Abstract Body: Background
Dysregulation of autophagy is known to have detrimental effects on cardiac remodeling. FYCO1, a novel regulator of autophagy mediates the transport of autophagosomes, thereby amplifying autophagic flux. Here, we investigate the impact of FYCO1 on myocardial healing via autophagy modulation.

Methods
FYCO1-Tg mice crossed with RFP-EGFP-LC3 reporter mice (FYCO1-TGxRGFP) were utilized to analyze autophagic flux via confocal microscopy following permanent ligation of the left anterior descending artery (LAD) to induce myocardial ischemia. Autophagy activity was evaluated via Western blot of p62 and LC3 II. Macrophage infiltration and apoptosis was assessed by immunofluorescence microscopy, while Masson's Trichrome staining detected fibrosis and infarct size. Cardiac function was determined by echocardiography.

Results
FYCO1-TGxRGFP mice displayed significantly enhanced autophagic flux post MI, as evidenced by increased p62 (WT LAD: 2,9±0,4; TG LAD:4,0±0,5) and LC3 II (WT LAD: 1,6±0,2; TG LAD:14,0±1,4) protein levels. Confocal microscopy revealed an accumulation of autolysosomes in WT mice 30 days post MI (WT autophagosomes: 1±0,4; WT autolysosomes: 38,6±3,8), contrasting with the sustained ratio of autophagosomes to autolysosomes in FYCO1-TGxRGFP mice (TG autophagosomes:43,3±5,1; TG autolysosomes: 73,5±12,4), implying the preservation of adequate autophagic flux. FYCO1 overexpression reduced macrophage infiltration into the border zone post MI (WT LAD: 132,4 ±14,3; TG LAD: 18,91±3,7 and inhibited apoptosis induction shown by cleaved caspase7 activity (WT LAD: 64,6±10,1; TG LAD: 9,2±2,1). Moreover, FYCO1-TGxRGFP mice exhibited significantly reduced fibrosis (WT:19,6±1,8%; TG:10,6±1,6%) and infarct size (WT:34,5 ±3,9%; TG:5,5±2%) in the left ventricle (LV), accompanied by marked improvements in global heart function post MI (EF WT: 32,7±3,2%; TG: 56,4±3,9%) compared to WT mice.

Conclusion
In conclusion, FYCO1 mitigates adverse consequences of ischemic injury via induction of autophagy and a previously unrecognized role in modulating inflammation in response to myocardial infarction.