scholarly journals β-Adrenergic stimulation does not activate p38 MAP kinase or induce PGC-1α in skeletal muscle

2013 ◽  
Vol 304 (8) ◽  
pp. E844-E852 ◽  
Author(s):  
Sang Hyun Kim ◽  
Meiko Asaka ◽  
Kazuhiko Higashida ◽  
Yumiko Takahashi ◽  
John O. Holloszy ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Camp Response Element Binding ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Adrenergic Stimulation ◽  
Response Element ◽  
Peroxisome Proliferator Activated Receptor ◽  
Brown Adipose

There are reports that the β-adrenergic agonist clenbuterol induces a large increase in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle. This has led to the hypothesis that the increases in PGC-1α and mitochondrial biogenesis induced in muscle by endurance exercise are mediated by catecholamines. In the present study, we evaluated this possibility and found that injecting rats with clenbuterol or norepinephrine induced large increases in PGC-1α and mitochondrial proteins in brown adipose tissue but had no effect on PGC-1α expression or mitochondrial biogenesis in skeletal muscle. In brown adipocytes, the increase in PGC-1α expression induced by β-adrenergic stimulation is mediated by activation of p38 mitogen-activated protein kinase (p38 MAPK), which phosphorylates and activates the cAMP response element binding protein (CREB) family member activating transcription factor 2 (ATF2), which binds to a cyclic AMP response element (CRE) in the PGC-1α promoter and mediates the increase in PGC-1α transcription. Phospho-CREB does not have this effect. Our results show that the reason for the lack of effect of β-adrenergic stimulation on PGC-1α expression in muscle is that catecholamines do not activate p38 or increase ATF2 phosphorylation in muscle.

Mechanisms of calcium-induced mitochondrial biogenesis and GLUT4 synthesis

2007 ◽  
Vol 32 (5) ◽  
pp. 840-845 ◽  
Author(s):  
David C. Wright
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Mitochondrial Biogenesis ◽  
Glucose Transporter ◽  
Mitochondrial Protein ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Adaptive Responses ◽  
Peroxisome Proliferator Activated Receptor ◽  
Skeletal Muscle Insulin Resistance

Regularly performed aerobic exercise leads to increases in skeletal muscle mitochondria and glucose transporter 4 (GLUT4) protein content, resulting in an enhanced capacity to oxidize substrates and improvements in insulin- and contraction-mediated glucose uptake. Although the specific mechanisms governing these adaptive responses have not been fully elucidated, accumulating evidence suggests that the increase in cytosolic Ca2+ that occurs with each wave of sacrolemmal depolarization is a key component of these processes. Treating L6 muscle cells with agents that increase Ca2+ without causing reductions in ~P or the activation of 5′-AMP-activated protein kinase leads to increases in GLUT4 and mitochondrial protein contents. This effect is likely controlled through calcium/calmodulin-dependent protein kinase (CaMK), since KN93, a specific CaMK inhibitor, blocks these adaptive responses. Recent findings provide evidence that the activation of p38 mitogen-activated protein kinase (MAPK) is involved in the pathway through which Ca2+/CaMK mediates mitochondrial and GLUT4 biogenesis. p38 MAPK initiates GLUT4 and mitochondrial biogenesis through the activation      of transcription factors and transcriptional coactivators such as myocyte enhancer factor 2 (MEF2) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). Subsequent increases in the content of these proteins further enhance Ca2+-induced GLUT4 and mitochondrial biogenesis. Since decreases in mitochondrial and GLUT4 contents are associated with skeletal muscle insulin resistance, an understanding of the mechanisms by which these processes can be normalized will aid in the prevention and treatment of type 2 diabetes.

