scholarly journals Exercise, PGC-1α, and metabolic adaptation in skeletal muscleThis paper article is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 424-427 ◽  
Author(s):  
Zhen Yan
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Peer Review Process ◽  
Mitogen Activated Protein Kinase ◽  
Metabolic Adaptation ◽  
Peroxisome Proliferator ◽  
Muscle Adaptation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exercise Induced

Endurance exercise promotes skeletal muscle adaptation, and exercise-induced peroxisome proliferator-activated receptor γ coactivator-1α (Pgc-1α) gene expression may play a pivotal role in the adaptive processes. Recent applications of mouse genetic models and in vivo imaging in exercise studies have started to delineate the signaling-transcription pathways that are involved in the regulation of the Pgc-1α gene. These studies revealed the importance of p38 mitogen-activated protein kinase/activating transcription factor 2 and protein kinase D/histone deacetylase 5 signaling transcription axes in exercise-induced Pgc-1α transcription and metabolic adaptation in skeletal muscle. The signaling-transcription network that is responsible for exercise-induced skeletal muscle adaption remains to be fully elucidated.

scholarly journals FoxO6 and PGC-1α form a regulatory loop in myogenic cells

2013 ◽  
Vol 33 (3) ◽  
Author(s):  
Shih Ying Chung ◽  
Wei Chieh Huang ◽  
Ching Wen Su ◽  
Kuan Wei Lee ◽  
Hsiang Cheng Chi ◽  
...  
Keyword(s):  
Myogenic Differentiation ◽  
Metabolic Adaptation ◽  
Peroxisome Proliferator ◽  
Type I ◽  
Peroxisome Proliferator Activated Receptor ◽  
Expression Levels ◽  
Wide Range ◽  
Exercise Induced ◽  
Regulatory Loop

Transcription factors of the FoxO (forkhead box O) family regulate a wide range of cellular physiological processes, including metabolic adaptation and myogenic differentiation. The transcriptional activity of most FoxO members is inhibitory to myogenic differentiation and overexpression of FoxO1 inhibits the development of oxidative type I fibres in vivo. In this study, we found that FoxO6, the last discovered FoxO family member, is expressed ubiquitously in various tissues but with higher expression levels in oxidative tissues, such as brain and oxidative muscles. Both the expression level and promoter activity of FoxO6 were found to be enhanced by PGC-1α (peroxisome-proliferator-activated receptor γ co-activator 1α), thus explained its enriched expression in oxidative tissues. We further demonstrated that FoxO6 represses the expression of PGC-1α via direct binding to an upstream A/T-rich element (AAGATATCAAAACA,−2228–2215) in the PGC-1α promoter. Oxidative low-intensity exercise induced PGC-1α but reduced FoxO6 expression levels in hind leg muscles, and the binding of FoxO6 to PGC-1α promoter was also prevented by exercise. As FoxO6 promoter can be co-activated by PGC-1α and its promoter in turn can be repressed by FoxO6, it suggests that FoxO6 and PGC-1α form a regulatory loop for setting oxidative metabolism level in the skeletal muscle, which can be entrained by exercise.

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.

scholarly journals Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo

2004 ◽  
Vol 377 (2) ◽  
pp. 339-346 ◽  
Author(s):  
Guoqiang JIANG ◽  
Qing DALLAS-YANG ◽  
Subarna BISWAS ◽  
Zhihua LI ◽  
Bei B. ZHANG
Keyword(s):  
Insulin Sensitivity ◽  
Protein Kinase ◽  
Insulin Signalling ◽  
Serine Phosphorylation ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Obese Rats ◽  
Mitogen Activated Protein

Peroxisome-proliferator-activated receptor γ agonists such as rosiglitazone, a thiazolidinedione, improve insulin sensitivity in vivo, but the underlying mechanism(s) remains unclear. Phosphorylation of IRS1 (insulin receptor substrate protein 1) on certain serine residues, including S307 and S612 in rodent IRS1 (equivalent to S312 and S616 in human IRS1), has been shown to play a negative role in insulin signalling. In the present study, we investigated whether rosiglitazone improves insulin sensitivity by decreasing IRS1 inhibitory serine phosphorylation. In HEK-293 (human embryonic kidney 293) cells stably expressing recombinant IRS1 and in 3T3L1 adipocytes, rosiglitazone attenuated PMA-induced IRS1 S307/S612 phosphorylation and decreased insulin-stimulated Akt phosphorylation. We observed increased IRS1 S307 phosphorylation and concomitant decrease in insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation, and Akt threonine phosphorylation in adipose tissues of Zucker obese rats compared with lean control rats. Treatment with rosiglitazone at 30 mg/kg body weight for 24 and 48 h increased insulin signalling and decreased IRS1 S307 phosphorylation concomitantly. Whereas the 48 h treatment reversed hyper-phosphorylation (and activation) of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, the 24 h treatments only decreased hyper-phosphorylation of p38 mitogen-activated protein kinase. The treatment of the Zucker obese rats with rosiglitazone also reversed the high circulating levels of non-esterified fatty acids, which have been shown to be correlated with increased IRS1 serine phosphorylation in other animal models. Taken together, these results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal contributes to the insulin sensitizing effects by rosiglitazone.

scholarly journals Exercise-induced mitogen-activated protein kinase signalling in skeletal muscle

