PGC-1alpha Proteins and the Control of Energy Metabolism

Summary

Principal Investigator: Bruce M Spiegelman
Abstract: DESCRIPTION (provided by applicant): We are in the midst of an epidemic of metabolic diseases such as obesity and diabetes, so a better understanding of the basic pathways of energy homeostasis is critical to the development of new medical therapies. Previous studies, including work funded under this grant, have shown that the PGC1 coactivators are major regulators of energy metabolism in mammalian systems. PGC1a regulates mitochondrial biogenesis and oxidative metabolism in many tissues, and links these genetic programs to the external environment. PGC1a controls important metabolic programs in the liver, brown fat, heart and skeletal muscle. In skeletal muscle, the PGC1a gene is induced during many kinds of exercise in mice and humans, and drives programs of mitochondrial biogenesis, fiber-type switching and resistance to atrophy/dystrophy. Most recently, we have shown that PGC1a initiates a novel program of angiogenesis that is potent and independent of the canonical HIF angiogenesis pathway. In preliminary data for this proposal, we show that the PGC1a gene gives rise to several novel proteins in muscle via alternative splicing. The original PGC1a (now called PGC1a1) and a new shorter form (termed PGC1a4) are both highly induced during exercise in mice. When expressed in primary culture or in vivo, PGC1a4 induced muscle cell hypertrophy but not mitochondrial biogenesis. This hypertrophy is associated with regulation of several genes of the myostatin and IGF1 pathways, both key signaling transduction systems of muscle growth. Our first Aim will test the hypothesis that PGC1a4 plays an important role in regulating physiological muscle hypertrophy and metabolic disease in vivo. To do this, we will create transgenic models of having both gain and loss of function of PGC1a4 in mice. We will combine these with different experimental models of muscle hypertrophy, atrophy and metabolic disease, including diet and age-induced obesity and diabetes. Our second Aim will investigate the mechanisms by which PGC1a4 can effect these changes in muscle cell growth and function. We will focus initially on the hypothesis that PGC1a4 works through the IGF1 and myostatin systems, since genes of these pathways are both robustly regulated by PGC1a4. Our last Aim will focus on the interaction between PGC1a1 and AMP kinase. We have created a murine strain with mutations in the AMPK sites in PGC1a1, and we will now critically test the hypothesis that this functional interaction contributes to the metabolic actions of both molecules in skeletal muscle and liver. Together, these studies promise to elucidate a major new pathway controlling skeletal muscle hypertrophy and muscle function. This has a direct impact on our ability to understand and provide new therapies in important diseases of aging, muscular dystrophies and obesity/diabetes.
Funding Period: 2002-06-01 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. ncbi Partnership of PGC-1alpha and HNF4alpha in the regulation of lipoprotein metabolism
    James Rhee
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, One Jimmy Fund Way, Boston, MA 02115, USA
    J Biol Chem 281:14683-90. 2006
  2. pmc Modulation of PGC-1 coactivator pathways in brown fat differentiation through LRP130
    Marcus P Cooper
    Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
    J Biol Chem 283:31960-7. 2008
  3. pmc Sensitivity of lipid metabolism and insulin signaling to genetic alterations in hepatic peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression
    Jennifer L Estall
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, USA
    Diabetes 58:1499-508. 2009
  4. pmc Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging
    Tina Wenz
    Department of Neurology, University of Miami School of Medicine, Miami, FL33136, USA
    Proc Natl Acad Sci U S A 106:20405-10. 2009
  5. pmc PGC-1alpha negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb(alpha) axis
    Jennifer L Estall
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 106:22510-5. 2009
  6. pmc PGC-1alpha regulates a HIF2alpha-dependent switch in skeletal muscle fiber types
    Kyle A Rasbach
    Department of Cell Biology, The Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 107:21866-71. 2010
  7. pmc The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex
    Jun Wu
    Dana Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 13:160-9. 2011
  8. pmc Separation of the gluconeogenic and mitochondrial functions of PGC-1{alpha} through S6 kinase
    Yaniv Lustig
    Department of Cell Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
    Genes Dev 25:1232-44. 2011
  9. pmc Disorder-to-order transition underlies the structural basis for the assembly of a transcriptionally active PGC-1α/ERRγ complex
    Srikripa Devarakonda
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 108:18678-83. 2011
  10. pmc Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1alpha and oxidative phosphorylation
    Zoltan Arany
    Dana Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 105:4721-6. 2008

