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1.  Peroxisome proliferator–activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis 
Journal of Clinical Investigation  2000;106(7):847-856.
Cardiac mitochondrial function is altered in a variety of inherited and acquired cardiovascular diseases. Recent studies have identified the transcriptional coactivator peroxisome proliferator–activated receptor γ coactivator-1 (PGC-1) as a regulator of mitochondrial function in tissues specialized for thermogenesis, such as brown adipose. We sought to determine whether PGC-1 controlled mitochondrial biogenesis and energy-producing capacity in the heart, a tissue specialized for high-capacity ATP production. We found that PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions known to increase cardiac mitochondrial energy production. Forced expression of PGC-1 in cardiac myocytes in culture induced the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy-transduction/energy-production pathways, increased cellular mitochondrial number, and stimulated coupled respiration. Cardiac-specific overexpression of PGC-1 in transgenic mice resulted in uncontrolled mitochondrial proliferation in cardiac myocytes leading to loss of sarcomeric structure and a dilated cardiomyopathy. These results identify PGC-1 as a critical regulatory molecule in the control of cardiac mitochondrial number and function in response to energy demands.
PMCID: PMC517815  PMID: 11018072
2.  PGC-1α Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic Steatosis 
PLoS Biology  2005;3(4):e101.
The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was targeted in mice. PGC-1α null (PGC-1α−/−) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1α−/− mice. With age, the PGC-1α−/− mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1α−/− mice, leading to reduced muscle performance and exercise capacity. PGC-1α−/− mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1α−/− mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1α−/− mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1α−/− mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1α−/− mice. These results demonstrate that PGC-1α is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.
Eliminating the activity of the gene PGC-1 α in mice reveals its role in post-natal metabolism and provides a link to obesity and some intriguing differences with another report of this knockout
doi:10.1371/journal.pbio.0030101
PMCID: PMC1064854  PMID: 15760270
3.  Transcriptional Control of Cardiac Fuel Metabolism and Mitochondrial Function 
As a persistent pump, the mammalian heart demands a high-capacity mitochondrial system. Significant progress has been made in delineating the gene regulatory networks that control mitochondrial biogenesis and function in striated muscle. The PPARγ coactivator-1 (PGC-1) coactivators serve as inducible boosters of downstream transcription factors that control the expression of genes involved in mitochondrial energy transduction, ATP synthesis, and biogenesis. PGC-1 gain-of-function and loss-of-function studies targeting two PGC-1 family members, PGC-1α and PGC-1β, have provided solid evidence that these factors are both necessary and sufficient for perinatal mitochondrial biogenesis and maintenance of high-capacity mitochondrial function in postnatal heart. In humans, during the development of heart failure owing to hypertension or obesity-related diabetes, the activity of the PGC-1 coactivators, and several downstream target transcription factors, is altered. Gene targeting studies in mice have demonstrated that loss of PGC-1α and PGC-1β in heart leads to heart failure. Interestingly, the pattern of dysregulation within the PGC-1 transcriptional regulatory circuit distinguishes the heart disease caused by hypertension from that caused by diabetes. This transcriptional regulatory cascade and downstream metabolic pathways should be considered as targets for novel etiology-specific therapeutics aimed at the early stages of heart failure.
doi:10.1101/sqb.2011.76.011965
PMCID: PMC3340448  PMID: 22096028
4.  Rosiglitazone-Induced Mitochondrial Biogenesis in White Adipose Tissue Is Independent of Peroxisome Proliferator-Activated Receptor γ Coactivator-1α 
PLoS ONE  2011;6(11):e26989.
Background
Thiazolidinediones, a family of insulin-sensitizing drugs commonly used to treat type 2 diabetes, are thought to exert their effects in part by promoting mitochondrial biogenesis in white adipose tissue through the transcriptional coactivator PGC-1α (Peroxisome Proliferator-Activated Receptor γ Coactivator-1α).
Methodology/Principal Findings
To assess the role of PGC-1α in the control of rosiglitazone-induced mitochondrial biogenesis, we have generated a mouse model that lacks expression of PGC-1α specifically in adipose tissues (PGC-1α-FAT-KO mice). We found that expression of genes encoding for mitochondrial proteins involved in oxidative phosphorylation, tricarboxylic acid cycle or fatty acid oxidation, was similar in white adipose tissue of wild type and PGC-1α-FAT-KO mice. Furthermore, the absence of PGC-1α did not prevent the positive effect of rosiglitazone on mitochondrial gene expression or biogenesis, but it precluded the induction by rosiglitazone of UCP1 and other brown fat-specific genes in white adipose tissue. Consistent with the in vivo findings, basal and rosiglitazone-induced mitochondrial gene expression in 3T3-L1 adipocytes was unaffected by the knockdown of PGC-1α but it was impaired when PGC-1β expression was knockdown by the use of specific siRNA.
