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Background: Anthracyclines such as doxorubicin (Dox) cause cardiotoxicity and associated autophagic impairment, though controversy exists increasing autophagy ameliorates or exacerbates Dox cardiotoxicity. Because intermittent fasting (IF), a potent stimulus of autophagy, is presently under clinical investigation in multiple human clinical trials of cancer patients receiving chemotherapy, we tested whether IF would ameliorate or exacerbate Dox cardiotoxicity in multiple murine models. Methods: Chow-fed C57BL/6 mice (n=150) were randomized to ad libitum feeding ( adlib ) or IF (every other day) and treated with vehicle or Dox (5 mg/kg IP x 4 doses). Alternatively, to stimulate autophagy and lysosomal biogenesis transcriptionally, we employed adeno-associated virus 9 (AAV9)-driven overexpression of transcription factor EB (TFEB) vs null, followed by vehicle or Dox (n=40). We further analyzed TFEB nuclear content in myocardial tissue from patients with anthracycline cardiomyopathy vs non-failing donors and patients with other non-ischemic cardiomyopathies (n=17). Results: In Dox-treated mice (but not in vehicle controls), IF significantly reduced survival (18% absolute reduction or AR) ( figure A ), left ventricular ejection fraction (LVEF) (8% AR) ( figure B ) and heart weight index (12% relative reduction) ( figure C ) compared to adlib group. Mechanistically, in Dox-treated mice, IF significantly decreased phosphorylation of mammalian target of rapamycin, increased active, nuclear TFEB content, and increased levels of the atrophy factor muscle RING-finger protein-1. In myocardial tissue from patients with anthracycline cardiomyopathy, we observed a 3.5-fold increase (p<0.01) in nuclear TFEB content compared to both tissues from donors without heart failure and tissues from patients with other non-ischemic cardiomyopathies. Overexpression of TFEB exacerbated Dox-induced cardiotoxicity, including significant decreases in LVEF, left ventricular mass index, and survival. Conclusions: IF exacerbates Dox-related mortality and cardiomyopathy, likely by stimulating the autophagy-lysosomal transcriptional regulator TFEB. Our data raise concerns about the safety of IF and augmentation of TFEB activity in the context of anthracycline chemotherapy.

RationaleSodium-glucose co-transporter inhibitors (SGLT2i) are under active clinical investigation in patients with acute inflammatory conditions, based on their clinical cardio-and nephroprotective effects, and a pre-clinical study that demonstrated SGLT2i improve renal outcomes and survival in a lipopolysaccharide (LPS) model. However, a unified mechanism that explains how SGLT2i could prevent hemodynamic consequences of inflammatory conditions has not been described. Apolipoprotein M (ApoM) is inversely associated with mortality in inflammatory conditions and improves cardiac function in endotoxin-treated mice via sphingosine-1-phosphate (S1P) signaling.ObjectiveTest the hypothesis that pre-treatment with SGLT2i dapagliflozin (Dapa) improves hemodynamics in endotoxin-treated mice via the ApoM/S1P pathway.Methods and ResultsMice with diet-induced obesity were gavaged with vehicle or Dapa for 4 days prior to LPS (10 mg/kg, IP). We found that mice receiving Dapa restored circulating ApoM levels, likely by increasing expression of the multi-ligand protein receptor megalin in the proximal tubules. Dapa attenuated LPS-induced reductions in cardiac dysfunction including reductions in ejection fraction, cardiac index, and coronary sinus area as well as vascular permeability as ascertained by intravital microscopy. Using both ApoM transgenic and knockout mice and S1P receptor inhibitors, we show that the ApoM/S1P pathway is important for the beneficial effects of Dapa in the LPS model.ConclusionsIn the setting of acute inflammation, our data suggest that SGLT2i maintains levels of megalin, leading to preservation of ApoM, which in turn promotes endothelial barrier integrity and improves hemodynamics. Our studies suggest a novel mechanism by which SGLT2i can preserve intravascular volume in the acute inflammatory setting.