microRNAs (miRNAs) act as negative regulators of gene expression by inhibiting the translation or promoting the degradation of target mRNAs. Recent studies by our group and others have revealed profound and unexpected roles for miRNAs in the control of diverse aspects of cardiac function, including the control of myocyte growth, integrity of the ventricular wall, contractility, gene expression, and maintenance of cardiac rhythm, providing glimpses of undiscovered regulatory mechanisms and potential therapeutic targets for heart disease. Specific miRNAs are mis-expressed in diseased hearts, and gain and loss-of-function experiments in mice have shown these miRNAs to be necessary and sufficient for multiple forms of heart disease. Particularly fascinating is the discovery of a family of closely related miRNAs that are encoded by introns of myosin heavy chain genes. In the heart, these miRNAs control myosin expression, stress dependent growth and fibrosis, thyroid hormone responsiveness, and repress fast skeletal muscle gene expression. In skeletal muscle, a subset of these miRNAs regulates fast versus slow myofiber identity. We refer to these miRNAs and the myosin genes in which they are embedded, as the Myo-miR network. The Myo-miR network, which is evolutionarily conserved, is regulated by upstream signaling pathways and modulates downstream targets through mechanisms that are only beginning to be unveiled. The overall goal of this project is to define the molecular mechanisms whereby the Myo-miR network modulates cardiac and skeletal muscle function, development and disease. Ultimately, we hope to exploit our understanding of miRNA biology to uncover new disease mechanisms and therapeutic approaches for muscle disease.

Public Health Relevance

The goal of this project is to explore the mechanisms of action of stress-regulated microRNAs in the heart and, ultimately, to use our understanding of microRNA biology to uncover new disease mechanisms and therapeutic approaches for heart disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
Zip Code
Liu, Ning; Nelson, Benjamin R; Bezprozvannaya, Svetlana et al. (2014) Requirement of MEF2A, C, and D for skeletal muscle regeneration. Proc Natl Acad Sci U S A 111:4109-14
Baskin, Kedryn K; Bookout, Angie L; Olson, Eric N (2014) The heart-liver metabolic axis: defective communication exacerbates disease. EMBO Mol Med 6:436-8
Millay, Douglas P; Sutherland, Lillian B; Bassel-Duby, Rhonda et al. (2014) Myomaker is essential for muscle regeneration. Genes Dev 28:1641-6
Kreusser, Michael M; Lehmann, Lorenz H; Keranov, Stanislav et al. (2014) Cardiac CaM Kinase II genes ? and ? contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy. Circulation 130:1262-73
Olson, Eric N (2014) MicroRNAs as therapeutic targets and biomarkers of cardiovascular disease. Sci Transl Med 6:239ps3
Lee, Ji-Hoon; Bassel-Duby, Rhonda; Olson, Eric N (2014) Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila. Proc Natl Acad Sci U S A 111:9491-6
Mahmoud, Ahmed I; Porrello, Enzo R; Kimura, Wataru et al. (2014) Surgical models for cardiac regeneration in neonatal mice. Nat Protoc 9:305-11
Schober, Andreas; Nazari-Jahantigh, Maliheh; Wei, Yuanyuan et al. (2014) MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat Med 20:368-76
Aurora, Arin B; Porrello, Enzo R; Tan, Wei et al. (2014) Macrophages are required for neonatal heart regeneration. J Clin Invest 124:1382-92
Garg, Ankit; O'Rourke, Jason; Long, Chengzu et al. (2014) KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy. J Clin Invest 124:3529-39

Showing the most recent 10 out of 41 publications