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Decline of NAD, an essential redox cofactor in cellular metabolism, has been repeatedly observed in cardiometabolic diseases. We have earlier reported NAD decline in diabetic mouse hearts. While NAD precursor supplementation is beneficial in certain preclinical cardiometabolic disease models, we hereby test the alternate approach of whether inhibiting NAD consumption is protective against diabetic cardiomyopathy. SARM1 is a mitochondria-associated intracellular NAD hydrolase that promotes axonal degeneration. However, its role in heart disease has never been reported. We hypothesized that SARM1 deficiency attenuates diabetic cardiomyopathy and aimed to dissect mitochondria-linked molecular mechanisms. Wild-type (WT) and global SARM1-knockout (KO) male mice were injected with streptozotocin (STZ) to induce type 1 diabetes (T1D). 16-week T1D stress caused progressive decline in systolic (fractional shortening) and diastolic function (E'/A') in WT mice. T1D-KO mice had attenuated systolic and diastolic dysfunction, despite similar elevation of fasting glucose and no significant difference in plasma metabolites (243 aqueous and lipid species) compared to T1D-WT mice. T1D-WT hearts showed reduced tissue NAD pool compared to non-diabetic mice (ND-WT). SARM1 deficiency restored the tissue NAD pool in T1D-KO hearts. RNA-seq analysis identified 1948 differentially expressed genes in T1D-WT hearts, compared to ND-WT hearts, and Gene Module Network Analysis showed downregulation of genes from OXPHOS complexes in T1D-WT hearts. Mitochondrial transcription factor Tfam protein was also downregulated in T1D-WT hearts. SARM1 deficiency did not reverse downregulation of OXPHOS genes and Tfam protein in T1D-KO hearts, indicating that SARM1 did not regulate transcription of genes related to mitochondrial biogenesis. Mitochondria of T1D-WT hearts had 50% reduction in ADP-driven respiration, and fragmented and disorganized mitochondria in electron microscopy compared to ND-WT, which were reversed in T1D-KO hearts. However, mitochondrial NAD decline in T1D-WT hearts was not reversed in T1D-KO hearts, indicating other molecular mechanisms for improved mitochondrial function. T1D-WT hearts had increased mitochondrial recruitment of LC3B, which was reversed in T1D-KO hearts. Mitochondrial levels of PINK1 and Rab9, the markers of ubiquitin-mediated and alternative mitophagy respectively, did not change significantly in both T1D-WT and T1D-KO hearts, compared to ND-WT. There was significantly upregulated mRNA and protein expression of BNIP3, involved in receptor-mediated mitophagy, in T1D-WT hearts. SARM1 deficiency reversed the upregulation of BNIP3 mRNA and protein in T1D-KO hearts. In summary, our data suggest that SARM1 mediates cardiac and mitochondrial dysfunction in diabetic cardiomyopathy by promoting excess BNIP3-mediated mitophagy. The molecular mechanisms underlying the regulation of BNIP3-mediated mitophagy by SARM1 and the translational potential of SARM1 inhibition require further investigation. This work has been supported by research funds from NIGMS (1P20GM139763-01, to CFL), NHLBI (1R01HL164854-01A1, to CFL), American Heart Association (17SDG33330003, to CFL), and Oklahoma Center for Adult Stem Cell Research (to CFL); from a recruitment grant and a seed grant of the Presbyterian Health Foundation of Oklahoma (to CFL); and from OMRF Pre-doctoral Scholarship (to KM).
Nizami et al. (Fri,) studied this question.