The data show that nicotinamide riboside, the most energy-efficient among NAD precursors, could be useful for treatment of heart failure, notably in the context of DCM, a disease with few therapeutic options.
Dilated cardiomyopathy (DCM) is a disease of multifactorial etiologies, the risk of which is increased by male sex and age. There are few therapeutic options for patients with DCM who would benefit from identification of common targetable pathways. We used bioinformatics to identify the Nmrk2 gene involved in nicotinamide adenine dinucleotde (NAD) coenzyme biosynthesis as activated in different mouse models and in hearts of human patients with DCM while the Nampt gene controlling a parallel pathway is repressed. A short NMRK2 protein isoform is also known as muscle integrin binding protein (MIBP) binding the α7β1 integrin complex. We investigated the cardiac phenotype of Nmrk2-KO mice to establish its role in cardiac remodeling and function. Young Nmrk2-KO mice developed an eccentric type of cardiac hypertrophy in response to pressure overload rather than the concentric hypertrophy observed in controls. Nmrk2-KO mice developed a progressive DCM-like phenotype with aging, associating eccentric remodeling of the left ventricle and a decline in ejection fraction and showed a reduction in myocardial NAD levels at 24 months. In agreement with involvement of NMRK2 in integrin signaling, we observed a defect in laminin deposition in the basal lamina of cardiomyocytes leading to increased fibrosis at middle age. The α7 integrin was repressed at both transcript and protein level at 24 months. Nmrk2 gene is required to preserve cardiac structure and function, and becomes an important component of the NAD biosynthetic pathways during aging. Molecular characterization of compounds modulating this pathway may have therapeutic potential.
Background: Skeletal muscle aging is marked by the development of a sarcopenic phenotype, a global decline of muscle energetic capacities, and an intolerance to exercise. Among the metabolic disorders involved in this syndrome, NAD metabolism was shown to be altered in skeletalmuscle, with an important role for the NAMPT enzyme recycling the nicotinamide precursor. An alternative pathway for NAD biosynthesis has been described for the nicotinamide riboside vitamin B3 precursor used by the NMRK kinases, including the striated muscle-specific NMRK2.Aim: With this study, our goal is to explore the ability of 16-month-old Nmrk2−/− mice to perform endurance exercise and study the consequences on muscle adaptation to exercise.Methods: 10 control and 6 Nmrk2−/− mice were used and randomly assigned to sedentary and treadmill endurance training groups. After 9 weeks of training, heart and skeletal muscle samples were harvested and used for gene expression analysis, NAD levels measurements and immunohistochemistry staining.Results: Endurance training triggered a reduction in the expression of Cpt1b and AcadL genes involved in fatty acid catabolism in the heart of Nmrk2−/− mice, not in control mice. NAD levels were not altered in heart or skeletal muscle, nor at baseline neither after exercise training in any group. Myh7 gene encoding for the slow MHC-I was more strongly induced by exercise in Nmrk2−/− mice than in controls. Moreover, IL-15 expression levels is higher in Nmrk2−/− mice skeletal muscle at baseline compared to controls. No fiber type switch was observed in plantaris after exercise, but fast fibers diameter was reduced in aged control mice, not in Nmrk2−/− mice. No fiber type switch or diameter modification was observed in soleus muscle.Conclusion: In this study, we demonstrated for the first time a phenotype in old Nmrk2−/− mice in response to endurance exercise training. Although NMRK2 seems to be predominantly dispensable to maintain global NAD levels in heart and skeletal muscle, we demonstrated a maladaptive metabolic response to exercise in cardiac and skeletal muscle, showing that NMRK2 has a specific and restricted role in NAD signaling compared to the NAMPT pathway.
