SARM1 NAD Hydrolase Deficiency Normalizes Fibrosis and Ameliorates Cardiac Dysfunction in Diabetic Hearts.

Decline in cellular NAD levels emerges as a hallmark of diseases such as diabetes and heart failure. Strategies to activate NAD synthesis pathways and replenish NAD levels have shown promises to treat heart disease. However, how NAD consumption mechanisms lead to NAD depletion and disease pathogeneses are less understood. SARM1 is an intracellular NAD hydrolase, and its role in heart disease has never been investigated. We therefore hypothesized that SARM1 deficiency may protect hearts against diabetic cardiomyopathy. Male C57BL/6 wild-type (WT) and SARM1-KO mice were challenged with 16-week diabetic stress initiated by streptozotocin injections (STZ). Longitudinal cardiac function was measured by echocardiography after 8 or 16 weeks of diabetes, and tissue and plasma samples were harvested for biochemical and molecular analyses. Chronic diabetic stress lowered cardiac NAD levels and led to progressive decline in systolic function of WT mice. Diabetic SARM1-KO mice showed improved systolic function and increased cardiac NAD levels, compared to diabetic WT mice. Progressive decline in diastolic function induced by chronic diabetes was also improved by SARM1 deficiency. Heart weights and hyperglycemia were similar in diabetic WT or diabetic SARM1-KO mice. Metabolomic analyses of plasma showed significant changes in 58 out of ~300 aqueous metabolites assessed when comparing non-diabetic WT to diabetic WT plasma, including increased levels of glucose and branched-chain amino acids. However, the 58 metabolites showed no changes in levels when comparing diabetic WT to diabetic SARM1-KO plasma. Similarly, we found that 26 out of 85 lipid species showed significant changes when comparing non-diabetic WT to diabetic WT plasma, and only one of these 26 lipid metabolites showed a significant change between diabetic WT and diabetic SARM1-KO plasma. The data suggest that cardioprotection in SARM1-KO mice was likely due to the reversal of cardiac pathogenic mechanisms but not improved systemic metabolic state. To determine how SARM1 deficiency affects cardiac NAD metabolism, expression of genes in NAD metabolic pathways were assessed. Levels of Bst1 and Cd38 did not change in SARM1-KO hearts, suggesting that SARM1 deficiency did not induce compensatory changes in expression of the other NAD hydrolases. SARM1-KO hearts showed lower expressions in some of the NAD consuming genes (e.g. Sirtuins) and NAD synthesis genes (e.g. Nmnats). Cardiac dysfunction marker, Nppb expression, was induced in diabetic WT hearts, and was reversed by SARM1 deficiency. Cardiac fibrosis and pro-fibrotic genes (e.g. ctgf) were induced in diabetic WT hearts and were suppressed by SARM1 deficiency. Using the total SARM1 KO mice, our data support that SARM1 deficiency normalizes decline in NAD levels and pro-fibrotic pathways to ameliorate diabetic cardiomyopathy. Further experiments are warranted to dissect the cell-type specific roles of SARM1 in diabetic hearts.