Triiodothyronine induces UCP-1 expression and mitochondrial biogenesis in human adipocytes

2012 ◽  
Vol 302 (2) ◽  
pp. C463-C472 ◽  
Author(s):  
Joo-Young Lee ◽  
Nobuyuki Takahashi ◽  
Midori Yasubuchi ◽  
Young-Il Kim ◽  
Hikari Hashizaki ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Mitochondrial Biogenesis ◽  
Uncoupling Protein ◽  
Human Adipose Tissue ◽  
Energy Utilization ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Brown Adipose

Uncoupling protein (UCP)-1 expressed in brown adipose tissue plays an important role in thermogenesis. Recent data suggest that brown-like adipocytes in white adipose tissue (WAT) and skeletal muscle play a crucial role in the regulation of body weight. Understanding of the mechanism underlying the increase in UCP-1 expression level in these organs should, therefore, provide an approach to managing obesity. The thyroid hormone (TH) has profound effects on mitochondrial biogenesis and promotes the mRNA expression of UCP in skeletal muscle and brown adipose tissue. However, the action of TH on the induction of brown-like adipocytes in WAT has not been elucidated. Thus we investigate whether TH could regulate UCP-1 expression in WAT using multipotent cells isolated from human adipose tissue. In this study, triiodothyronine (T3) treatment induced UCP-1 expression and mitochondrial biogenesis, accompanied by the induction of the CCAAT/enhancer binding protein, peroxisome proliferator-activated receptor-γ coactivator-1α, and nuclear respiratory factor-1 in differentiated human multipotent adipose-derived stem cells. The effects of T3 on UCP-1 induction were dependent on TH receptor-β. Moreover, T3 treatment increased oxygen consumption rate. These findings indicate that T3 is an active modulator, which induces energy utilization in white adipocytes through the regulation of UCP-1 expression and mitochondrial biogenesis. Our findings provide evidence that T3 serves as a bipotential mediator of mitochondrial biogenesis.

scholarly journals Potentiation of liver X receptor transcriptional activity by peroxisome-proliferator-activated receptor gamma co-activator 1alpha

2003 ◽  
Vol 371 (1) ◽  
pp. 89-96 ◽  
Author(s):  
Hannes OBERKOFLER ◽  
Elisabeth SCHRAML ◽  
Franz KREMPLER ◽  
Wolfgang PATSCH
Keyword(s):  
Mutational Analysis ◽  
Liver X Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Brown Adipocyte ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Transcriptional Responses ◽  
Response Element ◽  
Peroxisome Proliferator Activated Receptor ◽  
Co Activation

Peroxisome-proliferator-activated receptor (PPAR) γ co-activator 1α (PGC-1α/PPARGC1) plays an important role in energy metabolism by co-ordinating transcriptional programmes of mitochondrial biogenesis, adaptive thermogenesis and fatty acid β-oxidation. PGC-1α has also been identified to play a role in the intermediary metabolism by co-activating key transcription factors of hepatic gluconeogenesis and glucose uptake in muscles. In the present study, we show that PGC-1α serves as a co-activator for the liver X receptor (LXR) α, known to contribute to the regulation of cellular cholesterol homoeostasis. In transient transfection studies, PGC-1α amplified the LXR-mediated autoregulation of the LXRα promoter in a human brown adipocyte line and in 3T3-L1 cells via an LXR response element described previously. LXR-mediated transactivation via a natural LXR response element from the cholesteryl ester transfer-protein gene promoter was also enhanced by PGC-1α in a ligand-dependent manner. Mutational analysis showed that the LXXLL signature motif (L2) of PGC-1α was essential for co-activation of LXR-mediated transcriptional responses. This motif is located in the vicinity of the binding region for a putative repressor described previously. The repressor sequesters PGC-1α from PPARα and the glucocorticoid receptor, and this repressor did not interfere with PGC-1α-mediated co-activation of LXR-dependent gene transcription. Moreover, inhibition of p38 mitogen-activated protein kinase signalling, shown to abolish the co-activation of PPARα by PGC-1α, had only a moderate inhibitory effect on the co-activation of LXR. These results identify PGC-1α as a bona fide LXR co-activator and implicate distinct interfaces of PGC-1α and/or additional cofactors in the modulation of LXR and PPARα transcriptional activities.

