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(Circulation. 2007;115:2540-2548.)
© 2007 American Heart Association, Inc.

Basic Science for Clinicians

Peroxisome Proliferator–Activated Receptor Coactivator-1 (PGC-1) Regulatory Cascade in Cardiac Physiology and Disease

Brian N. Finck, PhD; Daniel P. Kelly, MD

From the Centers for Human Nutrition (B.N.F.) and Cardiovascular Research (B.N.F., D.P.K.) and Departments of Medicine (B.N.F., D.P.K.), Molecular Biology and Pharmacology (D.P.K.), and Pediatrics (D.P.K.), Washington University School of Medicine, St Louis, Mo.

Correspondence to Daniel P. Kelly, MD, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8086, St. Louis, MO 63110. E-mail dkelly{at}im.wustl.edu

Key Words: cardiomyopathy • cardiovascular diseases • diabetes mellitus • fatty acids • genes • glucose • metabolism

	Introduction

Top Introduction Mitochondrial Fatty Acid and... Evidence for a Link... The PGC-1 Family of... Transcriptional Control of... The Critical Role of... Do Derangements in PGC-1{alpha}... Implications for Human Heart... References

 
The constant workload of the heart requires a high-capacity mitochondrial system to match ATP production with functional demands. In the adult mammalian heart, ATP synthesis occurs primarily through complete oxidation of fatty acids and glucose in the mitochondrion. Mitochondrial metabolic pathways are exquisitely regulated at many levels. Mitochondrial oxidative flux is modulated by concentrations of substrates and metabolite intermediates and by posttranslational modification of enzymes catalyzing key, rate-limiting reactions. Importantly, the capacity for mitochondrial oxidative energy metabolism also is regulated at the level of gene transcription. The present review summarizes recent work that defines the role of a transcriptional coactivator, peroxisome proliferator–activated receptor coactivator-1 (PGC-1), as a master regulator of myocardial energy metabolism in diverse physiological and pathophysiological conditions.

	Mitochondrial Fatty Acid and Glucose Utilization Pathways

Top Introduction Mitochondrial Fatty Acid and... Evidence for a Link... The PGC-1 Family of... Transcriptional Control of... The Critical Role of... Do Derangements in PGC-1{alpha}... Implications for Human Heart... References

 
The mitochondrion is an efficient ATP synthesis machine that rapidly converts energy stored in fatty acids, glucose, and lactate into high-energy phosphates, which provide the fuel driving contractile function, ion homeostasis, and other cellular processes within the cardiac myocyte. Fatty acids enter the mitochondrion intact and are catabolized in the mitochondrial fatty acid ß-oxidation spiral. Oxidation of fatty acids in this pathway produces reducing equivalents (NADH and FADH₂) and acetyl-CoA, a 2-carbon molecule that can enter the tricarboxylic acid cycle for further oxidation (Figure 1). For glucose to enter the oxidative pathways of the mitochondrion, it must first undergo anaerobic metabolism in the cytosol of the cardiac myocyte and be converted to pyruvate (Figure 1). This 3-carbon intermediate can then be converted to lactate outside the mitochondrion or oxidized in the mitochondrial matrix to generate acetyl-CoA for the tricarboxylic acid cycle. Oxidation of acetyl-CoA in the tricarboxylic acid cycle produces NADH and FADH₂, which carry electrons to the electron transport chain. The electron transport chain then produces ATP through the process of oxidative phosphorylation (OXPHOS). The ATP synthesized in the mitochondrion is exported to the cytosol for use in myriad enzymatic reactions and specialized cellular processes such as excitation-contraction coupling and ion homeostasis.

View larger version (26K): [in this window] [in a new window]   Figure 1. Mitochondrial energy transduction and ATP synthesis pathways. The schematic depicts the major pathways of mitochondrial energy metabolism. OMM indicates outer mitochondrial membrane; IMM, inner mitochondrial membrane; CPT, carnitine palmitoyltransferase; TCA, tricarboxylic acid; and ANT, adenine nucleotide translocator.

