The heart requires highly efficient metabolism to maintain the levels of ATP needed for contractility and pump function. Aberrant cardiac metabolism is associated with obesity, type 2 diabetes and heart failure, which represent major health epidemics. Nuclear hormone receptors and their coactivators and corepressors play critical roles in the control of energy metabolism by regulating the expression of genes involved in energy homeostasis and mitochondrial function. Transcriptional control by nuclear hormone receptors is mediated by the Mediator, a large multiprotein complex that functions as a hub to control gene expression through association with transcriptional activators and repressors. We have discovered that MED13/Thrap1, a component of the Mediator complex, functions as a central regulator of cardiac metabolism and, in so doing, influences cardiac function and metabolic homeostasis in mice. Thus, elevated cardiac expression of MED13 enhances cardiac function and metabolic rate and confers resistance to obesity, whereas MED13 deficiency in the heart causes diminished cardiac metabolism and susceptibility to obesity. MED13 is negatively regulated by microRNAs 208 and 378, which control stress-dependent cardiac remodeling and metabolism. The overall goals of this project are to define the precise mechanisms whereby MED13 and the microRNAs that regulate it control metabolism, energy homeostasis, mitochondrial biogenesis, cardiac stress-responsiveness and phenotypic switching of cardiac and skeletal muscles. These studies will provide important new insights into a previously unrecognized regulatory network for the control of striated muscle metabolism and function, and will open opportunities for therapeutic modulation of metabolic syndromes and muscle diseases through the Mediator-microRNA network.

Public Health Relevance

Dysregulation of cardiac metabolism and mitochondrial function is associated with obesity, type 2 diabetes, and heart failure, diseases with catastrophic cardiovascular outcomes. We have discovered that MED13/Thrap1, a component of the Mediator complex, functions as a central regulator of cardiac metabolism and, in so doing, influences cardiac function and metabolic homeostasis. By defining the mechanisms whereby MED13 controls metabolism and energy homeostasis, we will provide new insights into the regulation of muscle energy metabolism and offer novel therapeutic strategies for modulating these processes in the settings of heart and skeletal muscle disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111665-02
Application #
8389880
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2011-12-01
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2013
Total Cost
$528,320
Indirect Cost
$196,043
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Amoasii, Leonela; Olson, Eric N; Bassel-Duby, Rhonda (2018) Control of Muscle Metabolism by the Mediator Complex. Cold Spring Harb Perspect Med 8:
Polster, Alexander; Nelson, Benjamin R; Papadopoulos, Symeon et al. (2018) Stac proteins associate with the critical domain for excitation-contraction coupling in the II-III loop of CaV1.1. J Gen Physiol 150:613-624
Zhang, Yu; Long, Chengzu; Li, Hui et al. (2017) CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice. Sci Adv 3:e1602814
Kyrychenko, Viktoriia; Kyrychenko, Sergii; Tiburcy, Malte et al. (2017) Functional correction of dystrophin actin binding domain mutations by genome editing. JCI Insight 2:
Abad, Maria; Hashimoto, Hisayuki; Zhou, Huanyu et al. (2017) Notch Inhibition Enhances Cardiac Reprogramming by Increasing MEF2C Transcriptional Activity. Stem Cell Reports 8:548-560
Millay, Douglas P; Gamage, Dilani G; Quinn, Malgorzata E et al. (2016) Structure-function analysis of myomaker domains required for myoblast fusion. Proc Natl Acad Sci U S A 113:2116-21
Amoasii, Leonela; Holland, William; Sanchez-Ortiz, Efrain et al. (2016) A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism. Genes Dev 30:434-46
Carroll, Kelli J; Makarewich, Catherine A; McAnally, John et al. (2016) A mouse model for adult cardiac-specific gene deletion with CRISPR/Cas9. Proc Natl Acad Sci U S A 113:338-43
Long, Chengzu; Amoasii, Leonela; Mireault, Alex A et al. (2016) Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science 351:400-3
Tao, Ge; Kahr, Peter C; Morikawa, Yuka et al. (2016) Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury. Nature 534:119-23

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