Effect of nitric oxide synthase inhibition on mitochondrial biogenesis in rat skeletal muscle

2007 ◽  
Vol 102 (1) ◽  
pp. 314-320 ◽  
Author(s):  
G. D. Wadley ◽  
G. K. McConell
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Acute Exercise ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exercise Induced ◽  
Edl Muscle ◽  
Oxide Synthase

The purpose of this study was to determine whether nitric oxide synthase (NOS) inhibition decreased basal and exercise-induced skeletal muscle mitochondrial biogenesis. Male Sprague-Dawley rats were assigned to one of four treatment groups: NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME, ingested for 2 days in drinking water, 1 mg/ml) followed by acute exercise, no l-NAME ingestion and acute exercise, rest plus l-NAME, and rest without l-NAME. The exercised rats ran on a treadmill for 53 ± 2 min and were then killed 4 h later. NOS inhibition significantly ( P < 0.05; main effect) decreased basal peroxisome proliferator-activated receptor-γ coactivator 1β (PGC-1β) mRNA levels and tended ( P = 0.08) to decrease mtTFA mRNA levels in the soleus, but not the extensor digitorum longus (EDL) muscle. This coincided with significantly reduced basal levels of cytochrome c oxidase (COX) I and COX IV mRNA, COX IV protein and COX enzyme activity following NOS inhibition in the soleus, but not the EDL muscle. NOS inhibition had no effect on citrate synthase or β-hydroxyacyl CoA dehydrogenase activity, or cytochrome c protein abundance in the soleus or EDL. NOS inhibition did not reduce the exercise-induced increase in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) mRNA in the soleus or EDL. In conclusion, inhibition of NOS appears to decrease some aspects of the mitochondrial respiratory chain in the soleus under basal conditions, but does not attenuate exercise-induced mitochondrial biogenesis in the soleus or in the EDL.

scholarly journals (–)-Epicatechin is associated with increased angiogenic and mitochondrial signalling in the hindlimb of rats selectively bred for innate low running capacity

2013 ◽  
Vol 124 (11) ◽  
pp. 663-674 ◽  
Author(s):  
Maik Hüttemann ◽  
Icksoo Lee ◽  
Guy A. Perkins ◽  
Steven L. Britton ◽  
Lauren G. Koch ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Mitogen Activated Protein Kinase ◽  
Male Rats ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
In Vitro Experiments ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mitogen Activated Protein

Alternative approaches to reduce congenital muscle dysfunction are needed in cases where the ability to exercise is limited. (−)-Epicatechin is found in cocoa and may stimulate capillarity and mitochondrial proliferation in skeletal muscle. A total of 21 male rats bred for LCR (low running capacity) from generation 28 were randomized into three groups: vehicle for 30 days (control); (−)-epicatechin for 30 days; and (−)-epicatechin for 30 days followed by 15 days without (−)-epicatechin. Groups 2 and 3 received 1.0 mg of (−)-epicatechin/kg of body mass twice daily, whereas water was given to the control group. The plantaris muscle was harvested for protein and morphometric analyses. In addition, in vitro experiments were conducted to examine the role of (−)-epicatechin on mitochondrial respiratory kinetics at different incubation periods. Treatment for 30 days with (−)-epicatechin increased capillarity (P<0.001) and was associated with increases in protein expression of VEGF (vascular endothelial growth factor)-A with a concomitant decrease in TSP-1 (thrombospondin-1) and its receptor, which remained after 15 days of (−)-epicatechin cessation. Analyses of the p38 MAPK (mitogen-activated protein kinase) signalling pathway indicated an associated increase in phosphorylation of MKK3/6 (MAPK kinase 3/6) and p38 and increased protein expression of MEF2A (myocyte enhancer factor 2A). In addition, we observed significant increases in protein expression of PGC-1α (peroxisome-proliferator-activated receptor γ co-activator 1α), PGC-1β, Tfam and cristae abundance. Interestingly, these increases associated with (−)-epicatechin treatment remained after 15 days of cessation. Lastly, in vitro experiments indicated that acute exposure of LCR muscle to (−)-epicatechin incubation was not sufficient to increase mitochondrial respiration. The results suggest that increases in skeletal muscle capillarity and mitochondrial biogenesis are associated with 30 days of (−)-epicatechin treatment and sustained for 15 days following cessation of treatment. Clinically, the use of this natural compound may have potential application in populations that experience muscle fatigue and are unable to perform endurance exercise.

scholarly journals Effects of Rhizome Extract of Dioscorea batatas and Its Active Compound, Allantoin, on the Regulation of Myoblast Differentiation and Mitochondrial Biogenesis in C2C12 Myotubes