The capacity for mitochondrial oxidative metabolism and respiratory function is controlled dynamically by gene regulatory programs in both heart and skeletal muscle. For example, a marked increase in cardiac mitochondrial number and activity is observed during the postnatal developmental period.^1,2 This rapid expansion of mitochondrial capacity after birth involves activation of a cascade of gene regulatory events that coordinate mitochondrial genome replication with increased expression of nuclear and mitochondrial genes encoding proteins involved in catabolic and ATP-synthesizing pathways within the mitochondrion.^3,4 This mitochondrial biogenic response also is induced in response to physiological demands such as exercise training^5–7 and by thyroid hormone.^8–12 Thus, the regulation of cardiac myocyte mitochondrial functional capacity is a dynamic process that responds to physiological and nutritional inputs.

In a variety of myocardial disease states, the regulatory pathways controlling mitochondrial function and biogenesis are perturbed. For example, acquired forms of cardiomyopathy are associated with a decline in overall mitochondrial oxidative catabolism while reliance on anaerobic glycolytic pathways is increased.^13–18 This fuel shift may initially be adaptive to diminish oxygen consumption. Over time, however, this metabolic shift can become maladaptive, leading to a state of myocyte energy insufficiency related to reduced capacity for mitochondrial ATP production. In support of this notion, magnetic resonance spectroscopy studies have shown reduced "high-energy" phosphate stores and flux in animal models and in humans during the transition to heart failure.^19–22 This deficiency may contribute to the pathological remodeling that occurs in end-stage heart failure. Indeed, the ratio of phosphocreatine to ATP correlates with heart failure severity and is a strong predictor of cardiovascular mortality.²³ Consistent with these observations, the expression of numerous genes involved in mitochondrial oxidative metabolism, including fatty acid oxidation, is downregulated in the pathologically hypertrophied and failing heart.^24–34

	Evidence for a Link Between Derangements in Mitochondrial Energy Metabolism and Cardiomyopathy

Top Introduction Mitochondrial Fatty Acid and... Evidence for a Link... The PGC-1 Family of... Transcriptional Control of... The Critical Role of... Do Derangements in PGC-1{alpha}... Implications for Human Heart... References

 
A critical question related to the deactivation of mitochondrial metabolism in heart failure is whether such energy metabolic abnormalities contribute to the pathology of, or are secondary to, the pathological remodeling of heart failure. Altered metabolism was originally considered a byproduct of these pathological states. However, emerging evidence, including observations of the phenotypic expression of genetic defects in humans and animal models, supports the notion that derangements in mitochondrial energy metabolism contribute to cardiac dysfunction. For example, human mitochondrial DNA mutations resulting in global impairment in mitochondrial respiratory function cause hypertrophic or dilated cardiomyopathy and cardiac conduction defects.^35–37 Mutations in nuclear genes encoding mitochondrial fatty acid oxydation enzymes may also manifest as cardiomyopathy.^38–41 Interestingly, cardiomyopathies resulting from inborn errors in mitochondrial fatty acid oxydation enzymes are often provoked by physiological or pathophysiological conditions that increase dependence on fat oxidation for myocardial ATP production such as prolonged exercise or fasting associated with infectious illness.^39,41

A causal relationship between mitochondrial dysfunction and cardiomyopathy also is evidenced by several genetically engineered mouse models. Targeted deletion of the adenine nucleotide translocator 1, which transports mitochondrially generated ATP to the cytosol, leads to mitochondrial dysfunction and cardiomyopathy.⁴² Mice with cardiac-specific deletion of transcription factor of activated mitochondria, which controls transcription and replication of the mitochondrial genome, also exhibit marked impairments in mitochondrial metabolism, severe cardiomyopathy, and premature mortality.⁴³ Cardiomyopathy and/or conduction defects also are observed in several mouse models with targeted deletion of specific FAO enzymes.^44–46 Taken together, the cardiac phenotype caused by genetic defects in mitochondrial energy transduction or ATP production in humans and mice provides proof of concept for causal links between derangements in mitochondrial energy metabolism and cardiac dysfunction.

