title: Long-Term Endurance Exercise in Humans Stimulates Cell Fusion of Myoblasts along with Fusogenic Endogenous Retroviral Genes In Vivo.
abstract: Myogenesis is defined as growth, differentiation and repair of muscles where cell fusion of myoblasts to multinucleated myofibers is one major characteristic. Other cell fusion events in humans are found with bone resorbing osteoclasts and placental syncytiotrophoblasts. No unifying gene regulation for natural cell fusions has been found. We analyzed skeletal muscle biopsies of competitive cyclists for muscle-specific attributes and expression of human endogenous retrovirus (ERV) envelope genes due to their involvement in cell fusion of osteoclasts and syncytiotrophoblasts. Comparing muscle biopsies from post- with the pre-competitive seasons a significant 2.25-fold increase of myonuclei/mm fiber, a 2.38-fold decrease of fiber area/nucleus and a 3.1-fold decrease of satellite cells (SCs) occurred. We propose that during the pre-competitive season SC proliferation occurred following with increased cell fusion during the competitive season. Expression of twenty-two envelope genes of muscle biopsies demonstrated a significant increase of putative muscle-cell fusogenic genes Syncytin-1 and Syncytin-3, but also for the non-fusogenic erv3. Immunohistochemistry analyses showed that Syncytin-1 mainly localized to the sarcolemma of myofibers positive for myosin heavy-chain isotypes. Cellular receptors SLC1A4 and SLC1A5 of Syncytin-1 showed significant decrease of expression in post-competitive muscles compared with the pre-competitive season, but only SLC1A4 protein expression localized throughout the myofiber. Erv3 protein was strongly expressed throughout the myofiber, whereas envK1-7 localized to SC nuclei and myonuclei. Syncytin-1 transcription factors, PPARγ and RXRα, showed no protein expression in the myofiber, whereas the pCREB-Ser133 activator of Syncytin-1 was enriched to SC nuclei and myonuclei. Syncytin-1, Syncytin-3, SLC1A4 and PAX7 gene regulations along with MyoD1 and myogenin were verified during proliferating or actively-fusing human primary myoblast cell cultures, resembling muscle biopsies of cyclists. Myoblast treatment with anti-Synycytin-1 abrogated cell fusion in vitro. Our findings support functional roles for ERV envelope proteins, especially Syncytin-1, contributing to cell fusion of myotubes.
authors.affiliation: Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Am Sportpark Muengersdorf, Cologne, Germany; University Hospital Zurich, Department of Neurology, Frauenklinikstrasse, Zurich, Switzerland; Institute of Human Movement Sciences and Sport, Exercise Physiology, ETH Zurich, Winterthurerstrasse, Zurich, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Frese
authors.affiliation: Friedrich-Alexander University Erlangen-Nürnberg, University-Clinic Erlangen, Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, Erlangen, Universitaetsstrasse, Erlangen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ruebner
authors.affiliation: Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Am Sportpark Muengersdorf, Cologne, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Suhr
authors.affiliation: Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Am Sportpark Muengersdorf, Cologne, Germany.
authors.forename: Thierry M
authors.initials: TM
authors.lastname: Konou
authors.affiliation: Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Am Sportpark Muengersdorf, Cologne, Germany.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Tappe
authors.affiliation: Institute of Human Movement Sciences and Sport, Exercise Physiology, ETH Zurich, Winterthurerstrasse, Zurich, Switzerland; University of Zurich, Balgrist University Hospital, Department of Orthopaedics, Forchstrasse, Zurich, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Toigo
authors.affiliation: University Hospital Zurich, Department of Neurology, Frauenklinikstrasse, Zurich, Switzerland.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Jung
authors.affiliation: Friedrich-Alexander University Erlangen-Nürnberg, University-Clinic Erlangen, Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, Erlangen, Universitaetsstrasse, Erlangen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Henke
authors.affiliation: Friedrich-Alexander University Erlangen-Nürnberg, University-Clinic Erlangen, Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, Erlangen, Universitaetsstrasse, Erlangen, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Steigleder
authors.affiliation: Friedrich-Alexander University Erlangen-Nürnberg, University-Clinic Erlangen, Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, Erlangen, Universitaetsstrasse, Erlangen, Germany.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Strissel
authors.affiliation: Friedrich-Alexander University Erlangen-Nürnberg, University-Clinic Erlangen, Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, Erlangen, Universitaetsstrasse, Erlangen, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Huebner
authors.affiliation: Friedrich-Alexander University Erlangen-Nürnberg, University-Clinic Erlangen, Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, Erlangen, Universitaetsstrasse, Erlangen, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.affiliation: Institute of Anatomy, Friedrich-Alexander University of Erlangen-Nürnberg, Krankenhausstrasse, Erlangen, Germany.
authors.forename: Piet
authors.initials: P
authors.lastname: van der Keylen
authors.affiliation: Ludwig Maximilian University Munich, Department of Neurology, Friedrich Baur Institute, Ziemssenstrasse, Munich, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
authors.affiliation: German Sport University Cologne, Outpatient Clinic for Sports Traumatology and Public Health Consultation, Am Sportpark Muengersdorf, Cologne, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schiffer
authors.affiliation: University Hospital and University Zurich, Division of Surgical Research, Raemistrasse, Zurich, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Frese
authors.affiliation: Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Am Sportpark Muengersdorf, Cologne, Germany; The German Research Centre of Elite Sport, German Sport University Cologne, Am Sportpark Muengersdorf, Cologne, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.affiliation: Friedrich-Alexander University Erlangen-Nürnberg, University-Clinic Erlangen, Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, Erlangen, Universitaetsstrasse, Erlangen, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Strick
mesh_terms: D000293:Adolescent; D001642:Bicycling; D002459:Cell Fusion; D002478:Cells, Cultured; D016616:Cryoultramicrotomy; D020077:Endogenous Retroviruses / Q000235:genetics*; D015444:Exercise; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005814:Genes, Viral; D006801:Humans; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000821:virology*; D010807:Physical Endurance; D060888:Real-Time Polymerase Chain Reaction; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism; D013997:Time Factors