Conclusions/Significance
These results indicate that in white adipose tissue PGC-1α is dispensable for basal and rosiglitazone-induced mitochondrial biogenesis but required for the rosiglitazone-induced expression of UCP1 and other brown adipocyte-specific markers. Our study suggests that PGC-1α is important for the appearance of brown adipocytes in white adipose tissue. Our findings also provide evidence that PGC-1β and not PGC-1α regulates basal and rosiglitazone-induced mitochondrial gene expression in white adipocytes.
doi:10.1371/journal.pone.0026989
PMCID: PMC3210129  PMID: 22087241
5.  Ablation of PGC-1β Results in Defective Mitochondrial Activity, Thermogenesis, Hepatic Function, and Cardiac Performance 
PLoS Biology  2006;4(11):e369.
The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) has been implicated in important metabolic processes. A mouse lacking PGC-1β (PGC1βKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1βKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1β ablation was partially compensated by up-regulation of PGC-1α in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1βKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1β was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1βKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1βKO mice have impaired mitochondrial function. Lack of PGC-1β also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1β plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress.
The authors conduct an in-depth analysis of a PGC-1β knockout mouse; these animals posses specific defects in basal mitochondrial function and adaptation to metabolic stress.
doi:10.1371/journal.pbio.0040369
PMCID: PMC1634886  PMID: 17090215
6.  MITOCHONDRIAL BIOGENESIS AND HEALTHY AGING 
Experimental gerontology  2008;43(9):813-819.
Aging is associated with an overall loss of function at the level of the whole organism that has origins in cellular deterioration. Most cellular components, including mitochondria, require continuous recycling and regeneration throughout the lifespan. Mitochondria are particularly susceptive to damage over time as they are the major bioenergetic machinery and source of oxidative stress in cells. Effective control of mitochondrial biogenesis and turnover, therefore, becomes critical for the maintenance of energy production, the prevention of endogenous oxidative stress and the promotion of healthy aging. Multiple endogenous and exogenous factors regulate mitochondrial biogenesis through the peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). Activators of PGC-1α include nitric oxide, CREB and AMPK. Calorie restriction (CR) and resveratrol, a proposed CR mimetic, also increase mitochondrial biogenesis through activation of PGC-1α. Moderate exercise also mimics CR by inducing mitochondrial biogenesis. Negative regulators of PGC-1α such as RIP140 and 160MBP suppress mitochondrial biogenesis. Another mechanism involved in mitochondrial maintenance is mitochondrial fission/fusion and this process also involves an increasing number of regulatory proteins. Dysfunction of either biogenesis or fission/fusion of mitochondria is associated with diseases of the neuromuscular system and aging, and a greater understanding of the regulation of these processes should help us to ultimately control the aging process.
doi:10.1016/j.exger.2008.06.014
PMCID: PMC2562606  PMID: 18662766
7.  Regulation of PPARγ Coactivator-1α Function and Expression in Muscle: Effect of Exercise 
PPAR Research  2010;2010:937123.
PPARγ coactivator-1α (PGC-1α) is considered to be a major regulator of mitochondrial biogenesis. Though first discovered in brown adipose tissue, this coactivator has emerged as a coordinator of mitochondrial biogenesis in skeletal muscle via enhanced transcription of many nuclear genes encoding mitochondrial proteins. Stimuli such as exercise provoke the activation of signalling cascades that lead to the induction of PGC-1α. Posttranslational modifications also regulate the function of PGC-1α, with a multitude of upstream molecules targeting the protein to modify its activity and/or expression. Previous research has established a positive correlation between resistance to fatigue and skeletal muscle mitochondrial content. Recently, studies have begun to elucidate the specific role of PGC-1α in exercise-related skeletal muscle adaptations, with several studies identifying it as a dominant regulator of organelle synthesis. This paper will highlight the function, regulation, and expression of PGC-1α, as well as the role of the coactivator during exercise adaptations.
doi:10.1155/2010/937123
PMCID: PMC2933917  PMID: 20847946
8.  Activation of Nuclear Receptor Coactivator PGC-1α by Arginine Methylation 
Genes & development  2005;19(12):1466-1473.
Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a tissue-specific and inducible transcriptional coactivator for several nuclear receptors, plays a key role in energy metabolism. We report here that PGC-1α coactivator activity is potentiated by arginine methylation by protein arginine methyltransferase 1 (PRMT1), another nuclear receptor coactivator. Mutation of three substrate arginines in the C-terminal region of PGC-1α abolished the cooperative coactivator function of PGC-1α and PRMT1, and compromised the ability of PGC-1α to induce endogenous target genes. Finally, endogenous PRMT1 contributes to PGC-1α coactivator activity, and to the induction of genes important for mitochondrial biogenesis.
doi:10.1101/gad.1295005
PMCID: PMC1151663  PMID: 15964996
arginine methylation; coactivator; mitochondrial biogenesis; nuclear receptor; transcription
9.  PGC-1α-Mediated Branched-Chain Amino Acid Metabolism in the Skeletal Muscle 
PLoS ONE  2014;9(3):e91006.
Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α) is a coactivator of various nuclear receptors and other transcription factors, which is involved in the regulation of energy metabolism, thermogenesis, and other biological processes that control phenotypic characteristics of various organ systems including skeletal muscle. PGC-1α in skeletal muscle is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Branched-chain amino acid (BCAA) metabolism mainly occurs in skeletal muscle mitochondria, and enzymes related to BCAA metabolism are increased by exercise. Using murine skeletal muscle overexpressing PGC-1α and cultured cells, we investigated whether PGC-1α stimulates BCAA metabolism by increasing the expression of enzymes involved in BCAA metabolism. Transgenic mice overexpressing PGC-1α specifically in the skeletal muscle had increased the expression of branched-chain aminotransferase (BCAT) 2, branched-chain α-keto acid dehydrogenase (BCKDH), which catabolize BCAA. The expression of BCKDH kinase (BCKDK), which phosphorylates BCKDH and suppresses its enzymatic activity, was unchanged. The amount of BCAA in the skeletal muscle was significantly decreased in the transgenic mice compared with that in the wild-type mice. The amount of glutamic acid, a metabolite of BCAA catabolism, was increased in the transgenic mice, suggesting the activation of muscle BCAA metabolism by PGC-1α. In C2C12 cells, the overexpression of PGC-1α significantly increased the expression of BCAT2 and BCKDH but not BCKDK. Thus, PGC-1α in the skeletal muscle is considered to significantly contribute to BCAA metabolism.
doi:10.1371/journal.pone.0091006
PMCID: PMC3956461  PMID: 24638054
10.  Regulation of carnitine palmitoyltransferase I (CPT-Iα) gene expression by the peroxisome proliferator activated receptor gamma coactivator (PGC-1) isoforms 
Summary
The peroxisome proliferator-activated receptor gamma coactivators (PGC-1) have important roles in mitochondrial biogenesis and metabolic control in a variety of tissues. There are multiple isoforms of PGC-1 including PGC-1α and PGC-1β. Both the PGC-1α and β isoforms promote mitochondrial biogenesis and fatty acid oxidation, but only PGC-1α stimulates gluconeogenesis in the liver. Carnitine palmitoyltransferase I (CPT-I) is a key enzyme regulating mitochondrial fatty acid oxidation. In these studies, we determined that PGC-1β stimulated expression of the “liver” isoform of CPT-I (CPT-Iα) but that PGC-1β did not induce pyruvate dehydrogenase kinase 4 (PDK4) which is a regulator of pyruvate metabolism. The CPT-Iα gene is induced by thyroid hormone. We found that T3 increased the expression of PGC-1β and that PGC-1β enhanced the T3 induction of CPT-Iα. The thyroid hormone receptor interacts with PGC-1β in a ligand dependent manner. Unlike PGC-1α, the interaction of PGC-1β and the T3 receptor does not occur exclusively through the leucine-X-X-leucine-leucine motif in PGC-1β. We have found that PGC-1β is associated with the CPT-Iα gene in vivo. Overall, our results demonstrate that PGC-1β is a coactivator in the T3 induction of CPT-Iα and that PGC-1β has similarities and differences with the PGC-1α isoform.
doi:10.1016/j.mce.2006.11.012
PMCID: PMC1892282  PMID: 17239528
PGC-1; carnitine palmitoyltransferase (CPT-Iα); fatty acid oxidation; thyroid hormone (T3); CREB binding protein (CBP)
11.  Effects of Electroacupuncture on PGC-1α Expression in Brown Adipose Tissue 
The inducible coactivator PGC-1α plays master regulator in mitochondrial biogenesis and thermogenesis in brown adipose tissues (BATs). BAT is a natural antiobesity organ which dissipates chemical energy in the form of heat through specialized mitochondrial protein UCP-1. Eletroacupuncture (EA) has been widely used as an alternative treatment for obesity and its related disorders such as type 2 diabetes. The molecular mechanism of electroacupuncture on treatment of obesity is still unclear. We hypothesized that electroacupuncture induced PGC-1α expression to increase the energy expenditure in BAT. Rats were randomly divided into control group and electroacupuncture treatment group. We investigated the effects of electroacupuncture at Zusanli (ST36) acupoint on the expressions of PGC-1α and its associated genes in the BAT of rats using real-time PCR and western blotting. We found that electroacupuncture effectively induces the expression of PGC-1α and UCP-1 by 4-fold and 5-fold in the BAT of rats, respectively. Our results indicated that the molecular mechanism of electroacupuncture for the treatment of obesity may be, or at least partially, through induction of both PGC-1α and UCP-1 expressions to increase energy expenditure in BAT.