	The PGC-1 Family of Transcriptional Coactivators: Inducible Regulators of Cardiac Mitochondrial Biogenesis and Function

Top Introduction Mitochondrial Fatty Acid and... Evidence for a Link... The PGC-1 Family of... Transcriptional Control of... The Critical Role of... Do Derangements in PGC-1{alpha}... Implications for Human Heart... References

 
What controls the adaptive cardiac mitochondrial biogenic response during development and in response to physiological demands? How is the transcription of nuclear and mitochondrial genes encoding mitochondrial enzymes and proteins coordinately and precisely orchestrated during postnatal cardiac mitochondrial biogenesis? These questions were partially answered with the discovery of the PGC-1 family of transcriptional coactivators. PGC-1s are proteins that enhance the transcriptional activity of transcription factors through direct protein-protein interactions (reviewed elsewhere^47–49). PGC-1 was first discovered by Bruce Spiegelman’s laboratory⁵⁰ in a yeast 2-hybrid screen designed to discover regulatory proteins that distinguish brown adipose tissue from white adipose tissue. Brown adipose tissue is enriched in mitochondria specialized to generate heat through uncoupled respiration. In contrast, white adipose tissue is relatively poor in mitochondria. PGC-1, an inducible brown adipose tissue–enriched protein, was shown to drive mitochondrial biogenesis and uncoupled respiration in brown adipocytes. Subsequently, PGC-1 was shown to induce the production of mitochondria capable of high-level coupled respiration and poised for ATP production in cardiac myocytes.⁵¹ Two related proteins, PGC-1ß and PGC-1–related coactivator, also have been identified and, together with PGC-1, make up the PGC-1 family.^52,53

Unlike most known transcriptional coactivators, PGC-1 and PGC-1ß expression is enriched in tissues with high-capacity mitochondrial systems and is markedly inducible. PGC-1 and PGC-1ß are highly expressed in brown adipose tissue, heart, slow-twitch skeletal muscle, and kidney.^50,52 The expression of PGC-1 is induced rapidly by physiological conditions known to increase the demand for mitochondrial ATP production such as cold exposure, exercise, and fasting.^{50,51,54–59} Because PGC-1 is the most extensively studied isoform in the heart, our review focuses on this PGC-1 family member. However, it is likely that the other PGC-1 family members serve additional roles in controlling cardiac metabolism.

	Transcriptional Control of Mitochondrial Metabolism

Top Introduction Mitochondrial Fatty Acid and... Evidence for a Link... The PGC-1 Family of... Transcriptional Control of... The Critical Role of... Do Derangements in PGC-1{alpha}... Implications for Human Heart... References

 
Because PGC-1 proteins cannot bind DNA directly, these coactivators exert their effects through interactions with transcription factors bound to specific DNA elements in the promoter region of genes (Figure 2). Recent advances in the study of gene transcriptional control have demonstrated that DNA-bound transcription factors interact with complexes of coactivator and corepressor proteins, some of which have enzymatic activity leading to chromatin modification (eg, acetylation and methylation). The chromatin remodeling function of coactivator complexes enhances the probability that a gene will be transcribed by the RNA polymerase II complex (Figure 2). Other coactivators work by interacting directly with the RNA polymerase machinery (eg, RNA polymerase II or the TRAP/DRIP complex).^60,61 PGC-1 does not possess intrinsic enzymatic activity common to many coactivator proteins. Instead, PGC-1 functions as an adaptor or scaffold to recruit other coactivator proteins that remodel chromatin.^60,62 PGC-1 also docks with a protein called ménage-à-trois 1, which is a component of the cyclin-dependent kinase 7 complex that phosphorylates RNA polymerase II and selectively modulates its activity.⁶³ In addition, PGC-1 is known to interact directly with the TRAP/DRIP complex to link with RNA polymerase II (Figure 2).⁶⁰ Finally, PGC-1 possesses an RNA processing domain that may also contribute to its transcriptional regulatory function.⁶⁴

View larger version (25K): [in this window] [in a new window]   Figure 2. PGC-1 is a transcriptional coactivator. The schematic uses the PPAR/retinoid X receptor (RXR) complex as an example of how PGC-1 coactivators dock to transcription factor targets and recruit protein complexes that activate transcription. Top, The PPAR heterodimer binds cognate nuclear receptor response elements (NRRE) within the promoter region of the target gene. Middle, PPAR then recruits PGC-1, which facilitates interactions with other coactivators with enzymatic activity such as the ability to modify chromatin by acetylating histones (eg, SRC-1, p300). Bottom, PGC-1 also is known to directly interact with the transcription initiation machinery (TRAP/DRIP), which provides a molecular bridge between the coactivator complex and RNA polymerase II (POL II). Finally, evidence exists that PGC-1 plays a role in RNA processing via an RNA recognition motif in its C-terminus.

