Macronutrient Regulation of Alternative Pre-mRNA Splicing

Summary

Principal Investigator: Scot R Kimball
Abstract: DESCRIPTION (provided by applicant): We have recently discovered a novel and evolutionarily conserved homeostatic response wherein alternative splicing of the pre-mRNA encoding troponin T, a protein that affects muscle force production, is tightly regulated in response to changes in body weight. The effect is based on weight rather than mass or compartmentation of mass within the body because an external load has the same effect as an increment in native body weight. In contrast, the response is affected by body composition, as load-induced changes in troponin T pre-mRNA alternative splicing are impaired in obese, but not lean, Zucker rats, leading to inappropriate expression of troponin T isoforms. Moreover, in preliminary studies, we have found a similar dysregulation in rats fed a high-fat diet enriched in saturated fatty acids. Notably, high-fat diet-induced changes in troponin T pre-mRNA alternative splicing manifest prior to detectable alterations in either body weight or composition, suggesting that alternative splicing is directly modulated in response to dietary macronutrients. In other preliminary studies we have found that the effect of a high-fat diet on pre-mRNA splicing is not unique to troponin T, but instead is observed for pre-mRNAs encoding an array of proteins. Hence, the objective of the studies proposed in the present application is to identify the mechanism(s) through which dietary fatty acids regulate alternative splicing of pre-mRNA, and delineate the functional consequences of such alterations. We hypothesize that consumption of a high-fat diet results in an altered pattern of pre-mRNA splicing in skeletal muscle, leading to expression of protein isoforms that exhibit reduced force production and/or calcium sensitivity, as well as altered metabolism. The hypothesis will be tested via the following three specific aims: (1) Establish optimal conditions for high-fat diet-induced changes in alternative splicing of the troponin T pre- mRNA in skeletal muscle, (2) Characterize high-fat diet-induced changes in the contractile properties of skeletal muscle, and, (3) Characterize and delineate the molecular mechanism(s) involved in high-fat diet- induced changes in alternative splicing of pre-mRNA in skeletal muscle across the transcriptome, and identify altered signaling and metabolic pathways. From these experiments, we will obtain an unprecedented scale and depth of understanding of how quantitative variation in alternative splicing is controlled, and how diet affects that regulation. In addition, the results will open a new window into how diet changes pathways involved in body weight homeostasis. Overall, the studies proposed here are highly original and will address a deficit in our knowledge about the plasticity of quantitative alternatie splicing in general, and mechanisms through which macronutrients affect and in some cases disrupt the way metazoans functionally and metabolically adapt to changes in their weight. We expect the proposed research to reveal biomarkers for pre-disease states caused by poor diet, and candidate molecules and pathways for pharmacological manipulation to provide new and innovative approaches for the prevention and treatment of metabolic disorders.
Funding Period: 2013-09-01 - 2017-08-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. 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. ..
  2. A MULTILEVEL APPROACH TO ENERGY BALANCE AND CANCER ACROSS THE LIFECOURSE
    Graham A Colditz; Fiscal Year: 2013
    ..To address these aims, we propose four research projects and five cores that form a cohesive, transdisciplinary center focused on research, training/career development, and dissemination. ..
  3. Southern California Children's Enviromental Health Center (SC-CEHC)
    Rob S McConnell; Fiscal Year: 2013
    ....
  4. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  5. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  6. Carnitine Acetyltransferase in Defending Mitochondrial and Metabolic Function
    Deborah M Muoio; Fiscal Year: 2013
    ..Primary outcome measures will include indirect calorimetry, multiple measures of insulin action and metabolic flux, along with state-of-the-art mass spectrometry-based metabolic profiling. ..
  7. Genomic Analysis of the genotype-phenotype map
    Simon Tavare; Fiscal Year: 2013
    ..The goal of this project is to increase our understanding of the general principles that underlie the genotype-phenotype map by studying model organisms. ..
  8. The Wake Forest Center for Botanical Lipids and Inflammatory Disease Prevention
    Floyd H Chilton; Fiscal Year: 2013
    ....
  9. Genetic and Metabolic Fingerprints of Coativators "Program Project"
    BERT W O'MALLEY; Fiscal Year: 2013
    ..When complete, this PPG will afford a much greater understanding of NR and coregulator biology and will help define novel therapeutic leverage points for intervention of diseases associated with MS. ..
  10. Center of Research on Obesity and Cardiovascular Diseases
    Lisa A Cassis; Fiscal Year: 2013
    ....
  11. System Biology Center in New York
    SRINIVAS RAVI V IYENGAR; Fiscal Year: 2013
    ..abstract_text> ..
  12. Translational Systems Genetics of Mitochondria, Metabolism, and Aging
    Robert W Williams; Fiscal Year: 2013
    ....
  13. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
    ..This highly-integrated Program will make significant progress toward understanding the pathobiology of the enteric system in gastric emptying disorders and translate this knowledge into new diagnostic tools and therapy. ..
  14. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  15. IL-15 receptor-alpha and IL-15 action in aging skeletal muscle and adipose tissue
    LeBris S Quinn; Fiscal Year: 2013
    ..These studies will provide mechanistic information which could be exploited pharmacologically to modulate body composition and the pathological consequences of sarcopenia and adiposity in the elderly. ..
  16. Novel Mechanistic Targets of Steroid Hormones in the Brain
    Meharvan Singh; Fiscal Year: 2013
    ....
  17. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  18. Mechanism of Insulin Resistance in the Aged.
    Kitt F Petersen; Fiscal Year: 2013
    ....
  19. 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. ..
  20. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
    ....
  21. Transcriptome processing networks in skeletal muscle: mechanisms and functions
    THOMAS ALEXANDER COOPER; Fiscal Year: 2013
    ..This information will be used to understand normal processes in skeletal muscle useful for future development of therapeutic approaches to reverse or circumvent disease. ..
  22. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  23. 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. ..
  24. MYOSIN GENE DIVERSITY AND FUNCTION
    LESLIE ANNE LEINWAND; Fiscal Year: 2013
    ..These studies will allow us to integrate the in vitro biochemical/biophysical data into the context of functioning muscle. ..
  25. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
    ..abstract_text> ..
  26. The Impact of Maternal Health and Diet on Development of Fetal Metabolic Systems
    KENT L R THORNBURG; Fiscal Year: 2013
    ..The NHP is a critical model to identify these mechanisms because ofthe simlarities in development, as well as structure and function of metabolic systems..