2004 ◽  
Vol 63 (2) ◽  
pp. 227-232 ◽  
Author(s):  
Yun Chau Long ◽  
Ulrika Widegren ◽  
Juleen R. Zierath
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Muscle Contraction ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Cascades ◽  
Extracellular Signal ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Exercise Induced ◽  
Response To Exercise

Exercise training improves glucose homeostasis through enhanced insulin sensitivity in skeletal muscle. Muscle contraction through physical exercise is a physiological stimulus that elicits multiple biochemical and biophysical responses and therefore requires an appropriate control network. Mitogen-activated protein kinase (MAPK) signalling pathways constitute a network of phosphorylation cascades that link cellular stress to changes in transcriptional activity. MAPK cascades are divided into four major subfamilies, including extracellular signal-regulated kinases 1 and 2, p38 MAPK, c-Jun NH2-terminal kinase and extracellular signal-regulated kinase 5. The present review will present the current understanding of parallel MAPK signalling in human skeletal muscle in response to exercise and muscle contraction, with an emphasis on identifying potential signalling mechanisms responsible for changes in gene expression.

scholarly journals Protein Kinase A/CREB Signaling Prevents Adriamycin-Induced Podocyte Apoptosis via Upregulation of Mitochondrial Respiratory Chain Complexes

2017 ◽  
Vol 38 (1) ◽  
Author(s):  
Kewei Xie ◽  
Mingli Zhu ◽  
Peng Xiang ◽  
Xiaohuan Chen ◽  
Ayijiaken Kasimumali ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Respiratory Chain ◽  
Mitochondrial Respiratory Chain ◽  
Peroxisome Proliferator ◽  
Respiratory Chain Complexes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Kinase A ◽  
Mitochondrial Respiratory

ABSTRACT Previous work showed that the activation of protein kinase A (PKA) signaling promoted mitochondrial fusion and prevented podocyte apoptosis. The cAMP response element binding protein (CREB) is the main downstream transcription factor of PKA signaling. Here we show that the PKA agonist 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate–cyclic AMP (pCPT-cAMP) prevented the production of adriamycin (ADR)-induced reactive oxygen species and apoptosis in podocytes, which were inhibited by CREB RNA interference (RNAi). The activation of PKA enhanced mitochondrial function and prevented the ADR-induced decrease of mitochondrial respiratory chain complex I subunits, NADH-ubiquinone oxidoreductase complex (ND) 1/3/4 genes, and protein expression. Inhibition of CREB expression alleviated pCPT-cAMP-induced ND3, but not the recovery of ND1/4 protein, in ADR-treated podocytes. In addition, CREB RNAi blocked the pCPT-cAMP-induced increase in ATP and the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1-α). The chromatin immunoprecipitation assay showed enrichment of CREB on PGC1-α and ND3 promoters, suggesting that these promoters are CREB targets. In vivo, both an endogenous cAMP activator (isoproterenol) and pCPT-cAMP decreased the albumin/creatinine ratio in mice with ADR nephropathy, reduced glomerular oxidative stress, and retained Wilm's tumor suppressor gene 1 (WT-1)-positive cells in glomeruli. We conclude that the upregulation of mitochondrial respiratory chain proteins played a partial role in the protection of PKA/CREB signaling.

scholarly journals Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle

2015 ◽  
Vol 308 (9) ◽  
pp. C710-C719 ◽  
Author(s):  
Anna Vainshtein ◽  
Liam D. Tryon ◽  
Marion Pauly ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Acute Exercise ◽  
Transmembrane Protein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lipid Trafficking ◽  
Mitochondrial Transcription Factor ◽  
Energy Demands ◽  
Niemann Pick ◽  
Exercise Induced

Regular exercise leads to systemic metabolic benefits, which require remodeling of energy resources in skeletal muscle. During acute exercise, the increase in energy demands initiate mitochondrial biogenesis, orchestrated by the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Much less is known about the degradation of mitochondria following exercise, although new evidence implicates a cellular recycling mechanism, autophagy/mitophagy, in exercise-induced adaptations. How mitophagy is activated and what role PGC-1α plays in this process during exercise have yet to be evaluated. Thus we investigated autophagy/mitophagy in muscle immediately following an acute bout of exercise or 90 min following exercise in wild-type (WT) and PGC-1α knockout (KO) animals. Deletion of PGC-1α resulted in a 40% decrease in mitochondrial content, as well as a 25% decline in running performance, which was accompanied by severe acidosis in KO animals, indicating metabolic distress. Exercise induced significant increases in gene transcripts of various mitochondrial (e.g., cytochrome oxidase subunit IV and mitochondrial transcription factor A) and autophagy-related (e.g., p62 and light chain 3) genes in WT, but not KO, animals. Exercise also resulted in enhanced targeting of mitochondria for mitophagy, as well as increased autophagy and mitophagy flux, in WT animals. This effect was attenuated in the absence of PGC-1α. We also identified Niemann-Pick C1, a transmembrane protein involved in lysosomal lipid trafficking, as a target of PGC-1α that is induced with exercise. These results suggest that mitochondrial turnover is increased following exercise and that this effect is at least in part coordinated by PGC-1α. Anna Vainshtein received the AJP-Cell 2015 Paper of the Year award. Listen to a podcast with Anna Vainshtein and coauthor David A. Hood at http://ajpcell.podbean.com/e/ajp-cell-paper-of-the-year-2015-award-podcast/ .

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