PGC-1 interacts with and coactivates many members of the nuclear receptor transcription factor superfamily and nonnuclear transcription factors to transduce developmental, nutritional, and physiological stimuli to the control of diverse cellular energy metabolic pathways (Figure 3).^47,49 In heart, 3 major PGC-1 transcription factor partners have been identified. The first cardiac PGC-1 target identified was peroxisome proliferator–activated receptor- (PPAR),⁶⁵ a discovery based on the known interaction with PPAR. PGC-1 interacts with and coactivates PPAR and the related nuclear receptor PPARß (also known as PPAR).^66,67 The PPARs are ligand-activated nuclear receptors that are bound and activated by fatty acid derivatives and several clinically relevant drugs. Fibric acid lipid-lowering drugs activate PPAR while the thiazolidinediones work through PPAR to mediate their antidiabetic effects. High-affinity endogenous ligands for PPARs have not been identified with certainty, but PPARs are likely activated by fatty acid–derived metabolites. PPAR is enriched in the myocardium and plays important roles in regulating cardiac fatty acid uptake and mitochondrial fatty acid oxidation.^68–72 Mice lacking PPAR exhibit diminished capacity for fatty acid oxidation and increased reliance on glucose utilization pathways.^69,71,72 Conversely, mice overexpressing PPAR in heart (MHC-PPAR mice) rely almost exclusively on fatty acids and use very little glucose.^69–71 The PPARß isoform also is highly expressed in myocardium,⁶⁸ and PPARß overexpression drives fatty acid oxidation.⁷³ Mice with cardiac-specific deletion of the PPARß gene exhibit diminished capacity for fatty acid oxidation and severe cardiomyopathy.⁷⁴ Although PPAR is expressed at relatively low levels in adult heart, it is also worth noting that mice lacking PPAR in cardiac myocytes exhibit mild cardiac hypertrophy with preserved contractility.⁷⁵ The major biological role of the PPAR/PGC-1 complex in the myocardium appears to be the transcriptional control of enzymes involved in fatty acid uptake and oxidation (Figure 3).

View larger version (20K): [in this window] [in a new window]   Figure 3. The PGC-1 gene regulatory cascade. The schematic depicts the downstream gene regulatory actions of the inducible PGC-1 coactivators in the cardiac myocyte. The interaction of PGC-1 with its cognate transcription factor targets is shown linked to specific metabolic pathways. For example, PGC-1 coactivates members of the PPAR nuclear receptor transcription factor family to activate the expression of genes involved in mitochondrial fatty acid oxidation. PGC-1 coactivates ERRs to enhance expression of fatty acid oxidation and OXPHOS enzymes while inhibiting glucose oxidation. Finally, PGC-1 also coactivates NRF-1 to increase expression of nuclear- and mitochondrial-encoded enzymes involved in OXPHOS, the latter effect being mediated secondarily through induction of mitochondrial transcription factors, including transcription factor of activated mitochondria (Tfam). mtDNA indicates mitochondrial DNA.

The estrogen receptor related receptor (ERR) family (ERR, ß, ) of orphan nuclear receptors represents another major cardiac PGC-1 target (Figure 3).^76–79 This interaction was first discovered through a yeast 2-hybrid screen using PGC-1 as "bait."⁷⁷ Bona fide endogenous ligands for ERRs have not been identified; because of the small ligand-binding pocket, it is possible that none exist.⁸⁰ Interestingly, in contrast to other PGC-1 transcription factor partners, the activity of ERR is dependent on the presence of PGC-1. This observation has suggested to some that PGC-1 serves as a protein ligand for ERR.^78,80 ERR overexpression drives increased expression of genes encoding fatty acid oxidation and OXPHOS enzymes in a manner that is markedly enhanced by the presence of PGC-1 proteins.^77,79,81 Interestingly, the ERR-mediated activation of many of the target genes involved in fatty acid oxidation is dependent on the presence of PPAR, which is itself transcriptionally induced by ERR.⁸¹ This suggests that ERR mediates its effects on fatty acid oxidation, at least in part, by activating the expression of PPAR. The PGC-1/ERR complex is also a direct regulator of genes involved in glucose oxidation.⁸² On the basis of the gene targets and effects on PPAR expression, it is clear that ERR serves a central role in the cardiac PGC-1 gene regulatory cascade. Although ERRß and ERR also seem to play similar roles in controlling mitochondrial metabolism, further work is necessary to delineate ERR-specific functions in the myocardium.

