# Sex-specific benefits of a combined supplementation of B vitamins, nicotinamide riboside, folate and cobalamin, in a murine model of heart failure

## TL;DR

A B vitamin cocktail improved heart function and energy metabolism in male mice with heart failure, with some benefits also seen in females.

## Contribution

The study shows sex-specific benefits of B vitamins in treating established heart failure in mice.

## Key findings

- 3VitB increased survival and improved heart function in male mice with heart failure.
- Female mice showed improved physical performance and reduced heart cell hypertrophy after 3VitB treatment.
- The vitamin cocktail protected mitochondrial function in both sexes by supporting mitochondrial biogenesis.

## Abstract

Despite a substantial therapeutic arsenal to treat patients affected by heart failure (HF), no treatment specifically targets alterations of cardiac energy metabolism described in HF. Based on the results of previous studies demonstrating the cardiac preventive effects of B vitamins when introduced before inducing cardiac pressure overload in mice, we investigated the efficacy of a diet supplemented with a B vitamin cocktail (B3, B9 and B12 (3VitB)) to restore energy metabolism and improve cardiac function in an animal model of established HF. Four weeks after transverse aortic constriction (TAC) induction, male and female mice were treated with 3VitB. 3VitB increased life expectancy and reduced the TAC-induced alterations of cardiac parameters in males. Although these effects on survival and cardiac function were less clear in females due to their higher resistance to TAC, the 3VitB cocktail was beneficial in females as 8 weeks of treatment improved physical capacities and led to milder cardiomyocyte stress-induced hypertrophy in similar ways to those observed in males. In both sexes, 3VitB protected cardiac mitochondrial oxidative capacities, at least by supporting the process of mitochondrial biogenesis. Interestingly, our results revealed sex-specificities not only in response to cardiac pressure overload but also in response to 3VitB treatment. Overall, this study demonstrated the efficacy of 3VitB to preserved cardiac function and energy metabolism in an established HF model, especially in males that are more sensitive to cardiac pressure overload. This confers credit to vitamin supplementations and to metabolic therapy as new strategies to treat HF.

The online version contains supplementary material available at 10.1186/s13293-025-00764-x.

Alterations of energy metabolism and physical capacities are described in mouse model of established heart failure in males and females.Diet supplemented with nicotinamide riboside, vitamin B12 and B9 improved mitochondrial oxidative capacities and physical performance when introduced at an advance stage of heart failure.Males are more sensitive than females to the B vitamin cocktail treatment.Beneficial effects of these three B vitamins are associated with maintenance of mitochondrial biogenesis in both sexes.

Alterations of energy metabolism and physical capacities are described in mouse model of established heart failure in males and females.

Diet supplemented with nicotinamide riboside, vitamin B12 and B9 improved mitochondrial oxidative capacities and physical performance when introduced at an advance stage of heart failure.

Males are more sensitive than females to the B vitamin cocktail treatment.

Beneficial effects of these three B vitamins are associated with maintenance of mitochondrial biogenesis in both sexes.

The online version contains supplementary material available at 10.1186/s13293-025-00764-x.

Heart failure (HF) is a severe condition in which the heart struggles to pump blood effectively. While many treatments exist, none specifically target the changes in cardiac energy production processes (energy metabolism) that occur in this disease. In the present study, it has been explored whether a diet enriched with a cocktail of B vitamins (nicotinamide riboside (B3), folate (B9) and cobalamin (B12)), called 3VitB, could improve cardiac energy metabolism and function in a mouse model of established HF induced by cardiac pressure overload. Four weeks after cardiac stress induction, mice were treated with 3VitB. In male mice, this vitamin cocktail increased survival rates, improved heart function and physical capacities. Female mice, which naturally resist cardiac stress better, showed less marked improvements in survival and cardiac function, but after several weeks of treatment, they exhibited better physical performance and less harmful heart cell hypertrophy. In both sexes, 3VitB helped protect the heart’s mitochondria, the main energy producers of the cardiac cell, by supporting their renewal and function. The study also found differences between males and females in how their hearts responded to both stress and vitamin treatment. Overall, the findings of this study suggest that 3VitB supplementation helps preserve heart energy metabolism and function in HF, especially in males which are more vulnerable to cardiac stress. This supports the idea that vitamin supplements and metabolic therapies could be promising new approaches to treat HF.

The online version contains supplementary material available at 10.1186/s13293-025-00764-x.