Updating the effects of fatty acids on skeletal muscle
Similarly, exposure of cardiac myocytes to moderately high concentrations of fatty acids activates transcription of the muscle carnitine palmitoyltransferase (m CPT) gene (7).The peroxisome proliferator-activated receptors PPARα and PPARβ/δ (PPARδ) are ligand-activated nuclear receptors that activate transcription of genes encoding FAO enzymes as well as the uncoupling proteins (8–11).In this work, we reevaluated the effects of raising FFA on muscle mitochondrial biogenesis and capacity for fat oxidation.Rats were fed a high-fat diet and given daily injections of heparin to raise FFA.We interpret our results as evidence that raising FFA induces an increase in mitochondrial biogenesis in muscle by activating PPARδ.It has been reported that high-fat diets induce increased expression of mitochondrial fatty acid oxidation (FAO) enzymes in skeletal muscle, and it has been suggested that this adaptation results in an increase in the capacity to oxidize fatty acids (1–6).Both PPARα and PPARδ are expressed in skeletal muscle, with PPARδ being the predominant isoform (12, 13).The PPARs are activated by long-chain fatty acids (14, 15).
Medium-chain acyl-Co A dehydrogenase, long-chain acyl-Co A dehydrogenase, and very long-chain acyl-Co A dehydrogenase were all significantly increased in epitrochlearis muscles of rats in which plasma FFA were raised daily for 4 weeks.
1) and UCP3, which are encoded in PPARδ target genes, suggested that the increase in FFA resulted in activation of PPARδ.
To explore this possibility, we used the Ch IP assay to measure binding of PPARδ to the PPAR response element on the m CPT-1 promoter.
m CPT type 1 (m CPT1) m RNA was also significantly increased in triceps muscles in response to elevation of plasma FFA (Fig. The genes that encode these FAO enzymes are regulated by PPARδ and PPARα (8, 9, 11, 18).
Expression of the uncoupling proteins is also regulated by these nuclear receptors (9, 11, 19), and uncoupling protein 3 (UCP3) expression was increased in muscle of rats in which plasma FFA were raised (chow group 1.0 ± 0.16 vs.
Representative Western blots and average protein values for mitochondrial enzymes used as markers for the citrate cycle [citrate synthase (CS)] and respiratory chain [NADH-ubiquinone oxidoreductase (NUO), succinate-ubiquinone oxidoreductase 70-k Da subunit (SUO), cytochrome c (Cyt c), COXI, COXIV], and ATP synthase subunit α (ATP-syn) in epitrochlearis muscles are shown. ∗, P Increased expression of a range of mitochondrial enzymes in response to raising plasma FFA levels.