How does PGC-1 regulate mitochondrial DNA replication and transcription? Early studies of PGC-1 demonstrated that it activates mitochondrial biogenesis by activating the nuclear respiratory factor 1 (NRF-1).⁵⁶ Subsequent studies revealed that this mechanism also is relevant in heart.⁵¹ NRF-1 is a nuclear-encoded transcription factor that is coactivated by PGC-1 to regulate transcription of genes involved in mitochondrial OXPHOS, mitochondrial DNA transcription, and mitochondrial biogenesis.^51,56,83,84 Importantly, NRF-1 also stimulates expression of transcription factor of activated mitochondria, which in turn drives the transcription and replication of the mitochondrial genome.^84–86 The importance of NRF-1 in this process was evidenced by studies wherein cotransfection of a dominant-negative NRF-1 cDNA blocked the mitochondrial biogenic response to PGC-1.⁵⁶ Thus, through multiple downstream transcription factor targets, PGC-1 triggers the coordinate activation of nuclear and mitochondrial genes driving mitochondrial biogenesis and increased capacity for mitochondrial fatty acid oxidation and OXPHOS (Figure 3). In this way, PGC-1 serves as a master regulator of mitochondrial oxidative metabolism that coordinates the capacity of each step required for ATP synthesis.

	The Critical Role of PGC-1 in the Physiological Control of Myocardial Energy Metabolism: Lessons From Gain-of-Function and Loss-of-Function Mice

Top Introduction Mitochondrial Fatty Acid and... Evidence for a Link... The PGC-1 Family of... Transcriptional Control of... The Critical Role of... Do Derangements in PGC-1{alpha}... Implications for Human Heart... References

 
PGC-1 is highly inducible in response to physiological conditions that signal increased demand for myocardial ATP production, particularly when reliance on fatty acids as a fuel is increased.^50,51 For example, myocardial PGC-1 is induced in response to acute food deprivation⁵¹ and diabetes mellitus,^70,87 when the myocardium switches to the preferential utilization of fatty acids. In addition, cardiac (A. Wende and D. Kelly, unpublished data, 2005) and skeletal muscle^57–59 PGC-1 expression is activated by exercise training, a physiological stimulus wherein both fatty acid and glucose utilization is increased to meet the heightened demand for ATP synthesis.

Genetic gain-of-function and loss-of-function approaches in mice have served as a powerful means of demonstrating the important physiological roles that PGC-1 plays in regulating mitochondrial number and metabolism. For example, studies of transgenic mice with inducible, cardiac-specific overexpression of PGC-1 have shown that PGC-1 is sufficient to drive a robust mitochondrial biogenic response.^51,88 The role of PGC-1 in regulating mitochondrial function also has been probed through the use of targeted gene deletion (knockout) mouse models. Two independent mouse models with constitutive inactivation of PGC-1 have been generated.^89,90 Interestingly, mice lacking PGC-1 (PGC-1^–/– mice) demonstrate that PGC-1 is not essential for the fundamental process of mitochondrial biogenesis; myocardial mitochondrial volume density is not significantly altered in PGC-1^–/– mice.^89,91 However, studies of PGC-1^–/– mice have provided important information about the requirement for PGC-1 in the adaptive energy metabolic response to physiological stress in multiple organ systems. PGC-1^–/– mice exhibit diminished capacity for endurance treadmill exercise, and isolated myofibers from PGC-1^–/– mice fatigue prematurely.⁸⁹ PGC-1 deficiency also results in a defect in body temperature homeostasis, resulting in a dramatic core body temperature response to cold exposure.^89,90 PGC-1^–/– mice also have provided insight into the role of this coactivator in the heart. The expression of many genes involved in mitochondrial OXPHOS and fatty acid oxidation is diminished in myocardium of PGC-1^–/– mice.^34,91 Cardiac myocyte state 3 mitochondrial respiration rates are diminished in PGC-1^–/– mice.⁹¹ Collectively, these data suggest that PGC-1 is a critical factor in the control of a high-capacity mitochondrial system.