doi:10.1155/2013/625104
PMCID: PMC3892755  PMID: 24489587
12.  Twist-1 is a PPAR δ-inducible, negative feedback regulator of PGC-1 α in brown fat metabolism 
Cell  2009;137(1):73-86.
Summary
Brown fat is specialized in energy expenditure, a process that is principally controlled by the transcriptional co-activator PGC-1α. Here we describe a molecular network important for PGC-1α function and brown fat metabolism. We find that twist-1 is selectively expressed in adipose tissue, interacts with PGC-1α, and is recruited to the promoters of PGC-1α’s target genes to suppress mitochondrial metabolism and uncoupling. In vivo, transgenic mice expressing twist-1 in the adipose tissue are prone to high-fat diet induced obesity, whereas twist-1 heterozygous knockout mice are obesity-resistant. These phenotypes are attributed to their altered mitochondrial metabolism in the brown fat. Interestingly, the nuclear receptor PPARδ not only mediates the actions of PGC-1α, but also regulates twist-1 expression, suggesting a negative feedback regulatory mechanism. These findings reveal an unexpected physiological role for twist-1 in the maintenance of energy homeostasis and have important implications for understanding metabolic control and metabolic diseases.
doi:10.1016/j.cell.2009.01.051
PMCID: PMC2688451  PMID: 19345188
13.  PGC-1-Related Coactivator, a Novel, Serum-Inducible Coactivator of Nuclear Respiratory Factor 1-Dependent Transcription in Mammalian Cells 
Molecular and Cellular Biology  2001;21(11):3738-3749.
The thermogenic peroxisome proliferator-activated receptor γ (PPAR-γ) coactivator 1 (PGC-1) has previously been shown to activate mitochondrial biogenesis in part through a direct interaction with nuclear respiratory factor 1 (NRF-1). In order to identify related coactivators that act through NRF-1, we searched the databases for sequences with similarities to PGC-1. Here, we describe the first characterization of a 177-kDa transcriptional coactivator, designated PGC-1-related coactivator (PRC). PRC is ubiquitously expressed in murine and human tissues and cell lines; but unlike PGC-1, PRC was not dramatically up-regulated during thermogenesis in brown fat. However, its expression was down-regulated in quiescent BALB/3T3 cells and was rapidly induced by reintroduction of serum, conditions where PGC-1 was not detected. PRC activated NRF-1-dependent promoters in a manner similar to that observed for PGC-1. Moreover, NRF-1 was immunoprecipitated from cell extracts by antibodies directed against PRC, and both proteins were colocalized to the nucleoplasm by confocal laser scanning microscopy. PRC interacts in vitro with the NRF-1 DNA binding domain through two distinct recognition motifs that are separated by an unstructured proline-rich region. PRC also contains a potent transcriptional activation domain in its amino terminus adjacent to an LXXLL motif. The spatial arrangement of these functional domains coincides with those found in PGC-1, supporting the conclusion that PRC and PGC-1 are structurally and functionally related. We conclude that PRC is a functional relative of PGC-1 that operates through NRF-1 and possibly other activators in response to proliferative signals.
doi:10.1128/MCB.21.11.3738-3749.2001
PMCID: PMC87014  PMID: 11340167
14.  The truncated splice variants, NT-PGC-1α and PGC-1α4, increase with both endurance and resistance exercise in human skeletal muscle 
Physiological Reports  2013;1(6):e00140.
Recently, a truncated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) splice variant, PGC-1α4, that originates from the alternative promoter was shown to be induced by resistance exercise and to elicit muscle hypertrophy without coactivation of “classical” PGC-1α targets involved in mitochondrial biogenesis and angiogenesis. In order to test if distinct physiological adaptations are characterized by divergent induction of PGC-1α splice variants, we investigated the expression of truncated and nontruncated PGC-1α splice variants and PGC-1α transcripts originating from the alternative and the proximal promoter, in human skeletal muscle in response to endurance and resistance exercise. Both total PGC-1α and truncated PGC-1α mRNA expression were increased 2 h after endurance (P < 0.01) and resistance exercise (P < 0.01), with greater increases after endurance exercise (P < 0.05). Expression of nontruncated PGC-1α increased significantly in both exercise groups (P < 0.01 for both groups) without any significant differences between the groups. Both endurance and resistance exercise induced truncated as well as nontruncated PGC-1α transcripts from both the alternative and the proximal promoter. Further challenging the hypothesis that induction of distinct PGC-1α splice variants controls exercise adaptation, both nontruncated and truncated PGC-1α transcripts were induced in AICAR-treated human myotubes (P < 0.05). Thus, contrary to our hypothesis, resistance exercise did not specifically induce the truncated forms of PGC-1α. Induction of truncated PGC-1α splice variants does not appear to underlie distinct adaptations to resistance versus endurance exercise. Further studies on the existence of numerous splice variants originating from different promoters are needed.