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 2023 ◽  
Author(s):  
Junnan Ma ◽  
Seok Yong Kang ◽  
Xianglong Meng ◽  
An Na Kang ◽  
Jong Hun Park ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Mitochondrial Biogenesis ◽  
Water Extract ◽  
Sirtuin 1 ◽  
Myoblast Differentiation ◽  
C2c12 Myotubes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dioscorea Batatas

With the aging process, a loss of skeletal muscle mass and dysfunction related to metabolic syndrome is observed in older people. Yams are commonly use in functional foods and medications with various effects. The present study was conducted to investigate the effects of rhizome extract of Dioscorea batatas (Dioscoreae Rhizoma, Chinese yam) and its bioactive compound, allantoin, on myoblast differentiation and mitochondrial biogenesis in skeletal muscle cells. Yams were extracted in water and allantoin was analyzed by high performance liquid chromatography (HPLC). The expression of myosin heavy chain (MyHC) and mitochondrial biogenesis-regulating factors, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), sirtuin-1 (Sirt-1), nuclear respiratory factor-1 (NRF-1) and transcription factor A, mitochondrial (TFAM), and the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) were determined in C2C12 myotubes by reverse transcriptase (RT)-polymerase chain reaction (RT-PCR) or western blot. The glucose levels and total ATP contents were measured by glucose consumption, glucose uptake and ATP assays, respectively. Treatment with yam extract (1 mg/mL) and allantoin (0.2 and 0.5 mM) significantly increased MyHC expression compared with non-treated myotubes. Yam extract and allantoin significantly increased the expression of PGC-1α, Sirt-1, NRF-1 and TFAM, as well as the phosphorylation of AMPK and ACC in C2C12 myotubes. Furthermore, yam extract and allantoin significantly increased glucose uptake levels and ATP contents. Finally, HPLC analysis revealed that the yam water extract contained 1.53% of allantoin. Yam extract and allantoin stimulated myoblast differentiation into myotubes and increased energy production through the upregulation of mitochondrial biogenesis regulators. These findings indicate that yam extract and allantoin can help to prevent skeletal muscle dysfunction through the stimulation of the energy metabolism.

scholarly journals An Increase in Murine Skeletal Muscle Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α (PGC-1α) mRNA in Response to Exercise Is Mediated by β-Adrenergic Receptor Activation

Endocrinology ◽  
2007 ◽  
Vol 148 (7) ◽  
pp. 3441-3448 ◽  
Author(s):  
Shinji Miura ◽  
Kentaro Kawanaka ◽  
Yuko Kai ◽  
Mayumi Tamura ◽  
Masahide Goto ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Adrenergic Receptor ◽  
Ex Vivo ◽  
Specific Inhibitor ◽  
Receptor Activation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Brown Adipose ◽  
Exercise Induced

A single bout of exercise increases expression of peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α mRNA, which may promote mitochondrial biogenesis in skeletal muscle. In brown adipose tissue, cold exposure up-regulates PGC-1α expression via adrenergic receptor (AR) activation. Because exercise also activates the sympathetic nervous system, we examined whether exercise-induced increase in PGC-1α mRNA expression in skeletal muscle was mediated via AR activation. In C57BL/6J mice, injection of the β2-AR agonist clenbuterol, but not α-, β1-, or β3-AR agonists, increased PGC-1α mRNA expression more than 30-fold in skeletal muscle. The clenbuterol-induced increase in PGC-1α mRNA expression in mice was inhibited by pretreatment with the β-AR antagonist propranolol. In ex vivo experiments, direct exposure of rat epitrochlearis to β2-AR agonist, but not α-, β1-, and β3-AR agonist, led to an increase in levels of PGC-1α mRNA. Injection of β2-AR agonist did not increase PGC-1α mRNA expression in β1-, β2-, and β3-AR knockout mice (β-less mice). PGC-1α mRNA in gastrocnemius was increased 3.5-fold in response to running on a treadmill for 45 min. The exercise-induced increase in PGC-1α mRNA was inhibited by approximately 70% by propranolol or the β2-AR-specific inhibitor ICI 118,551. The exercise-induced increase in PGC-1α mRNA in β-less mice was also 36% lower than that in wild-type mice. These data indicate that up-regulation of PGC-1α expression in skeletal muscle by exercise is mediated, at least in part, by β-ARs activation. Among ARs, β2-AR may mediate an increase in PGC-1α by exercise.

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