highlighted Sarcalumenin (Srl) as a downstream target.
• CRTC manipulation in zebrafish and human cardiomyocytes recapitulated cardiac dysfunction and affected Srl expression and action potential duration.

Conclusions:

• CRTC plays a significant cardiac-autonomous role in regulating cardiac hypertrophy.
• A conserved signaling pathway involving Calcineurin-CRTC-Sarcalumenin is identified as critical for cardiac function and hypertrophy.
• This pathway represents a novel target for understanding and potentially treating cardiac diseases.