Deletion Of SARM1 NAD Hydrolase Ameliorates Diabetic Cardiomyopathy By Regulating Mitochondrial Metabolism And Mitophagy

Diabetes is a major risk factor of heart disease. Decline of NAD, a redox cofactor in cellmetabolism, is a hallmark of cardiometabolic disease. Here, we test if inhibiting NAD consumptionmay be therapeutic in diabetic cardiomyopathy. SARM1 is an intracellular NAD hydrolase thatpromotes neuronal death. However, its role in diabetic hearts has never been reported. Wehypothesized that SARM1 deficiency attenuates diabetic cardiomyopathy and aimed to determineunderlying molecular mechanisms.C57BL/6N wild-type (WT) and SARM1-knockout (KO) male mice were injected with streptozotocin(STZ) induce type 1 diabetes (T1D). 16-week T1D stress caused progressive systolic (fractionalshortening) and diastolic dysfunction (E’/A’, e/E’) in WT mice. T1D-KO mice had attenuatedsystolic and diastolic dysfunction, despite similar elevation of fasting glucose and no significantdifferences in plasma metabolites (243 aqueous and lipid species) from T1D-WT and T1D-KOmice. T1D-WT hearts had reduced NAD pool compared to non-diabetic (ND-WT), which waselevated by SARM1 deletion. T1D-WT hearts had upregulated cardiomyopathy gene markers(Nppb, Myh7/Myh6 ratio) that were normalized in T1D-KO hearts. Chronic T1D induced cardiacfibrosis and upregulation of profibrotic genes (Ctgf, Inhbb), both of which were attenuated in T1D-KO hearts. RNA-seq analysis identified 1948 differentially expressed genes in T1D-WT hearts,compared to non-diabetic WT hearts. Gene Module Network Analysis identified suppressedmitochondrial processes in T1D-WT hearts. Expressions of a majority of genes from complexes Ito V were lowered in T1D-WT hearts and partially reversed in T1D-KO, suggesting that SARM1promotes mitochondrial dysfunction in diabetic hearts.Mitochondria of T1D-WT hearts had 50% reduction in ADP-driven respiration compared to ND-WT, which was reversed in T1D-KO mitochondria. T1D-WT hearts had elevated expression ofBNIP3 and mitochondrial recruitment of LC3B, which were attenuated in T1D-KO hearts. Insummary, our data suggest that SARM1 regulates mitochondrial metabolism and mitophagy indiabetic hearts. However, underlying pathogenic mechanisms of SARM1 in diabetic heart andtranslational potential of SARM1 inhibition require further investigation.