The additive effects of nicotinamide mononucleotide and melatonin on mitochondrial biogenesis and fission/fusion, autophagy, and microRNA-499 in the aged rat heart with reperfusion injury

The prognosis of myocardial ischemia/reperfusion (I/R) injury is poor in elderly patients. Aging increases the susceptibility of the heart to cell death from I/R injury and prevents the optimal effectiveness of cardioprotective modalities. Since the interaction of aging with cardioprotection is multifactorial, combination therapy may overcome the above-mentioned burden through correcting various components of the injury. Here, we explored the effects of nicotinamide mononucleotide (NMN)/melatonin combination therapy on mitochondrial biogenesis and fission/fusion, autophagy, and microRNA-499 in the aged rat heart with reperfusion injury. Ex vivo model of myocardial I/R injury was established by coronary occlusion and re-opening in 30 aged male Wistar rats (400–450 g, 22–24 months old). NMN (100 mg/kg/48 h, intraperitoneally) was administered over 28 days before I/R, and melatonin (50 µM) was added to the perfusion solution at early reperfusion. CK-MB release and expression of mitochondrial biogenesis genes and proteins, mitochondrial fission/fusion proteins, autophagy genes, and microRNA-499 were assessed. NMN/melatonin combination therapy concomitantly decreased CK-MB release in aged reperfused hearts ( P