Nicotinamide Mononucleotide Administration Prevents Doxorubicin-Induced Cardiotoxicity and Loss in Physical Activity in Mice

Abstract

Doxorubicin (Doxo) is a widely used antineoplastic drug with limited clinical application due to its deleterious dose-related side effects. We investigated whether nicotinamide mononucleotide (NMN) could protect against Doxo-induced cardiotoxicity and physical dysfunction in vivo. To assess the short- and long-term toxicity, two Doxo regimens were tested, acute and chronic. In the acute study, C57BL6/J (B6) mice were injected intraperitoneally (i.p.) once with Doxo (20 mg/kg) and NMN (180 mg/kg/day, i.p.) was administered daily for five days before and after the Doxo injection. In the chronic study, B6 mice received a cumulative dose of 20 mg/kg Doxo administered in fractionated doses for five days. NMN (500 mg/kg/day) was supplied in the mice’s drinking water beginning five days before the first injection of Doxo and continuing for 60 days after. We found that NMN significantly increased tissue levels of NAD+ and its metabolites and improved survival and bodyweight loss in both experimental models. In addition, NMN protected against Doxo-induced cardiotoxicity and loss of physical function in acute and chronic studies, respectively. In the heart, NMN prevented Doxo-induced transcriptomic changes related to mitochondrial function, apoptosis, oxidative stress, inflammation and p53, and promyelocytic leukemia nuclear body pathways. Overall, our results suggest that NMN could prevent Doxo-induced toxicity in heart and skeletal muscle.

Generation of a p21 Reporter Mouse and Its Use to Identify and Eliminate p21high Cells In Vivo

“…The use of DOXO in the treatment of various types of cancer has made it one of the most widely used chemotherapeutic agents, but it induces dose-dependent multisystem toxicity, particularly cardiovascular damage [ 27 ]. Transcriptome analysis indicated that cardiotoxicity induced by acute DOXO treatment was associated with dysregulation of the expression of genes associated with the p53 pathway [ 24 , 28 ]. It has been suggested that this may be achieved through cell-cycle arrest.…”

“…However, DOXO exhibits deteriorating effects on healthy tissues. An analysis of the transcriptome indicated that cardiotoxicity induced by acute DOXO treatment was associated with dysregulation of the expression of genes associated with the p53-p21 pathway [ 24 ]. Although models of DOXO-induced cellular senescence have been established in vitro, the association between DOXO-mediated organ toxicity and cellular senescence, particularly p21, has not been precisely described to date.…”

Nicotinamide Mononucleotide Supplementation Alleviates Doxorubicin-Induced Multi-Organ Fibrosis

“…Doxorubicin has been reported to induce multi-organ injury including in the heart, liver and lungs [8]. Substantial evidence indicates that NAD + levels play crucial roles in heart and liver injury [22,24,26,27]. In this study, a multi-organ injury mice model was established by a cumulative 20 mg/kg DOX injection.…”

“…DNA damage caused by ionizing radiation, ultraviolet light or DNA toxic drugs leads to rapid phosphorylation of H2A.X at Ser139 and labeling of damaged DNA regions with the γH2AX protein [35]. DOX causes p53 pathway transcriptomic changes, which can be regulated by NMN [26]. Activation of p53-p21 can result in cell cycle arrest and a DNA damage response [36].…”

“…Thus, supplementing NMN might be more efficient than other NAD + precursors [25]. Although NMN was reported to prevent cardiotoxicity and improve physical activity in mice [26], no studies have focused on its effect on multi-organ injury. Whether multi-organ injury is associated with NAD + levels or can be alleviated by NMN treatment remains unknown.…”