Research Grants

  1. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
  2. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
  3. Dysfunctional PGC-1alpha expression in skeletal muscle during diabetes
    S Russ Price; Fiscal Year: 2013
  4. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  5. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
  6. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
  7. Calcineurin signaling, PGC-1 alpha and protein-energy wasting in kidney disease
    S Russ Price; Fiscal Year: 2013
  8. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
  9. Regulation of glycolytic muscle metabolism
    Jiandie D Lin; Fiscal Year: 2013
  10. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013

Detail Information

Publications21

  1. ncbi Partnership of PGC-1alpha and HNF4alpha in the regulation of lipoprotein metabolism
    James Rhee
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, One Jimmy Fund Way, Boston, MA 02115, USA
    J Biol Chem 281:14683-90. 2006
    ..These data point to a crucial role for the PGC-1alpha/HNF4alpha partnership in hepatic lipoprotein metabolism...
  2. pmc Modulation of PGC-1 coactivator pathways in brown fat differentiation through LRP130
    Marcus P Cooper
    Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
    J Biol Chem 283:31960-7. 2008
    ..Conversely, the cAMP response controlled by PGC-1alpha is not regulated by LRP130. These data implicate LRP130 in brown fat cell development and differentiation...
  3. pmc Sensitivity of lipid metabolism and insulin signaling to genetic alterations in hepatic peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression
    Jennifer L Estall
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA, USA
    Diabetes 58:1499-508. 2009
    ..However, how moderate changes in PGC-1alpha activity affect metabolism and energy homeostasis has yet to be determined...
  4. pmc Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging
    Tina Wenz
    Department of Neurology, University of Miami School of Medicine, Miami, FL33136, USA
    Proc Natl Acad Sci U S A 106:20405-10. 2009
    ....
  5. pmc PGC-1alpha negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb(alpha) axis
    Jennifer L Estall
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 106:22510-5. 2009
    ..Thus, PGC-1alpha can impact hepatic and systemic metabolism by regulating the levels of a nuclear receptor ligand...
  6. pmc PGC-1alpha regulates a HIF2alpha-dependent switch in skeletal muscle fiber types
    Kyle A Rasbach
    Department of Cell Biology, The Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 107:21866-71. 2010
    ..These data indicate that HIF2α acts downstream of PGC-1α as a key regulator of a muscle fiber-type program and the adaptive response to exercise...
  7. pmc The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex
    Jun Wu
    Dana Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 13:160-9. 2011
    ..These findings suggest that modulation of the UPR through PGC1α represents an alternative avenue to improve skeletal muscle function and achieve metabolic benefits...
  8. pmc Separation of the gluconeogenic and mitochondrial functions of PGC-1{alpha} through S6 kinase
    Yaniv Lustig
    Department of Cell Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
    Genes Dev 25:1232-44. 2011
    ..These data illustrate that S6 kinase can modify PGC-1α and thus allow molecular dissection of its functions, providing metabolic flexibility needed for dietary adaptation...
  9. pmc Disorder-to-order transition underlies the structural basis for the assembly of a transcriptionally active PGC-1α/ERRγ complex
    Srikripa Devarakonda
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 108:18678-83. 2011
    ..These data also provide structural insight into the versatile coactivation profile of PGC-1α and can readily be extended to understand other transcriptional coregulators...
  10. pmc Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1alpha and oxidative phosphorylation
    Zoltan Arany
    Dana Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 105:4721-6. 2008
    ..Moreover, the data identify microtubule inhibitors and protein synthesis inhibitors as modulators of PGC-1alpha and oxidative phosphorylation...
  11. pmc Abnormal glucose homeostasis in skeletal muscle-specific PGC-1alpha knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk
    Christoph Handschin
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA
    J Clin Invest 117:3463-74. 2007
    ..These data clearly illustrate a causal role for muscle PGC-1alpha in maintenance of glucose homeostasis and highlight an unexpected cytokine-mediated crosstalk between skeletal muscle and pancreatic islets...
  12. ncbi Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals
