title: Intertissue control of the nucleolus via a myokine-dependent longevity pathway.
abstract: Recent evidence indicates that skeletal muscle influences systemic aging, but little is known about the signaling pathways and muscle-released cytokines (myokines) responsible for this intertissue communication. Here, we show that muscle-specific overexpression of the transcription factor Mnt decreases age-related climbing defects and extends lifespan in Drosophila. Mnt overexpression in muscle autonomously decreases the expression of nucleolar components and systemically decreases rRNA levels and the size of the nucleolus in adipocytes. This nonautonomous control of the nucleolus, a regulator of ribosome biogenesis and lifespan, relies on Myoglianin, a myokine induced by Mnt and orthologous to human GDF11 and Myostatin. Myoglianin overexpression in muscle extends lifespan and decreases nucleolar size in adipocytes by activating p38 mitogen-activated protein kinase (MAPK), whereas Myoglianin RNAi in muscle has converse effects. Altogether, these findings highlight a key role for myokine signaling in the integration of signaling events in muscle and distant tissues during aging.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Developmental Biology, Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: fabio.demontis@stjude.org.
authors.forename: Fabio
authors.initials: F
authors.lastname: Demontis
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vishal K
authors.initials: VK
authors.lastname: Patel
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Norbert
authors.initials: N
authors.lastname: Perrimon
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002466:Cell Nucleolus / Q000378:metabolism*; D004330:Drosophila / Q000254:growth & development / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D008136:Longevity; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D055435:Myostatin / Q000235:genetics / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D029721:Drosophila Proteins; D055435:Myostatin; D012335:RNA, Ribosomal; D016212:Transforming Growth Factor beta; C121965:myo protein, Drosophila; D048051:p38 Mitogen-Activated Protein Kinases