Effect of lifelong carnitine supplementation on plasma and tissue carnitine status, hepatic lipid metabolism and stress signalling pathways and skeletal muscle transcriptome in mice at advanced age

Abstract

While strong evidence from clinical studies suggests beneficial effects of carnitine supplementation on metabolic health, serious safety concerns associated with carnitine supplementation have been raised from studies in mice. Considering that the carnitine doses in these mice studies were up to 100 times higher than those used in clinical studies, the present study aimed to address possible safety concerns associated with long-term supplementation of a carnitine dose used in clinical trials. Two groups of NMRI mice were fed either a control or a carnitine-supplemented diet (1 g/kg diet) from weaning to 19 months of age, and parameters of hepatic lipid metabolism and stress signalling and skeletal muscle gene expression were analysed in the mice at 19 months of age. Concentrations of free carnitine and acetylcarnitine in plasma and tissues were higher in the carnitine than in the control group (P<0·05). Plasma concentrations of free carnitine and acetylcarnitine were higher in mice at adult age (10 and 15 months) than at advanced age (19 months) (P<0·05). Hepatic mRNA and protein levels of genes involved in lipid metabolism and stress signalling and hepatic and plasma lipid concentrations did not differ between the carnitine and the control group. Skeletal muscle transcriptome analysis in 19-month-old mice revealed only a moderate regulation between carnitine and control group. Lifelong carnitine supplementation prevents an age-dependent impairment of plasma carnitine status, but safety concerns associated with long-term supplementation of carnitine at doses used in clinical trials can be considered as unfounded.

Levocarnitine does not impair chemotherapy cytotoxicity against acute lymphoblastic leukemia

“…Supplemented mice had significantly higher free carnitine concentrations at time of sacrifice than non-supplemented mice (44.3±5.0 vs. 39.7±4.9 μM, p=0.04). Though a modest difference, other studies supplementing mice with similar doses of LC report variability in the effect on serum/ plasma carnitine levels, ranging between approximately 0.65 to 20 μM higher [32][33][34][35].…”

Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis

“…Both LC and NR effects on plasma metabolic risk factors may be dose dependent. LC with 2000 mg daily for 24 weeks resulted in lower glucose and plasma lipid levels in NASH patients [31] as well as improved insulin sensitivity [32], whereas 19 months treatment with a very low dose of 100 mg/kg LC daily in mice did not reveal any significant effects on plasma lipid levels [33]. Similarly, studies in mice reported lowering effects of 400 mg/kg NR on ALT [27], fasting glucose and an improvement in insulin sensitivity [9,29].…”

Effects and underlying cellular pathway involved in the impairment of the neurovascular unit following exposure of adult male mice to low doses of di(2-ethylhexyl) phthalate alone or in an environmental phthalate mixture

“…The phthalates were first dissolved in absolute ethanol, then incorporated into food as previously detailed (Ahmadpour et al, 2021 studies showing an external co-exposure to these molecules and the presence of their metabolites in urinary samples (Dewalque et al, 2014;Martine et al, 2013). Mice were weighed weekly for the duration of the exposure and phthalate doses were adjusted to their body weights and calculated for a daily food intake of 5 g per animal (Cheema et al, 2019;Dombret et al, 2017). It has already been shown that such a phthalate exposure protocol had no effect on the body weight of individuals between the first and the last day of treatment (Ahmadpour et al, 2021).…”