Cardiac hypoxia drives Fbln5 secretion to disrupt peripheral circadian rhythms

Nearly all living organisms have an ecological rhythm that consists of 24-hr intrinsic oscillations dictated by an endogenous circadian clock. Research to date indicates that the suprachiasmatic nucleus (SCN) in the hypothalamus serves as the master pacemaker that synchronizes peripheral tissue clocks. However, the extent to which non-SCN tissues contribute to the regulation of peripheral clocks remains unclear. Previous work from our lab demonstrates that cardiac-specific deletion of the core clock protein Brain and Muscle ARNT-Like 1 ( Bmal1; Bmal1 cKO) disrupts both centrally and peripherally entrained rhythms, suggesting a role for the cardiac clock in regulating circadian function in extra-cardiac tissues. Mice with cardiac-specific Bmal1 deletion exhibited time-dependent increases in body temperature and locomotor activity during the "siesta" phase of the active period compared to wild-type (WT) controls, without significant changes in markers of SCN neuronal activity. Bmal1 cKO mice demonstrated attenuated day-night differences in skeletal muscle and kidney core clock gene expression ( Bmal1, Clock, Per1 ) and other circadian regulated genes ( PDK4, PPAR- α ) compared to WT mice. Proteomic analysis of serum from Bmal1 cKO and WT mice identified fibulin-5 (Fbln5) as a potential cardiokine mediating these effects, with rhythmic expression of Fbln5 disrupted in the heart of Bmal1 cKO mice. Exogenous treatment of synchronized C2C12 myotubes and human renal epithelial cells with recombinant Fbln5 abolished rhythmic clock gene expression, further supporting the role of Fbln5 in modulating peripheral clock function. Fbln5 is positively stimulated by hypoxia, together providing a model in which cardiac-specific Bmal1 deletion impairs the cardiac circadian response to oxygen, leading to dysregulated secretion of Fbln5 and subsequent disruption of muscle and kidney circadian rhythms. These findings are critical to advance circadian science and identify therapies to mitigate the harmful consequences of a broken clock. Funding: American Heart Association Transformational Project Award, 24TPA1282573, Wyoming Sensory Biology Center of Biomedical Research Excellence, 2P20GM121310-06 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.