	Do Derangements in PGC-1 Signaling Contribute to Cardiac Pathological Remodeling and Heart Failure?

Top Introduction Mitochondrial Fatty Acid and... Evidence for a Link... The PGC-1 Family of... Transcriptional Control of... The Critical Role of... Do Derangements in PGC-1{alpha}... Implications for Human Heart... References

 
The expression of PGC-1 and its targets, including the PPARs and ERRs, is downregulated in pathological forms of cardiac hypertrophy and in the failing heart (Figure 4).^{26,31,34,63,92,93} Conversely, PGC-1 expression is increased in physiological forms of hypertrophy related to postnatal growth⁵¹ or exercise training (A. Wende and D. Kelly, unpublished data, 2005; Figure 4). As noted above, the downregulation of PGC-1 expression that occurs with pathological forms of cardiac hypertrophy is consistent with the derangements in mitochondrial metabolism known to occur in the hypertrophied and failing heart. This gene regulatory response occurs very early in the hypertrophic response, suggesting that it is a primary event rather than an indirect consequence of pathological hypertrophy. This conclusion is supported further by the observation that the expression and activity of ERR, PPAR, and PGC-1 are downregulated by short-term treatment with hypertrophic agonists in cultured cardiac myocytes.^25,31,34

View larger version (25K): [in this window] [in a new window]   Figure 4. Divergent regulation of PGC-1 and mitochondrial biogenesis in physiological and pathological forms of cardiac hypertrophy. Physiological cardiac growth resulting from postnatal maturation or endurance exercise is associated with increased PGC-1 expression and marked expansion of mitochondrial volume density and oxidative capacity. Conversely, pathological hypertrophy is linked to decreased PGC-1 and mitochondrial dysfunction. Cardiomyopathic remodeling also is associated with damaged and dysfunctional mitochondria, leading to intramyocellular lipid accumulation and reactive oxygen species generation. Moreover, in failing heart, mitochondrial dysfunction may lead to an energy-deficient state, which could contribute to the pathology of the disease.

The development of mouse models with altered PGC-1 activity has provided the opportunity to address whether the deactivation of the PGC-1 regulatory system is adaptive or maladaptive under pathological conditions. The PGC-1^–/– mice produced by the Spiegelman laboratory exhibit moderate, age-related baseline cardiac dysfunction.⁹¹ In contrast, PGC-1^–/– mice produced by the Kelly laboratory do not exhibit cardiac dysfunction under basal conditions. However, this second line of PGC-1^–/– mice exhibit a blunted heart rate response to exercise and ß-adrenergic stimulation.⁸⁹ Similarly, mice lacking PGC-1ß also exhibit an impaired chronotropic response to dobutamine stimulation.⁹⁴ Mice lacking PGC-1 develop signatures of heart failure, including a marked drop in cellular ATP concentration, when a band is placed around the aorta to induce pressure overload.³⁴ Interestingly, PGC-1 overexpression prevented cyclin-dependent kinase 9–mediated deactivation of mitochondrial gene expression and apoptosis.³¹ These studies strongly suggest that the mitochondrial derangements known to occur in the failing heart are, at least in part, related to a downregulation of the PGC-1 regulatory cascade. The specific circuits downstream of PGC-1 involved in this pathological response represent an area of active investigation.

Several mouse models with prolonged tissue-specific overexpression of PGC-1 also have provided insight into the relationship between dysregulation of PGC-1 and cardiac function. Mice with constitutive, cardiac-specific PGC-1 overexpression (MHC–PGC-1 mice) exhibit activation of cardiac myocyte mitochondrial biogenesis, leading ultimately to death from heart failure.⁵¹ Subsequently, a tissue-specific, tetracycline-inducible PGC-1 mouse was established (tet-on PGC-1 mice).⁸⁸ In both models, prolonged cardiac PGC-1 overexpression caused a mitochondrial biogenic response and cardiomyopathy associated with mitochondrial ultrastructural abnormalities. The basis for cardiomyopathy after PGC-1 activation is unknown but likely involves dysregulated mitochondrial metabolism and/or alterations in sarcomeric proteins. It is interesting to note that in human skeletal muscle disease states associated with genetic defects in the mitochondrial genome, a secondary mitochondrial biogenesis occurs, leading to the "ragged red fiber" histological appearance.⁹⁵ The role of this exuberant mitochondrial proliferation in the pathogenesis of striated muscle disease is unknown, but it is tempting to speculate that the proliferative response involves activation of the PGC-1 regulatory cascade.