    Christoph Handschin
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 282:30014-21. 2007
    ..Our data demonstrate a critical role for PGC-1alpha in maintenance of normal fiber type composition and of muscle fiber integrity following exertion...
  13. ncbi Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation
    Marc Uldry
    Dana Farber Cancer Institute, Harvard Medical School, 1 Jimmy Fund Way, Boston, MA 02115, USA
    Cell Metab 3:333-41. 2006
    ....
  14. pmc Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-gamma coactivator 1alpha
    Zoltan Arany
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 103:10086-91. 2006
    ..Moreover, the data suggest that elevating PGC-1alpha activity may have therapeutic potential in the treatment of heart failure...
  15. ncbi Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism
    Christophe Handschin
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Endocr Rev 27:728-35. 2006
    ..Recent studies have elucidated the function of the PGC-1 coactivators in different tissues and have highlighted the implications of PGC-1 dysregulation in diseases such as diabetes, obesity, cardiomyopathy, or neurodegeneration...
  16. pmc Defects in energy homeostasis in Leigh syndrome French Canadian variant through PGC-1alpha/LRP130 complex
    Marcus P Cooper
    Dana Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Genes Dev 20:2996-3009. 2006
    ..These data link LRP130 and PGC-1alpha to defective hepatic energy homeostasis in LSFC, and reveal a novel regulatory mechanism of glucose homeostasis...
  17. pmc Hypomorphic mutation of PGC-1beta causes mitochondrial dysfunction and liver insulin resistance
    Claudia R Vianna
    Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
    Cell Metab 4:453-64. 2006
    ..Importantly, these abnormalities do not cause insulin resistance in skeletal muscle but cause substantially reduced insulin action in the liver...
  18. ncbi The transcriptional coactivator PGC-1beta drives the formation of oxidative type IIX fibers in skeletal muscle
    Zoltan Arany
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 5:35-46. 2007
    ..Consequently, these transgenic animals can run for longer and at higher work loads than wild-type animals. Together, these data indicate that PGC-1beta drives the formation of highly oxidative fibers containing type IIX MHC...
  19. pmc PGC-1alpha regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy
    Christoph Handschin
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Genes Dev 21:770-83. 2007
    ..Thus, control of PGC-1alpha levels in skeletal muscle could represent a novel avenue to prevent or treat DMD...
  20. pmc A fundamental system of cellular energy homeostasis regulated by PGC-1alpha
    Lindsay M Rohas
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 104:7933-8. 2007
    ..In light of this compensatory system that limits the toxicity of mild uncoupling, the use of chemical uncoupling of mitochondria as a means of treating obesity should be re-evaluated...
  21. pmc A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy
    Jorge L Ruas
    Department of Cell Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
    Cell 151:1319-31. 2012
    ..Expression of PGC-1α4 is preferentially induced in mouse and human muscle during resistance exercise. These studies identify a PGC-1α protein that regulates and coordinates factors involved in skeletal muscle hypertrophy...

Research Grants30

  1. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  2. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  3. Dysfunctional PGC-1alpha expression in skeletal muscle during diabetes
    S Russ Price; Fiscal Year: 2013
    ..Use of Cn inhibitors could have a negative impact on both types of patients. Lastly, our results could be broadly applicable to Veterans suffering from many types of debilitating diseases associated with atrophy. ..
  4. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  5. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  6. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  7. Calcineurin signaling, PGC-1 alpha and protein-energy wasting in kidney disease
    S Russ Price; Fiscal Year: 2013
    ..Given the similarities of the wasting syndromes in a broad range of debilitating diseases (e.g., cancer, diabetes, heart disease), our findings may be widely applicable to many patients. ..
  8. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  9. Regulation of glycolytic muscle metabolism
    Jiandie D Lin; Fiscal Year: 2013
    ....
  10. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
    ..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..
  11. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  12. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..