doi:10.1002/phy2.140
PMCID: PMC3871455  PMID: 24400142
Exercise; human; PGC-1α; skeletal muscle
15.  Transcriptional integration of mitochondrial biogenesis 
Gene regulatory factors encoded by the nuclear genome are essential for mitochondrial biogenesis and function. Some of these factors act exclusively within the mitochondria to regulate the control of mitochondrial transcription, translation and other functions. Others govern the expression of nuclear genes required for mitochondrial metabolism and organelle biogenesis. The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators plays a major role in transducing and integrating physiological signals governing metabolism, differentiation and cell growth to the transcriptional machinery controlling mitochondrial functional capacity. Thus, the PGC-1 coactivators serve as a central component of the transcriptional regulatory circuitry that coordinately controls the energy-generating functions of mitochondria in accordance with the metabolic demands imposed by changing physiological conditions, senescence, and disease.
doi:10.1016/j.tem.2012.06.006
PMCID: PMC3580164  PMID: 22817841
Mitochondria; Peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1); Peroxisome proliferator-activated receptor (PPAR); transcription; gene regulation; metabolism
16.  The PPARα-PGC-1α Axis Controls Cardiac Energy Metabolism in Healthy and Diseased Myocardium 
PPAR Research  2007;2008:253817.
The mammalian myocardium is an omnivorous organ that relies on multiple substrates in order to fulfill its tremendous energy demands. Cardiac energy metabolism preference is regulated at several critical points, including at the level of gene transcription. Emerging evidence indicates that the nuclear receptor PPARα and its cardiac-enriched coactivator protein, PGC-1α, play important roles in the transcriptional control of myocardial energy metabolism. The PPARα-PGC-1α complex controls the expression of genes encoding enzymes involved in cardiac fatty acid and glucose metabolism as well as mitochondrial biogenesis. Also, evidence has emerged that the activity of the PPARα-PGC-1α complex is perturbed in several pathophysiologic conditions and that altered activity of this pathway may play a role in cardiomyopathic remodeling. In this review, we detail the current understanding of the effects of the PPARα-PGC-1α axis in regulating mitochondrial energy metabolism and cardiac function in response to physiologic and pathophysiologic stimuli.
doi:10.1155/2008/253817
PMCID: PMC2225461  PMID: 18288281
17.  Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network 
Biochimica et biophysica acta  2010;1813(7):1269-1278.
The PGC-1 family of regulated coactivators, consisting of PGC-1α, PGC-1β and PRC, plays a central role in a regulatory network governing the transcriptional control of mitochondrial biogenesis and respiratory function. These coactivators target multiple transcription factors including NRF-1, NRF-2 and the orphan nuclear hormone receptor, ERRα, among others. In addition, they themselves are the targets of coactivator and co-repressor complexes that regulate gene expression through chromatin remodeling. The expression of PGC-1 family members is modulated by extracellular signals controlling metabolism, differentiation or cell growth and in some cases their activities are known to be regulated by post-translational modification by the energy sensors, AMPK and SIRT1. Recent gene knockout and silencing studies of many members of the PGC-1 network have revealed phenotypes of wide ranging severity suggestive of complex compensatory interactions or broadly integrative functions that are not exclusive to mitochondrial biogenesis. The results point to a central role for the PGC-1 family in integrating mitochondrial biogenesis and energy production with many diverse cellular functions.
doi:10.1016/j.bbamcr.2010.09.019
PMCID: PMC3035754  PMID: 20933024
18.  Skeletal Muscle-Specific Expression of PGC-1α-b, an Exercise-Responsive Isoform, Increases Exercise Capacity and Peak Oxygen Uptake 
PLoS ONE  2011;6(12):e28290.