Many questions about the mechanistic basis for cardiac dysfunction in the setting of energy metabolic abnormalities related to altered PGC-1 activity remain unanswered. What is the compensatory role for the remaining isoforms in the context of isolated PGC-1 or PGC-1ß deficiency? What role do energy metabolic abnormalities play in the functional deficits, and can our understanding of human cardiomyopathies be enhanced by these mouse models? Finally, is the PGC-1 regulatory circuit a target for metabolic modulation therapies aimed at the failing heart?

	Implications for Human Heart Disease

Top Introduction Mitochondrial Fatty Acid and... Evidence for a Link... The PGC-1 Family of... Transcriptional Control of... The Critical Role of... Do Derangements in PGC-1{alpha}... Implications for Human Heart... References

 
Despite a relative abundance of information on the effects of PGC-1 in isolated cardiac myocytes or rodent model systems, little is known about the regulation and physiological roles of PGC-1 in human heart. PGC-1 is abundantly expressed in human skeletal muscle and myocardium.⁵⁴ However, to the best of our knowledge, it is unknown whether PGC-1 expression or activity is diminished in the failing heart or activated during physiological hypertrophic growth in humans. Interestingly, single nucleotide polymorphisms in the PGC-1 gene have been identified and linked to susceptibility to insulin resistance and type 2 diabetes mellitus.^96–99 However, whether these single nucleotide polymorphisms also are associated with increased risk of cardiovascular disease or outcome after a coronary event is not yet clear.

If PGC-1 proves to be an important determinant of cardiac function in human subjects, therapies aimed at specifically modulating cardiac PGC-1 activity may be useful to remedy cardiomyopathic disease. For example, specific PGC-1 regulatory limbs could be selectively enhanced by pharmacological activation of PPARs or ERRs. However, this approach must be viewed with caution, given that long-term PPAR activation can lead to cardiomyopathic remodeling.^70,100 Moreover, ligand administration would indiscriminately activate these nuclear receptors in all tissues. The inducible nature of PGC-1 gene expression gives hope that pharmacological or physiological stimuli also could be used to activate its expression. Although definitive proof is lacking, the benefits of exercise training in heart failure patients might involve induction of PGC-1 and its downstream gene regulatory program in both skeletal muscle and heart. Given recent progress in gene therapies that target the myocardium, it is possible that PGC-1 could be overexpressed via vectors that localize specifically to the heart. If so, modified forms of PGC-1 capable of activating specific metabolic programs could be delivered to the heart. However, this would likely require intermittent pulse therapy, given the adverse consequences associated with long-term activation of the cardiac PGC-1 pathway. Obviously, significant technical hurdles exist, and proof-of-principle studies in animal models are necessary. Nevertheless, metabolic therapies targeted to the PGC-1 cascade could prove to be a fruitful therapeutic avenue.

	Acknowledgments

 
We are indebted to all Kelly Laboratory members, past and present, who have contributed to the work presented here. We also wish to thank Mary Wingate for expert assistance in preparing this manuscript.

Sources of Funding

Part of the work described in this review was supported by National Institutes of Health grants R01 DK45416, R01 HL58493, P50 HL077113, and P01 HL57278; Clinical Nutrition Research Unit Core Center (P30 DK56341); Digestive Diseases Research Core Center (P30 DK52574); and Diabetes Research and Training Center (P60 DK20579).

Disclosures

Dr Kelly is a scientific consultant for GlaxoSmithKline, Novartis, and Phrixus, Inc.

	Footnotes

 
This article is the first in a series on the topic of "Targeting Metabolism as a Therapeutic Approach for Cardiovascular Diseases."

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Top Introduction Mitochondrial Fatty Acid and... Evidence for a Link... The PGC-1 Family of... Transcriptional Control of... The Critical Role of... Do Derangements in PGC-1{alpha}... Implications for Human Heart... References

 
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