Abstract
Background: Myocardial dysfunction is associated with an imbalance in mitochondrial fusion/fission dynamics in patients with diabetes. However, effective strategies to regulate mitochondrial dynamics in the diabetic heart are still lacking. This study investigated whether Nicotinamide riboside (NR) supplementation protects against diabetes-induced cardiac dysfunction by regulating mitochondrial fusion/fission and further explored the underlying mechanisms.Methods: Obese diabetic (db/db) and lean control (db/+) mice were each given NR oral supplementation in this study. NAD+ Content was determined in mice hearts and primary neonatal cardiomyocytes. Cardiac function was detected by echocardiography. Mitochondrial dynamics were analyzed by transmission electron microscopy in vivo and by confocal microscopy in vitro. Results: Here, we show an evident decrease in NAD+ level and mitochondrial fragmentation in the hearts of leptin receptor-deficient diabetic (db/db) mouse model. NR supplementation significantly increased NAD+ content in the diabetic heart tissues. Furthermore, NR treatment increased Mfn2 expression, promoted mitochondrial fusion, suppressed oxidative stress, reduced cardiomyocyte apoptosis and consequently improved cardiac function in db/db mice. In neonatal primary cardiomyocytes cultured in a high-glucose/high-fat medium, NR treatment also promoted mitochondrial fusion, suppressed mitochondria-derived ROS production and reduced cardiomyocyte apoptosis, which were all reversed when Mfn2 was knocked down. Mechanistically, chromatin immunoprecipitation (ChIP) and luciferase report assay analysis revealed that PGC1α and PPARα interdependently regulated Mfn2 transcription by binding to its promoter region. NR treatment elevated NAD+ levels and activated SIRT1, resulting in the deacetylation of PGC1α and promoting the transcription of Mfn2. Furthermore, the inhibition of SIRT1, PGC1α or PPARα blunted the positive effects of NR supplementation on Mfn2 expression and mitochondrial fusion. Conclusion: NR attenuates the development of diabetes-induced cardiac dysfunction by promoting mitochondrial fusion through the SIRT1-PGC1α-PPARα pathway, with PGC1α and PPARα being the interdependent co-regulatory factors for Mfn2. The promotion of mitochondrial fusion via oral supplementation of NR may be a potential strategy for delaying cardiac complications in patients with diabetes.