title: Supraphysiological levels of GDF11 induce striated muscle atrophy.
abstract: Growth and differentiation factor (GDF) 11 is a member of the transforming growth factor β superfamily recently identified as a potential therapeutic for age-related cardiac and skeletal muscle decrements, despite high homology to myostatin (Mstn), a potent negative regulator of muscle mass. Though several reports have refuted these data, thein vivoeffects of GDF11 on skeletal muscle mass have not been addressed. Usingin vitromyoblast culture assays, we first demonstrate that GDF11 and Mstn have similar activities/potencies on activating p-SMAD2/3 and induce comparable levels of differentiated myotube atrophy. We further demonstrate that adeno-associated virus-mediated systemic overexpression of GDF11 in C57BL/6 mice results in substantial atrophy of skeletal and cardiac muscle, inducing a cachexic phenotype not seen in mice expressing similar levels of Mstn. Greater cardiac expression ofTgfbr1may explain this GDF11-specific cardiac phenotype. These data indicate that bioactive GDF11 at supraphysiological levels cause wasting of both skeletal and cardiac muscle. Rather than a therapeutic agent, GDF11 should be viewed as a potential deleterious biomarker in muscle wasting diseases.
authors.affiliation: Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL, USA.|Myology Institute, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: David W
authors.identifier: 0000-0003-2129-4047
authors.initials: DW
authors.lastname: Hammers
authors.affiliation: Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL, USA.|Myology Institute, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Merscham-Banda
authors.affiliation: Cytokinetics Inc., San Francisco, CA, USA.
authors.forename: Jennifer Ying
authors.initials: JY
authors.lastname: Hsiao
authors.affiliation: Cytokinetics Inc., San Francisco, CA, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Engst
authors.affiliation: Cytokinetics Inc., San Francisco, CA, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hartman
authors.affiliation: Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL, USA lsweeney@ufl.edu.|Myology Institute, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: H Lee
authors.identifier: 0000-0002-6290-8853
authors.initials: HL
authors.lastname: Sweeney
mesh_terms: D000818:Animals; D001284:Atrophy; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis*; D000229:Dependovirus / Q000235:genetics; D015870:Gene Expression; D055412:Growth Differentiation Factors / Q000096:biosynthesis*; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D054792:Muscle, Striated / Q000473:pathology*; D032446:Myoblasts / Q000187:drug effects; D055435:Myostatin; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D019485:Bone Morphogenetic Proteins; C119153:Gdf11 protein, mouse; D055412:Growth Differentiation Factors; C525912:Mstn protein, mouse; D055435:Myostatin; D051899:Smad2 Protein; D051900:Smad3 Protein
keywords: activin receptor; cachexia; cardiac atrophy; muscle mass; myostatin