Ca2+ controls cardiac function by acting as the primary regulator of the sarcomeric contractile machinery and as a second messenger in the signal transduction pathways that control cardiac growth, metabolism and pathological remodeling. Ca2+ handling in striated muscle is tightly regulated by Ca2+ pumps in the sarcoplasmic reticulum (SR) and plasma membranes that maintain intracellular Ca2+ levels ~10,000-fold lower than extracellular and SR concentrations. Ca2+ release from the SR membrane transiently increases Ca2+ levels in the cytosol, triggering actomyosin cross-bridge formation within the sarcomere to generate contractile force. Reuptake of Ca2+ into the SR by sarcoplasmic reticulum Ca2+-ATPase (SERCA) is necessary for muscle relaxation and restores SR Ca2+ levels for subsequent contraction-relaxation cycles. SERCA thus serves as a central regulator of cardiac function, as well as the pathogenic signaling cascades that drive heart disease. The activity of SERCA in the heart is modulated by phospholamban (PLN), a tiny peptide that interacts with SERCA in the SR membrane and diminishes Ca2+ pump activity. Recently, we discovered that a cardiac- specific RNA annotated as a long noncoding RNA actually encodes a previously unrecognized micropeptide, which we named DWORF (Dwarf Open Reading Frame). DWORF is localized to the SR of cardiomyocytes and interacts with SERCA. DWORF is among the most dramatically down-regulated proteins in failing hearts, pointing to its potential involvement in the response of the heart to stress and contractile dysfunction. The overall goals of this project are to define the functions of DWORF and to decipher the mechanisms that govern its expression in normal and diseased hearts. Manipulation of the activity of this novel micropeptide represents a potential strategy to enhance cardiac contractility in the setting of heart disease. The discovery of DWORF also provides a new inroad into our understanding of the signaling mechanisms involved in the control of cardiac function and suggests a previously unrecognized role for micropeptides in the control of cardiac physiology and pathology.

Public Health Relevance

Calcium controls heart function by regulating the contractile machinery and acting as a second messenger in signaling pathways that control cardiac growth, metabolism and pathological remodeling. We recently discovered a previously unrecognized micropeptide, which we named DWORF (Dwarf Open Reading Frame) that is involved in calcium handling and is among the most dramatically down-regulated proteins in failing hearts. The overall goals of this project are to define the functions of DWORF and to decipher the mechanisms that govern its expression in normal and diseased hearts. The discovery of DWORF provides a new inroad into our understanding of the signaling mechanisms involved in the control of cardiac function and suggests a previously unrecognized role for micropeptides in the control of cardiac physiology and pathology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL130253-01
Application #
9006942
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wong, Renee P
Project Start
2015-12-16
Project End
2019-11-30
Budget Start
2015-12-16
Budget End
2016-11-30
Support Year
1
Fiscal Year
2016
Total Cost
$554,826
Indirect Cost
$205,827
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
Liu, Ning; Garry, Glynnis A; Li, Stephen et al. (2017) A Twist2-dependent progenitor cell contributes to adult skeletal muscle. Nat Cell Biol 19:202-213
Baskin, Kedryn K; Makarewich, Catherine A; DeLeon, Susan M et al. (2017) MED12 regulates a transcriptional network of calcium-handling genes in the heart. JCI Insight 2:
Makarewich, Catherine A; Olson, Eric N (2017) Mining for Micropeptides. Trends Cell Biol 27:685-696
Papizan, James B; Garry, Glynnis A; Brezprozvannaya, Svetlana et al. (2017) Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice. J Clin Invest 127:3730-3740
Bi, Pengpeng; Ramirez-Martinez, Andres; Li, Hui et al. (2017) Control of muscle formation by the fusogenic micropeptide myomixer. Science 356:323-327
Kyrychenko, Viktoriia; Kyrychenko, Sergii; Tiburcy, Malte et al. (2017) Functional correction of dystrophin actin binding domain mutations by genome editing. JCI Insight 2:
Zhou, Huanyu; Morales, Maria Gabriela; Hashimoto, Hisayuki et al. (2017) ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression. Genes Dev 31:1770-1783
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
Moon, Jesung; Zhou, Huanyu; Zhang, Li-Shu et al. (2017) Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist. Proc Natl Acad Sci U S A 114:1649-1654
Shi, Jun; Bi, Pengpeng; Pei, Jimin et al. (2017) Requirement of the fusogenic micropeptide myomixer for muscle formation in zebrafish. Proc Natl Acad Sci U S A 114:11950-11955

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