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

Abstract

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.

The Possible Protective Role of Ginger Extract Versus Vitamin E Against Simvastatin-Induced Skeletal Myotoxicity in Adult Male Albino Rats: Histological, Physiological and Biochemical Study

“…In the present study, the characteristic presence of abnormal, subsarcolemmal and perinuclear, zonal accumulation of numerous, giant mitochondria, sometimes with destructed cristae is consistent with that of the ragged red fibers indicative of mitochondrial myopathies previously described by many authors [40,41] . In the mitochondrial myopathies, segmental distributions of mtDNA mutations can occur along the length of the muscle fiber [42] , concurrent with a corresponding upregulation of mitochondrial copy number in the mutant areas, presumably as a compensatory response to the mtDNA defect [43] .…”

“…A similar observation has been reported in the mitochondrial myopathic mice on oral supplementation with nicotinamide riboside, with an increase in mitochondrial mass, mtDNA, and respiratory chain protein amounts, indicating active oxidative metabolism that efficiently prevented development and progression of mitochondrial myopathy in mice [41] .…”

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

“…Young POLG mice and mice with increased FGF21 activity exhibit several starvation-like traits, including decreased adiposity and BAT thermogenesis (20,21). Interestingly, although FGF21 is also a well-established marker of mitochondrial disease and dysfunction (22,23), its precise role in mediating mitochondrial stress and metabolic adaptation has yet to be elucidated. To address this problem, we injected adenoviruses containing either a scrambled (shScram) or shorthairpin RNA targeting FGF21 (shFGF21) into 4-mo-old WT and POLG mice after 6 wk of HFD feeding, generating four experimental cohorts.…”

Dietary restriction and Sirtuin 1 in metabolic health: connections and divergences

“…In agreement with the ability of these strategies to increase NAD + availability, all these compounds led to higher SIRT1 activity and ameliorations in glucose homeostasis. In the case of nicotinamide riboside or PARP inhibition, higher energy expenditure, decreased body weight gain upon high-fat feeding and enhanced mitochondrial biogenesis have also been reported (71,72,76,77) . It is interesting that NAD + boosting strategies and STAC both converge at preventing high-fat diet-induced body weight gain, a phenomenon never observed in models of moderate SIRT1 overexpression (49)(50)(51) .…”