Nicotinic acid (NA) is the oldest lipid-lowering drug and has been used for more than five decades in the treatment of atherosclerosis and metabolic disorders. The lipid-lowering mechanism of NA has been extensively investigated and traditionally attributed to its antilipolytic effect on adipocytes through binding with the NA receptor G-protein-coupled receptor 109A (GPR109A). However, the circulating free fatty acid (FFA) level rebound and over-shoot the baseline due to long-term NA treatment even though its lipid-lowering effects persist. Thus, despite a long history of clinical use, to date the precise mechanism by which NA lowers plasma lipid is far from clear. In such a context, in the present thesis it has been hypothesized that NA induces type II to type I muscle fiber transition, thereby increasing the oxidative capacity of overall skeletal muscle, which may be the background mechanism of lipid-lowering properties of NA. It has been already found that NA supplementation counteracts the obesity-induced muscle fiber transition from oxidative type I to glycolytic type II and increases the number of type I fibers in skeletal muscle of obese Zucker rats. These effects were likely mediated by the induction of key regulators of fiber transition, peroxisome proliferator-activated receptor delta (PPARdelta), PPARγ coactivator-1alpha (PGC-1alpha) and PPARgamma coactivator-1beta (PGC-1beta), leading to type II to type I fiber transition and upregulation of genes involved in fatty acid oxidation, mitochondrial oxidative phosphorylation, and angiogenesis. So, the main intention of the present thesis studies was to investigate the hypothesis that, whether NA administration also influences fiber type distribution and thereby the metabolic phenotype of different skeletal muscles in two farm animal species, namely in pig as a model of non-ruminants (study 1) and in sheep as a model of ruminants (study 2). In order to investigate the hypotheses of study 1, twenty five male, 11 weeks old crossbred pigs (Danzucht x Pietrain) with an average body weight of 32.8 ± 1.3 (mean ± SD) kg were randomly allocated to two groups of 12 in control group and 13 pigs in NA group which were fed either a control or a diet supplemented with 750 mg NA/kg diet for 3 weeks. Fiber typing was performed in three different skeletal muscles (M. Longissimus dorsi, LD; M. Quadriceps femoris, QF; M. Gastrocnemius, G) and quantitative polymerase chain reaction (qPCR) was performed in LD muscle only. The percentage numbers of type I fibers in three different skeletal muscles were higher in the NA group and the percentage numbers of type II fibers were lower in the NA group compared to the control group. In line with this, the relative mRNA level of the type I fiber-specific myosin heavy chain, MYH7 gene tended (P < 0.15) to be higher; type II fiber-specific MYH2 and MYH4 genes were reduced or tended (P < 0.15) to be reduced, respectively, in LD muscle in the NA group compared to the control group of pigs. The relative mRNA levels of key regulators of muscle fiber transition, PGC-1beta was increased and PGC-1alpha was numerically increased by NA treatment. Genes involved in mitochondrial fatty acid utilization and thermogenesis [carnitine acylcarnitine translocase, fatty acid transport protein1, novel organic cation transporter 2, succinate dehydrogenase subunit A (SDHA), cytochrome c oxidase 4/1 and 6A1, (COX4/1 and COX6A1) and uncoupling proteins 3] measured in LD muscle were higher in the NA treated pigs compared to control pigs. In order to investigate the hypotheses of study 2, sixteen male, 11 weeks old Rhoen sheep with an average body weight of 29.6 ± 3.0 (mean ± SD) kg were randomly allocated to two groups of 8 sheep each and treated either without (control group) or with 1 g NA per day (NA group) for 4 weeks. After 4 weeks, the percentage numbers of type I fibers in three different skeletal muscles (LD; M. Semimembranosus, SM; M. Semitendinosus, ST) were higher in the NA treated sheep, whereas the percentage numbers of type II fibers were lower in the NA group compared to the control group of sheep. This effect was also reflected by the NA induced increase in the transcript level of fiber type I specific myosin heavy chain I, (MHCI) isoform in SM and ST muscles or tended (P < 0.15) to be increased in LD muscle; the fiber type II specific MHCIIA isoform was lowered in LD and SM muscles; fiber type II specific MHCIIX isoform was lowered in LD and tended (P < 0.15) to be lowered in SM muscle by NA treatment. The relative mRNA levels of the key regulators of muscle fiber transition, PGC-1α, PGC-1β and PPARδ, in all three muscles were higher or tended (P < 0.15) to be higher in the NA treated group compared to the control group sheep. Moreover, the protein level of PGC-1alpha was elevated in two muscles (LD and SM) of the NA group compared to the control group. In line with this, it was observed that the relative mRNA levels of genes involved in fatty acid oxidation and angiogenesis (SDHA, carnitine palmitoyltransferase 1B, solute carrier family 25 member 20, COX5A, COX6A1 and vascular endothelial growth factor A) in all three skeletal muscles of sheep were elevated by NA treatment.In conclusion, the overall finding of the present PhD thesis is that NA causes type II (fast-glycolytic) to type I (slow-oxidative) fiber switch and thereby increases the oxidative capacity in different types of skeletal muscle of pigs and sheep. This increased oxidative skeletal muscle capacity induced by NA might improve the pork quality because the oxidative muscle types tend to develop dark, firm and dry pork in response to intense physical activity and/or high psychological stress levels preslaughter. As well as the increased oxidative capacity of skeletal muscle to utilize fatty acids in ruminants could be particularly useful during metabolic states in which fatty acids are excessively mobilized from adipose tissue, such as in ketosis and/or fatty liver of high yielding dairy cows.
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