ABSTRACT
Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is expressed in skeletal muscles and regulates systemic metabolism. Thus, nutraceuticals targeting skeletal muscle PGC-1α have attracted attention to modulate systemic metabolism. As auraptene contained in citrus fruits promotes lipid metabolism and improves mitochondrial respiration, it could increase mitochondrial function through PGC-1α. Therefore, we hypothesized that PGC-1α is activated by auraptene and investigated its effect using Citrus hassaku extract powder (CHEP) containing >80% of auraptene. C2C12 myotubes were incubated with vehicle or CHEP for 24 h; C57BL/6J mice were fed a control diet or a 0.25% (w/w) CHEP-containing diet for 5 weeks. PGC-1α protein level and mitochondrial content increased following CHEP treatment in cultured myotubes and skeletal muscles. In addition, the number of oxidative fibers increased in CHEP-fed mice. These findings suggest that CHEP-mediated PGC-1α upregulation induced mitochondrial biogenesis and fiber transformation to oxidative fibers. Furthermore, as CHEP increased the expression of the protein sirtuin 3 and of phosphorylated AMP-activated protein kinase (AMPK) and the transcriptional activity of PGC-1α, these molecules might be involved in CHEP-induced effects in skeletal muscles. Collectively, our findings indicate that CHEP mediates PGC-1α expression in skeletal muscles and may serve as a dietary supplement to prevent metabolic disorders.
Subject(s)
Citrus/chemistry , Mitochondria, Muscle/drug effects , Muscle Fibers, Fast-Twitch/drug effects , Muscle, Skeletal/drug effects , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Plant Extracts/pharmacology , Animals , Cell Line , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Mitochondria, Muscle/physiology , Muscle Fibers, Fast-Twitch/metabolism , Muscle, Skeletal/metabolism , Muscle, Skeletal/ultrastructure , Myoblasts , Oxidation-Reduction , Powders , Up-Regulation/drug effectsABSTRACT
Fibrates and statins have been widely used to reduce triglyceride and cholesterol levels, respectively. Besides its lipid-lowering effect, the side effect of muscle atrophy after fibrate administration to humans has been demonstrated in some studies. Combination therapy with fibrates and statins also increases the risk of rhabdomyolysis. FoxO1, a member of the FoxO forkhead type transcription factor family, is markedly upregulated in skeletal muscle in energy-deprived states and induces muscle atrophy via the expression of E3-ubiquitine ligases. In this study, we investigated the changes in FoxO1 and its targets in murine skeletal muscle with fenofibrate treatment. High doses of fenofibrate (greater than 0.5% (wt/wt)) over one week increased the expression of FoxO1 and its targets in the skeletal muscles of mice and decreased skeletal muscle weight. These fenofibrate-induced changes were diminished in the PPARα knockout mice. When the effect of combination treatment with fenofibrate and lovastatin was investigated, a significant increase in FoxO1 protein levels was observed despite the lack of deterioration of muscle atrophy. Collectively, our findings suggest that a high dose of fenofibrate over one week causes skeletal muscle atrophy via enhancement of FoxO1, and combination treatment with fenofibrate and lovastatin may further increase FoxO1 protein level.
Subject(s)
Fenofibrate/adverse effects , Forkhead Box Protein O1/genetics , Forkhead Box Protein O1/metabolism , Gene Expression/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Lovastatin/adverse effects , Muscle, Skeletal/pathology , Muscular Atrophy/chemically induced , Muscular Atrophy/genetics , Animals , Atrophy , Drug Therapy, Combination/adverse effects , Fenofibrate/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Lovastatin/administration & dosage , Male , Mice, Inbred C57BL , Muscle, Skeletal/metabolism , Rhabdomyolysis/chemically induced , Rhabdomyolysis/geneticsABSTRACT
Peroxisome proliferator-activated receptor-gamma coactivator-1ß (PGC-1ß) is a transcriptional regulator whose increased expression activates energy expenditure-related genes in skeletal muscles. However, how PGC-1ß is regulated remains largely unclear. Here, we show that PGC-1ß gene expression is negatively correlated with the expression of a transcription factor, forkhead box protein O1 (FOXO1), whose expression is increased during muscle atrophy. In the skeletal muscles of FOXO1-overexpressing transgenic mice, PGC-1ß gene expression is decreased. Denervation or plaster cast-based unloading, as well as fasting, increases endogenous FOXO1 expression in skeletal muscles, with decreased PGC-1ß expression. In the skeletal muscles of FOXO1-knockout mice, the decrease in PGC-1ß expression caused by fasting was attenuated. Tamoxifen-inducible FOXO1 activation in C2C12 myoblasts causes a marked decrease of PGC-1ß expression. These findings together reveal that FOXO1 activation suppresses PGC-1ß expression. During atrophy with FOXO1 activation, decreased PGC-1ß may decrease energy expenditure and avoid wasting energy.
