The effect of long term carnitine supplementation on carnitine status and metabolic pathways of mice during aging
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Beschreibung
Aging is a biological characteristic of the individual being associated with several diseases such as type 2 diabetes, hypertension and cancer. The scientific understanding of the aging process is still limited. In the present work, the effect of dietary L-carnitine was investigated in mice during aging. The most prominent function of carnitine (3-hydroxy-4-N,N,Ntrimethylaminobutyrate) is facilitating the import of long-chain fatty acids into the mitochondrial matrix for ß-oxidation of fatty acids. However, carnitine influences also glucose metabolism and insulin sensitivity. Since the carnitine status is impaired in older subjects, it appears plausible that supplementation of carnitine improves metabolism and prevents the development of age-dependent diseases. The aim of the present work was to test the following hypotheses: (1) Carnitine improves the carnitine status of mice during the aging process. (2) The carnitine-induced improvement of carnitine status leads to changes in metabolic and stress signaling pathways in tissues of older mice. To test these hypotheses, eighty male mice obtained from Harlan with an age of three weeks and a mean body weight of 12 g (n = 80) were used. The mice were randomly assigned to two groups (control group, carnitine group) of 40 mice each. The control group received a nutritionally adequate semisynthetic diet with a low native carnitine content of < 1mg/kg diet. The carnitine group received the same diet supplemented with 1,000 mg L-carnitine/kg diet. At an age of 9, 15, 18 und 21 month 10 mice of each group were sacrificed and blood plasma, liver and skeletal muscle taken for the determination of carnitine concentration (free, acetyl) and qPCR and western blot analyses. In addition, genome-wide transcript profiling of skeletal muscle was carried out using microarray analysis. The carnitine status of the mice was improved by carnitine supplementation. Mice of the carnitine group had higher plasma and tissue carnitine concentrations at all time points than mice of the control group (P < 0.05). At 9 month of age, mice of the carnitine group had higher mRNA concentrations of PPARα, CPT-1A und genes involved in β-oxidation (MCAD, SCAD) in the liver than mice of the control group (P < 0.05). At 18 month of age, CPT-1A, genes involved in β-oxidation (LCAD, SCAD) and fatty acid transport (FABP1) in the liver were upregulated in mice of the carnitine group compared to control mice (P < 0.05). In addition, the mRNA concentrations of hepatic genes involved in fatty acid and cholesterol synthesis, such as SREBP-1c, SCD1, NR1H3 and NR1H2, at an age of 9 month and LDLR und NR1H3 at an age of 18 month were increased in mice of the carnitine group compared to those of the control group (P < 0.05). The microarray analysis of skeletal muscle of mice at the age of 18 month revealed that 326 genes were differentially expressed between the carnitine and the control group. Amongst the differentially expressed genes, two apoptotic genes, namely PERP und c-Myc, were identified. To sum up, regular supplementation of L-carnitine in mice improves the carnitine status in older mice. The improvement of carnitine status in older mice is associated with changes in the expression of genes involved in lipid metabolism in the liver and genes involved in apoptosis in skeletal muscle.
Autor*in
Uzman Bashir Cheema