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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

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Abstract

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 < .001). It also upregulated SIRT1/PGC-1α/Nrf1/TFAM profiles at both gene and protein levels, Mfn2 protein, and microRNA-499 expression, and downregulated Drp1 protein and Beclin1, LC3, and p62 genes (P < .05 to P < .001). The effect of combination therapy was greater than individual ones. Co-application of NMN/melatonin within the setting of I/R injury in the aged rat heart induced noticeable cardioprotection through modulation of a coordinated network including microRNA-499 expression along with mitochondrial biogenesis associated with SIRT1/PGC-1α/Nrf1/TFAM profiles, mitochondrial fission/fusion, and autophagy, therefore, appears to prevent the burden of myocardial I/R injury in elderly patients.

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Data available on request from the corresponding author.

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Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work has been supported by a grant from Molecular Medicine Research Center at Tabriz University of Medical Sciences, Tabriz-Iran (grant number: 59024).

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Authors and Affiliations

  1. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Behnaz Mokhtari

  2. Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Leila Hosseini, Mojgan Rajabi & Reza Badalzadeh

  3. Alavi Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran

    Leila Hosseini & Mojgan Rajabi

  4. Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Reza Badalzadeh

  5. Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark

    Poul Flemming Høilund-Carlsen

  6. Department of Clinical Research, University of Southern Denmark, Odense, Denmark

    Poul Flemming Høilund-Carlsen

  7. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Raheleh Salehinasab

Authors
  1. Behnaz Mokhtari
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  2. Leila Hosseini
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  4. Raheleh Salehinasab
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  5. Mojgan Rajabi
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  6. Reza Badalzadeh
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Contributions

R.B. did the study design and supervised the whole project. B.M. gathered and analyzed the data, contributed in interpretation of the results, and wrote the manuscript. L.H., R.S., and M.R. performed the experimental tests. B.M., R.B., and P.F.C. finalized the manuscript editing and critically revised the manuscript. All gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

Corresponding author

Correspondence to Reza Badalzadeh.

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The authors declare no competing interests.

Ethics approval

All experimental protocols and procedures were approved by the Institutional Animal Ethical Committee at the Faculty of Medicine of Tabriz University of Medical Sciences (Ethics approval number: IR.TBZMED.VCR.REC.1397.064).

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The authors declare no competing interests.

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Mokhtari, B., Hosseini, L., Høilund-Carlsen, P.F. et al. 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. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1701–1711 (2023). https://doi.org/10.1007/s00210-023-02383-y

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