Background
Maximal oxygen uptake (VO2max) predicts mortality and is associated with endurance performance. Trained subjects have a high VO2max due to a high cardiac output and high metabolic capacity of skeletal muscles. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a nuclear receptor coactivator, promotes mitochondrial biogenesis, a fiber-type switch to oxidative fibers, and angiogenesis in skeletal muscle. Because exercise training increases PGC-1α in skeletal muscle, PGC-1α-mediated changes may contribute to the improvement of exercise capacity and VO2max. There are three isoforms of PGC-1α mRNA. PGC-1α-b protein, whose amino terminus is different from PGC-1α-a protein, is a predominant PGC-1α isoform in response to exercise. We investigated whether alterations of skeletal muscle metabolism by overexpression of PGC-1α-b in skeletal muscle, but not heart, would increase VO2max and exercise capacity.
Methodology/Principal Findings
Transgenic mice showed overexpression of PGC-1α-b protein in skeletal muscle but not in heart. Overexpression of PGC-1α-b promoted mitochondrial biogenesis 4-fold, increased the expression of fatty acid transporters, enhanced angiogenesis in skeletal muscle 1.4 to 2.7-fold, and promoted exercise capacity (expressed by maximum speed) by 35% and peak oxygen uptake by 20%. Across a broad range of either the absolute exercise intensity, or the same relative exercise intensities, lipid oxidation was always higher in the transgenic mice than wild-type littermates, suggesting that lipid is the predominant fuel source for exercise in the transgenic mice. However, muscle glycogen usage during exercise was absent in the transgenic mice.
Conclusions/Significance
Increased mitochondrial biogenesis, capillaries, and fatty acid transporters in skeletal muscles may contribute to improved exercise capacity via an increase in fatty acid utilization. Increases in PGC-1α-b protein or function might be a useful strategy for sedentary subjects to perform exercise efficiently, which would lead to prevention of life-style related diseases and increased lifespan.
doi:10.1371/journal.pone.0028290
PMCID: PMC3234261  PMID: 22174785
19.  Skeletal muscle SIRT1 and the genetics of metabolic health: therapeutic activation by pharmaceuticals and exercise 
Silent mating type information regulation 2 homolog 1 (SIRT1) is implicated in the control of skeletal muscle mitochondrial content and function through deacetylation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and participation in the SIRT1/PGC-1α axis. The SIRT1/PGC-1α axis control of skeletal muscle mitochondrial biogenesis is an important therapeutic target for obesity and obesity-related metabolic dysfunction, as skeletal muscle mitochondrial dysfunction is implicated in the pathogenesis of multiple metabolic diseases. This review will establish the importance of the SIRT1/PGC-1α axis in the control of skeletal muscle mitochondrial biogenesis, and explore possible pharmacological and physiological interventions designed to activate SIRT1 and the SIRT1/PGC-1α axis in order to prevent and/or treat obesity and obesity-related metabolic disease. The current evidence supports a role for therapeutic activation of SIRT1 and the SIRT1/PGC-1α axis by both pharmaceuticals and exercise in the treatment and prevention of metabolic disease. Future research should be directed toward the feasibility of pharmaceutical activation of SIRT1 in humans and refining exercise prescriptions for optimal SIRT1 activation.
doi:10.2147/TACG.S31276
PMCID: PMC3681195  PMID: 23776383
SIRT1; PGC-1α; resveratrol; obesity; metabolic disease; exercise
20.  Deletion of the metabolic transcriptional coactivator PGC1β induces cardiac arrhythmia 
Cardiovascular Research  2011;92(1):29-38.
Aims
Peroxisome proliferator-activated receptor-γ coactivators PGC1α and PGC1β modulate mitochondrial biogenesis and energy homeostasis. The function of these transcriptional coactivators is impaired in obesity, insulin resistance, and type 2 diabetes. We searched for transcriptomic, lipidomic, and electrophysiological alterations in PGC1β−/− hearts potentially associated with increased arrhythmic risk in metabolic diseases.
Methods and results
Microarray analysis in mouse PGC1β−/− hearts confirmed down-regulation of genes related to oxidative phosphorylation and the electron transport chain and up-regulation of hypertrophy- and hypoxia-related genes. Lipidomic analysis showed increased levels of the pro-arrhythmic and pro-inflammatory lipid, lysophosphatidylcholine. PGC1β−/− mouse electrocardiograms showed irregular heartbeats and an increased incidence of polymorphic ventricular tachycardia following isoprenaline infusion. Langendorff-perfused PGC1β−/− hearts showed action potential alternans, early after-depolarizations, and ventricular tachycardia. PGC1β−/− ventricular myocytes showed oscillatory resting potentials, action potentials with early and delayed after-depolarizations, and burst firing during sustained current injection. They showed abnormal diastolic Ca2+ transients, whose amplitude and frequency were increased by isoprenaline, and Ca2+ currents with negatively shifted inactivation characteristics, with increased window currents despite unaltered levels of CACNA1C RNA transcripts. Inwardly and outward rectifying K+ currents were all increased. Quantitiative RT-PCR demonstrated increased SCN5A, KCNA5, RYR2, and Ca2+-calmodulin dependent protein kinase II expression.
