title: GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration.
abstract: Age-related frailty may be due to decreased skeletal muscle regeneration. The role of TGF-β molecules myostatin and GDF11 in regeneration is unclear. Recent studies showed an age-related decrease in GDF11 and that GDF11 treatment improves muscle regeneration, which were contrary to prior studies. We now show that these recent claims are not reproducible and the reagents previously used to detect GDF11 are not GDF11 specific. We develop a GDF11-specific immunoassay and show a trend toward increased GDF11 levels in sera of aged rats and humans. GDF11 mRNA increases in rat muscle with age. Mechanistically, GDF11 and myostatin both induce SMAD2/3 phosphorylation, inhibit myoblast differentiation, and regulate identical downstream signaling. GDF11 significantly inhibited muscle regeneration and decreased satellite cell expansion in mice. Given early data in humans showing a trend for an age-related increase, GDF11 could be a target for pharmacologic blockade to treat age-related sarcopenia.
authors.affiliation: Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Egerman
authors.affiliation: Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cadena
authors.affiliation: Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Gilbert
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Angelika
authors.initials: A
authors.lastname: Meyer
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Hallie N
authors.initials: HN
authors.lastname: Nelson
authors.affiliation: Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Susanne E
authors.initials: SE
authors.lastname: Swalley
authors.affiliation: Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Mallozzi
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Jacobi
authors.affiliation: Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Lori L
authors.initials: LL
authors.lastname: Jennings
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Ieuan
authors.initials: I
authors.lastname: Clay
authors.affiliation: Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Laurent
authors.affiliation: Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Shenglin
authors.initials: S
authors.lastname: Ma
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: Brachat
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Estelle
authors.initials: E
authors.lastname: Lach-Trifilieff
authors.affiliation: Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Tea
authors.initials: T
authors.lastname: Shavlakadze
authors.affiliation: Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Anne-Ulrike
authors.initials: AU
authors.lastname: Trendelenburg
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Brack
authors.affiliation: Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA. Electronic address: david.glass@novartis.com.
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
mesh_terms: D000375:Aging; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D055412:Growth Differentiation Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D055435:Myostatin / Q000378:metabolism; D051381:Rats; D012038:Regeneration; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D019485:Bone Morphogenetic Proteins; C492266:GDF11 protein, human; C492267:Gdf11 protein, rat; D055412:Growth Differentiation Factors; D055435:Myostatin