2. Academic Validation
  3. A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle

A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle

  • Science. 2016 Jan 15;351(6270):271-5. doi: 10.1126/science.aad4076.
Benjamin R Nelson 1,  Catherine A Makarewich 1,  Douglas M Anderson 1,  Benjamin R Winders 1,  Constantine D Troupes 2,  Fenfen Wu 3,  Austin L Reese 4,  John R McAnally 1,  Xiongwen Chen 2,  Ege T Kavalali 4,  Stephen C Cannon 3,  Steven R Houser 2,  Rhonda Bassel-Duby 1,  Eric N Olson 5
Affiliations

Affiliations

  • 1 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2 Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA. Department of Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
  • 3 Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 5 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. eric.olson@utsouthwestern.edu.
PMID: 26816378 DOI: 10.1126/science.aad4076
Abstract

Muscle contraction depends on release of CA(2+) from the sarcoplasmic reticulum (SR) and reuptake by the CA(2+)adenosine triphosphatase SERCA. We discovered a putative muscle-specific long noncoding RNA that encodes a peptide of 34 Amino acids and that we named dwarf open reading frame (DWORF). DWORF localizes to the SR membrane, where it enhances SERCA activity by displacing the SERCA inhibitors, phospholamban, sarcolipin, and myoregulin. In mice, overexpression of DWORF in cardiomyocytes increases peak CA(2+) transient amplitude and SR CA(2+) load while reducing the time constant of cytosolic CA(2+) decay during each cycle of contraction-relaxation. Conversely, slow skeletal muscle lacking DWORF exhibits delayed CA(2+) clearance and relaxation and reduced SERCA activity. DWORF is the only endogenous peptide known to activate the SERCA pump by physical interaction and provides a means for enhancing muscle contractility.

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