Conclusion
PGC1β−/− hearts showed a lysophospholipid-induced cardiac lipotoxicity and impaired bioenergetics accompanied by an ion channel remodelling and altered Ca2+ homeostasis, converging to produce a ventricular arrhythmic phenotype particularly during adrenergic stress. This could contribute to the increased cardiac mortality associated with both metabolic and cardiac disease attributable to lysophospholipid accumulation.
doi:10.1093/cvr/cvr155
PMCID: PMC3172981  PMID: 21632884
Mitochondria; Cardiac arrhythmia; Peroxisome proliferator-activated receptor-γ coactivator 1β; Metabolic disease; Lysophosphatidylcholine
21.  Total Skeletal Muscle PGC-1 Deficiency Uncouples Mitochondrial Derangements from Fiber Type Determination and Insulin Sensitivity 
Cell metabolism  2010;12(6):633-642.
SUMMARY
Evidence is emerging that the PGC-1 coactivators serve a critical role in skeletal muscle metabolism, function, and disease. Mice with total PGC-1 deficiency in skeletal muscle (PGC-1α−/−βf/f/MLC-Cre mice) were generated and characterized. PGC-1α−/−βf/f/MLC-Cre mice exhibit a dramatic reduction in exercise performance compared to single PGC-1α- or PGC-1β-deficient mice and wild-type controls. The exercise phenotype of the PGC-1α−/−βf/f/MLC-Cre mice was associated with a marked diminution in muscle respiratory capacity and mitochondrial structural derangements consistent with fusion/fission and biogenic defects together with rapid depletion of muscle glycogen stores during exercise. Surprisingly, the skeletal muscle fiber type profile of the PGC-1α−/−βf/f/MLC-Cre mice was not significantly different than the wild-type mice. Moreover, insulin sensitivity and glucose tolerance were not altered in the PGC-1α−/−βf/f/MLC-Cre mice. Taken together, we conclude that PGC-1 coactivators are necessary for the oxidative and mitochondrial programs of skeletal muscle but are dispensable for fundamental fiber type determination and insulin sensitivity.
doi:10.1016/j.cmet.2010.11.008
PMCID: PMC2999961  PMID: 21109195
22.  Estrogen-Related Receptor α Directs Peroxisome Proliferator-Activated Receptor α Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle 
Molecular and Cellular Biology  2004;24(20):9079-9091.
Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERRα have not been well defined. To identify ERRα-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERRα. ERRα upregulated a subset of PGC-1α target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration. These results were validated by independent analyses in cardiac myocytes, C2C12 myotubes, and cardiac and skeletal muscle of ERRα−/− mice. Consistent with the gene expression results, ERRα increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERRα are known targets for the nuclear receptor PPARα, and therefore, the interaction between these regulatory pathways was explored. ERRα activated PPARα gene expression via direct binding of ERRα to the PPARα gene promoter. Furthermore, in fibroblasts null for PPARα and ERRα, the ability of ERRα to activate several PPARα targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1α was also shown to activate ERRα gene expression. We conclude that ERRα serves as a critical nodal point in the regulatory circuitry downstream of PGC-1α to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.
doi:10.1128/MCB.24.20.9079-9091.2004
PMCID: PMC517878  PMID: 15456881
23.  Mice lacking PGC-1β in adipose tissues reveal a dissociation between mitochondrial dysfunction and insulin resistance 
Molecular Metabolism  2013;2(3):215-226.
Proper development and function of white adipose tissue (WAT), which are regulated by multiple transcription factors and coregulators, are crucial for glucose homeostasis. WAT is also the main target of thiazolidinediones, which are thought to exert their insulin-sensitizing effects by promoting mitochondrial biogenesis in adipocytes. Besides being expressed in WAT, the role of the coactivator PGC-1β in this tissue has not been addressed. To study its function in WAT, we have generated mice that lack PGC-1β in adipose tissues. Gene expression profiling analysis of WAT reveals that PGC-1β regulates mitochondrial genes involved in oxidative metabolism. Furthermore, lack of PGC-1β prevents the induction of mitochondrial genes by rosiglitazone in WAT without affecting the capacity of thiazolidinediones to enhance insulin sensitivity. Our findings indicate that PGC-1β is important for basal and rosiglitazone-induced mitochondrial function in WAT, and that induction of mitochondrial oxidative capacity is not essential for the insulin-sensitizing effects of thiazolidinediones.