Objective: Despite the indubitable beneficial effect of exercise to prevent of cardiovascular diseases, there is still a lack of studies investigating the impact of exercise in non-ischemic dilated cardiomyopathy. Here, we investigated the impact of voluntary exercise on cardiac function in a mouse model of non-ischemic dilated cardiomyopathy (αMHC-MerCreMer:Sf/Sf), induced by cardiac-specific inactivation of the Serum Response Factor.Materials and Methods: Seven days after tamoxifen injection, 20 αMHC-MerCreMer:Sf/Sf mice were assigned to sedentary (n = 8) and exercise (n = 12) groups. Seven additional αMHC-MerCreMer:Sf/Sf mice without tamoxifen injection were used as control. The exercise group performed 4 weeks of voluntary running on wheel (1.8 ± 0.12 km/day). Cardiac function, myocardial fibrosis, and mitochondrial energetic pathways were then blindly assessed.Results: Exercised mice exhibited a smaller decrease of left ventricular (LV) fractional shortening and ejection fraction compared to control mice. This was associated with a lower degree of LV remodeling in exercised mice, as shown by a lower LV end-systolic intrerventricular septal and posterior wall thickness decrease from baseline values compared to sedentary mice. Moreover, exercised mice displayed a reduced gene expression of atrial and brain natriuretic factors. These benefits were associated by a reduced level of myocardial fibrosis. In addition, exercised mice exhibited a higher mitochondrial aconitase, voltage-dependent anion-selective channel 1 and PPAR gamma coactivators-1 alpha proteins levels suggesting that the increase of mitochondrial biogenesis and/or metabolism slowed the progression of dilated cardiomyopathy in exercised animals.Conclusions: In conclusion, our results support the role of voluntary exercise to improve outcomes in non-ischemic dilated heart failure (HF) and also support its potential for a routine clinical use in the future.
Background NAD is a major coenzyme in energy metabolism and a substrate for SIRT1 and PARP1 enzymes involved in the response to energy and oxidative stress. We have shown the beneficial effects of nicotinamide riboside (NR), a new type of vitamin B3, on cardiac function and remodelling in a mouse model of dilated cardiomyopathy (DCM) triggered by deletion of the SRF transcription factor in the heart (Srf-HKO) (1). This functional improvement correlated with protection of NAD metabolism and a robust increase in cardiac expression of the Nicotinamide Riboside Kinase 2 (NMRK2) that phosphorylates NR to generate nicotinamide mononucleotide (NMN), an immediate precursor of NAD. Purpose We aim to understand the role of the NMRK2-mediated NAD biosynthetic pathway in the heart at baseline and in the DCM context. Methods We generated Nmrk2-KO mice that we bred with Srf-HKO to generate double KO mice (db-KO). We analysed cardiac function and remodelling by echocardiography and quantified myocardial NAD levels at baseline and following NR supplementation in food. Results Nmrk2KO mice developed a progressive eccentric remodelling of LV and decline in EF with aging. At 24-mo, we observed a reduction of myocardial NAD levels (−40% compared to wild type, p<0.05) and of LVEF (61%, SD 6.3% in Nmrk2-KO vs 78%, SD 1.5% in WT, p<0.05). To assess the contribution of cardiac Nmrk2 induction to NR response in DCM, we compared SrfH-KO and db-KO mice fed with control diet (CD) or NR supplemented diet for 40 days starting at young age (2-mo). NR reduced the extent of LV eccentric remodelling and drop in EF as well as the thinning of the LV posterior wall in both genotypes (2-way ANOVA, diet effect, p<0.01). Myocardial NAD levels were more reduced in db-KO mice under CD diet (−22% compared to control mice, p<0.05) than in Srf-HKO mice (−11%, non-significant), when we previously showed a 25% drop in myocardial NAD in aged SrfHKO mice (1). NR partially preserved cardiac NAD pool in db-KOmice (−10% compared to controls, non-significant). Parallel pathways for NMN synthesis were studied. Nampt gene expression was significantly repressed in db-KO mice fed with CD or NR diet compared to control mice (−50% in average, p<0.01), when there was only a trend toward lower expression in SrfHKO mice (−40% in average, p>0.05). Nmrk1 gene expression trended to increase in all groups compared to wild-type control mice. Conclusion We show that NMRK2 pathway plays a role in the maintenance of basal cardiac function and NAD levels when relying on the endogenous myocardial NR pool. In contrast, the beneficial effect of a therapeutic dose of NR is not affected by the lack of NMRK2 suggesting compensation by NMRK1 in the heart and/or that NR beneficial effects on cardiac function could be mediated through its action on systemic metabolism. Aging appears as an aggravating factor for the loss of myocardial NAD coenzyme in DCM. Acknowledgement/Funding Agence Nationale pour la Recherche, Fondation de France
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