Abstract 1618 Sarm1 deficiency protects against diabetic cardiomyopathy: Mechanisms via allevation of lipotoxicity and glucotoxicity

Heart failure occurs at nearly twice the rate in diabetic patients as compared to normal patients. NAD levels are reduced in both human and murine models of heart disease, including those with diabetes. Strategies to raise NAD in these models have primarily focused on increasing NAD synthesis. Alternatively, inhibition of NAD consumption provides another viable path to increasing NAD levels in diabetic hearts. Sterile Alpha and Tir Motif Containing 1 (SARM1) is an NAD hydrolase that mediates axonal degeneration through NAD degradation and promotion of mitochondrial dysfunction. However, the role SARM1 plays in heart disease has not been investigated. We subjected male wild type (WT) and global SARM1 knockout mice (KO) to chronic diabetic stress induced by streptozotocin injections. We showed that 16-week diabetic stress promoted progressive decline in systolic and diastolic function as measured by longitudinal echocardiography. SARM1 deletion (diabetic KO) improved both systolic and diastolic function of diabetic mice, despite similar glucose, and plasma aqueous and lipid metabolite levels as the diabetic wild-type mice. Diabetic KO hearts showed elevated NAD levels, suggesting that SARM1 may be activated to promote NAD decline in diabetic hearts. Transcriptomic analysis identified 1948 differentially expressed genes in diabetic WT hearts, compared to non-diabetic WT hearts. Gene Module Network Analysis identified upregulation of fatty acid metabolic processes and suppression of genes involved in mitochondrial processes in diabetic hearts. SARM1 deficiency reversed the upregulated fatty acid metabolic genes, improved mitochondrial respiration, and elevated NAD levels in diabetic hearts. Transmission electron microscopy of the hearts indicated the diabetic WT had substantial accumulation of lipid droplets. SARM1 deficiency abrogated these lipid abnormalities. In conjunction, we performed Oil Red O staining and found that levels of lipid accumulation were reduced in the diabetic KO hearts. Finally, we measured levels of O-linked N-acetylglucosamine (O-glycNAc) and found that these were elevated in diabetic hearts and reduced by SARM1 deficiency. Altogether, we found that SARM1 may play a role in the lipotoxicity and glucotoxicity seen in diabetic hearts by inducing mitochondrial dysfunction and modifying metabolic transcriptional networks. Future analysis will shed light on how SARM1 contributes to lipotoxicity and glucotoxicity as a new pathogenic mechanism of diabetic cardiomyopathy.