doi:10.1016/j.molmet.2013.05.004
PMCID: PMC3773830  PMID: 24049736
Peroxisome proliferator-activated receptor γ coactivator-1; Mitochondrial biogenesis; Adipocytes; Thiazolidinediones; Type 2 diabetes
24.  Transient upregulation of PGC-1α diminishes cardiac ischemia tolerance via upregulation of ANT1 
Prolonged cardiac overexpression of the mitochondrial biogenesis regulatory transcriptional coactivator PGC-1α disrupts cardiac contractile function and its genetic ablation limits cardiac capacity to enhance work-load. In contrast, transient induction of PGC-1α alleviates neuronal cell oxidative stress and enhances skeletal myotube antioxidant defenses. We explored whether transient upregulation of PGC-1α in the heart protects against ischemia-reperfusion injury. The transient induction of PGC-1α in the cardiac-restricted inducible PGC-1α transgenic mouse, increased PGC-1α protein levels 5-fold. Following 25 minutes of ischemia and 2 hours of reperfusion on a Langendorff perfusion apparatus, contractile recovery and the rate pressure product was significantly blunted in mice overexpressing PGC-1α vs. controls. Affymetrix gene array analysis showed a 3-fold PGC-1α-mediated upregulation of adenine nucleotide translocase 1 (ANT1). As ANT1 upregulation induces cardiomyocyte cell death we investigated whether the induction of ANT1 by PGC-1α contributes to this enhanced ischemia-stress susceptibility. Infection with adenovirus harboring PGC-1α into cardiac-derived H9c2 cells significantly upregulates ANT1 without changing basal cell viability. In response to anoxia-reoxygenation injury cell death is significantly increased following PGC-1α overexpression. This detrimental effect is abolished following siRNA knockdown of ANT1. Similarly, the attenuation of ANT-1 in the presence of PGC-1α overexpression preserves the mitochondrial membrane potential in response to hydrogen-peroxide stress. Interestingly, the isolated knockdown of ANT1 also protects H9c2 cells from anoxia-reoxygenation injury. Taken together these data suggest that transient induction of PGC-1α in the murine heart decreases ischemia-reperfusion contractile recovery and diminishes anoxia-reoxygenation tolerance in H9c2 cells. These adverse phenotypes appear to be mediated, in part, by PGC-1α induced upregulation of ANT1.
doi:10.1016/j.yjmcc.2010.06.008
PMCID: PMC2932777  PMID: 20600099
PGC-1α; Cardiac ischemia-reperfusion; ANT1
25.  The Transcriptional Coactivators, PGC-1α and β, Cooperate to Maintain Cardiac Mitochondrial Function During the Early Stages of Insulin Resistance 
We previously demonstrated a cardiac mitochondrial biogenic response in insulin resistant mice that requires the nuclear receptor transcription factor PPARα. We hypothesized that the PPARα coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is necessary for mitochondrial biogenesis in insulin resistant hearts and that this response was adaptive. Mitochondrial phenotype was assessed in insulin resistant mouse models in wild-type (WT) versus PGC-1α deficient (PGC-1α−/−) backgrounds. Both high fat-fed (HFD) WT and 6 week-old Ob/Ob animals exhibited a significant increase in myocardial mitochondrial volume density compared to standard chow fed or WT controls. In contrast, HFD PGC-1α−/− and Ob/Ob-PGC-1α−/− hearts lacked a mitochondrial biogenic response. PGC-1α gene expression was increased in 6 week-old Ob/Ob animals, followed by a decline in 8 week-old Ob/Ob animals with more severe glucose intolerance. Mitochondrial respiratory function was increased in 6 week-old Ob/Ob animals, but not in Ob/Ob-PGC-1α−/− mice and not in 8 week-old Ob/Ob animals, suggesting a loss of the early adaptive response, consistent with the loss of PGC-1α upregulation. Animals that were deficient for PGC-1α and heterozygous for the related coactivator PGC-1β (PGC-1α−/−β+/−) were bred to the Ob/Ob mice. Ob/Ob-PGC-1α−/−β+/− hearts exhibited dramatically reduced mitochondrial respiratory capacity. Finally, the mitochondrial biogenic response was triggered in H9C2 myotubes by exposure to oleate, an effect that was blunted with shRNA-mediated PGC-1 “knockdown”. We conclude that PGC-1 signaling is important for the adaptive cardiac mitochondrial biogenic response that occurs during the early stages of insulin resistance. This response occurs in a cell autonomous manner and likely involves exposure to high levels of free fatty acids.
doi:10.1016/j.yjmcc.2011.10.010
PMCID: PMC3294189  PMID: 22080103
diabetes; insulin resistance; cardiomyopathy; mitochondria; heart failure; metabolism

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