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

Research to date describes the suprachiasmatic nucleus (SCN) of the hypothalamus as the master pacemaker that synchronizes circadian rhythms in peripheral tissues. However, recent high-impact studies demonstrate that non-SCN tissues can also coordinate rhythms in other peripheral tissues. However, the extent to which the cardiac clock regulates peripheral clocks has not yet been tested. Therefore, we investigated the role of the cardiac clock in modulating extra-cardiac circadian function using a model of cardiac-specific deletion of the core clock protein Bmal1 (Bmal1 cKO). Bmal1 cKO mice demonstrated attenuated day-night differences in skeletal muscle core clock gene expression (Bmal1, Clock, Per1) and circadian expressed metabolic genes (Pdk4, Ppara) as well as impaired day-night muscle grip strength. In the kidney, Bmal1 cKO mice had blunted core clock gene and water balance gene expression (Avp) compared to WT mice. Proteomic analysis of serum identified fibulin 5 (Fbln5) as a potential cardiokine mediating peripheral circadian effects, with rhythmic expression of Fbln5 disrupted in the heart and serum of Bmal1 cKO mice compared to WT. Exogenous treatment of synchronized C2C12 myotubes and human renal cells with rFbln5 disrupted rhythmic clock gene expression. In vivo, supplementation of Fbln5 in the drinking water of healthy wildtype C57Bl6 mice also disrupted kidney muscle rhythms. RNA sequencing data suggested that Fbln5 alters circadian output programs via stress-activated mechanotransduction and metabolic remodeling. Importantly, these changes occur without overt SCN dysfunction. Together, we demonstrate a critical role for the heart in regulating peripheral circadian control through the novel circadian cardiokine Fbln5.