The Cardiac Circadian Clock Regulates Rhythms in Peripheral Tissues via Fibulin 5

Area of Science:

• Chronobiology
• Cardiovascular Physiology
• Molecular Biology

Background:

• The suprachiasmatic nucleus (SCN) is traditionally viewed as the master circadian pacemaker.
• Emerging evidence suggests non-SCN tissues can also regulate peripheral circadian rhythms.
• The specific role of the cardiac clock in controlling extra-cardiac tissues remains largely unexplored.

Purpose of the Study:

• To investigate the influence of the cardiac clock on peripheral circadian function.
• To determine if the heart can modulate circadian rhythms in other tissues.
• To identify potential molecular mediators of cardiac circadian influence.

Main Methods:

• Utilized a cardiac-specific Bmal1 knockout (Bmal1 cKO) mouse model.
• Assessed circadian gene expression and physiological function in skeletal muscle and kidney.
• Performed proteomic analysis of serum and in vitro/in vivo experiments with fibulin 5 (Fbln5).

Main Results:

• Bmal1 cKO mice exhibited disrupted circadian rhythms in skeletal muscle and kidney, including impaired grip strength and blunted gene expression.
• Fibulin 5 (Fbln5) was identified as a potential cardiokine with disrupted rhythmic expression in Bmal1 cKO mice.
• Exogenous Fbln5 administration disrupted peripheral circadian rhythms in vitro and in vivo, independent of SCN function.

Conclusions:

• The heart plays a critical role in regulating peripheral circadian rhythms.
• Fibulin 5 (Fbln5) acts as a novel circadian cardiokine mediating cardiac influence on extra-cardiac tissues.
• Cardiac circadian dysfunction can lead to systemic dysregulation of peripheral clocks.