TY - JOUR
T1 - Muscle physiology
T2 - A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle
AU - Nelson, Benjamin R.
AU - Makarewich, Catherine A.
AU - Anderson, Douglas M.
AU - Winders, Benjamin R.
AU - Troupes, Constantine D.
AU - Wu, Fenfen
AU - Reese, Austin L.
AU - McAnally, John R.
AU - Chen, Xiongwen
AU - Kavalali, Ege T.
AU - Cannon, Stephen C.
AU - Houser, Steven R.
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
N1 - Funding Information:
Supported by NIH grant R01NS075044, the New York Stem Cell Foundation, and Deutsche Forschungsgemeinschaft grant VA 742/1-2. We thank R. Froemke, J. Goldberg, G. Maimon, D. Okobi, B. ?lveczky, and R. Tsien for comments on earlier versions of this manuscript; K. Katlowitz, K. Kuchibhotla, and J. Merel for assistance with statistics and analysis; and O. Tchernichovski for valuable discussions and for providing the birds used in this study. Supplement contains additional data. The authors declare no competing financial interests. Author contributions: D.V., G.K., and M.A.L. designed the research; D.V., G.K., and D.L. performed the research; D.V., G.K., D.L., and M.A.L. analyzed the data; D.L. contributed reagents and analytic tools; and D.V., G.K., and M.A.L. wrote the paper. We thank C. Long for advice and expertise, N. Beetz for cDNA, J. Cabrera for graphics, S. Johnson for technical support, and the University of Texas Southwestern Medical Center Live Cell Imaging Core Facility under the direction of K. Luby-Phelps. This work was supported by grants from the NIH (HL-077439, HL-111665, HL-093039, DK-099653, U01-HL-100401, and AR-063182), Fondation Leducq Networks of Excellence, Cancer Prevention and Research Institute of Texas, and the Robert A. Welch Foundation (grant 1-0025 to E.N.O.). B.R.N. was support by a National Institute of Arthritis and Musculoskeletal Diseases, NIH, Ruth L. Kirschstein National Research Service Award (NRSA) (F30AR067094).
PY - 2016/1/15
Y1 - 2016/1/15
N2 - Muscle contraction depends on release of Ca2+ from the sarcoplasmic reticulum (SR) and reuptake by the Ca2+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 Ca2+ transient amplitude and SR Ca2+ load while reducing the time constant of cytosolic Ca2+ decay during each cycle of contraction-relaxation. Conversely, slow skeletal muscle lacking DWORF exhibits delayed Ca2+ 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.
AB - Muscle contraction depends on release of Ca2+ from the sarcoplasmic reticulum (SR) and reuptake by the Ca2+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 Ca2+ transient amplitude and SR Ca2+ load while reducing the time constant of cytosolic Ca2+ decay during each cycle of contraction-relaxation. Conversely, slow skeletal muscle lacking DWORF exhibits delayed Ca2+ 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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U2 - 10.1126/science.aad4076
DO - 10.1126/science.aad4076
M3 - Article
C2 - 26816378
AN - SCOPUS:84954349046
VL - 351
SP - 271
EP - 275
JO - Science
JF - Science
SN - 0036-8075
IS - 6270
ER -