Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3

Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD+/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD+ precursor, was previously shown to boost NAD+ levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD+ levels are a promising treatment strategy for mitochondrial myopathy.

Metabolic control of muscle and muscle stem cell function

Hongbo Zhang

Skeletal muscle composed of myofibers and a small amount of muscle stem cells (MuSCs). It plays important roles in energy metabolism. Some of the key metabolites, such as NAD+ and acetyl-CoA were recently found to regulate muscle and MuSCs function. Most of these functions are related to the cellular mitochondria. In my PhD thesis projects, we aimed at exploring the link between NAD+ levels, mitochondrial function, muscle structural homeostasis and MuSCs senescence. We also investigated the impact of acetyl-CoA on MuSCs activation and proliferation, through the control of protein acetylation. These projects mainly focus on three aspects: Rejuvenation of adult stem cells by NAD+ repletion. Aging is accompanied by SCs senescence. However, the initial signaling events mediating SCs senescence are still not well defined. We demonstrate the importance of mitochondrial activity as a pivotal modulator of MuSCs senescence. MuSCs from aged mice have reduced NAD+ levels, mitochondrial content and capacity for oxidative respiration. Importantly, the induction of the mitochondrial unfolded protein response (UPRmt), subsequent to increasing cellular NAD+ with the precursor nicotinamide riboside (NR), prevents MuSCs senescence and improves muscle function and regeneration in aged mice. NR also prevents MuSCs dysfunction in the mdx mouse, a known mouse model of accelerated MuSCs senescence. Extending these observations to other SC pools and on the organism as a whole, we demonstrate that NR delays neural and melanocyte SCs senescence, while also increasing mouse lifespan. Control of MuSCs function by acetyltransferase KAT2A. MuSCs are essential for skeletal muscle homeostasis and repair. The complete mechanism controlling MuSCs maintenance and differentiation, however, remains elusive. We found that the acetyltransferase KAT2A expression is essential for myogenic differentiation of MuSCs. KAT2A loss-of-function in cells blocks MuSCs differentiation, and in mice impairs muscle regeneration after damage. The regulation of KAT2A in MuSCs function might rely on its ability to enzymatically acetylate other proteins, and in particular the transcription factor PAX7. NAD+ repletion improves muscle function in muscular dystrophy. Duchenne muscular dystrophy (DMD) is caused by dystrophin gene mutations that lead to progressive muscle degeneration. Our bioinformatics analysis in mice and DMD patients suggests a role for NAD+ in protecting the muscle from metabolic and structural degeneration. Validating these findings, we reveal that the mdx mouse is characterized by reductions in muscle NAD+ levels, concurrent to increased PARP activity and reduced expression of nicotinamide phosphoribosyltransferase (NAMPT), the key enzymes for NAD+ consumption and biosynthesis. Replenishing the NAD+ pool by dietary NR supplementation benefits muscle function in mdx and mdx/Utr-/- mice, an effect replicated in C. elegans models of DMD. The beneficial effects of NAD+ repletion in muscular dystrophy are pleiotropic and rely on the improvement in mitochondrial function, structural protein expression and on reductions in general PARylation, inflammation and fibrosis. In summary, our work demonstrates the critical role of NAD+ and Acetyl-coA in maintaining muscle and MuSCs function. Repletion of NAD+ levels, by NR administration, and/or boosting the function of acetyltransferase KAT2A might be attractive strategies to maintain muscle homeostasis and MuSCs function in aging and muscular dystrophy.

EPFL2016

The activation of hepatic and muscle polyamine catabolism improves glucose homeostasis

Eija Riitta Pirinen

The mitochondrial biogenesis and energy expenditure regulator, PGC-1 alpha, has been previously reported to be induced in the white adipose tissue (WAT) and liver of mice overexpressing spermidine/spermine N (1)-acetyltransferase (SSAT). The activation of PGC-1 alpha in these mouse lines leads to increased number of mitochondria, improved glucose homeostasis, reduced WAT mass and elevated basal metabolic rate. The constant activation of polyamine catabolism produces a futile cycle that greatly reduces the ATP pools and induces 5'-AMP-activated protein kinase (AMPK), which in turn activates PGC-1 alpha in WAT. In this study, we have investigated the effects of activated polyamine catabolism on the glucose and energy metabolisms when targeted to specific tissues. For that we used a mouse line overexpressing SSAT under the endogenous SSAT promoter, an inducible SSAT overexpressing mouse model using the metallothionein I promoter (MT-SSAT), and a mouse model with WAT-specific SSAT overexpression (aP2-SSAT). The results demonstrated that WAT-specific SSAT overexpression was sufficient to increase the number of mitochondria, reduce WAT mass and protect the mice from high-fat diet-induced obesity. However, the improvement in the glucose homeostasis is achieved only when polyamine catabolism is enhanced at the same time in the liver and skeletal muscle. Our results suggest that the tissue-specific targeting of activated polyamine catabolism may reveal new possibilities for the development of drugs boosting mitochondrial metabolism and eventually for treatment of obesity and type 2 diabetes.

2012

Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis

Johan Auwerx, Dongryeol Ryu

Reduced mitochondria! electron transport chain activity promotes longevity and improves energy homeostasis via cell-autonomous and non-autonomous factors in multiple model systems. This mitohormetic effect is thought to involve the mitochondrial unfolded protein response (UPRmt), an adaptive stress-response pathway activated by mitochondria' proteotoxic stress. Using mice with skeletal muscle specific deficiency of Crifl (muscle-specific knockout [MKO]), an integral protein of the large mitoribosomal subunit (39S), we identified growth differentiation factor 15 (GDF15) as a UPRmt-associated cell non-autonomous myomitokine that regulates systemic energy homeostasis. MKO mice were protected against obesity and sensitized to insulin, an effect associated with elevated GDF15 secretion after UPRmt activation. In ob/ob mice, administration of recombinant GDF15 decreased body weight and improved insulin sensitivity, which was attributed to elevated oxidative metabolism and lipid mobilization in the liver, muscle, and adipose tissue. Thus, GDF15 is a potent mitohormetic signal that safeguards against the onset of obesity and insulin resistance.

Rockefeller Univ Press2017

Metabolic control of muscle and muscle stem cell function

Hongbo Zhang

EPFL2016