title: Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation.
abstract: Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor β superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes. In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain. We also highlight recent clinical findings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease. Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during development, growth, and aging.
authors.affiliation: From the Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., L.K., S.M.B., J.O., S.W., L.L.R., A.J.W., R.T.L.); Department of Neuroscience, Institut Pasteur, Paris, France (L.K.); Cardiovascular Division (T.P.), Department of Medicine, Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (Y.W.F., R.T.L.); Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA (J.O., S.W., A.J.W.); Division of Cardiology, Universitäres Herzzentrum, Zürich, Switzerland (B.H.); Department of Medicine, University of California, San Francisco (B.H., P.G.); and Division of Cardiology, San Francisco General Hospital, CA (P.G.).
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Walker
authors.affiliation: From the Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., L.K., S.M.B., J.O., S.W., L.L.R., A.J.W., R.T.L.); Department of Neuroscience, Institut Pasteur, Paris, France (L.K.); Cardiovascular Division (T.P.), Department of Medicine, Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (Y.W.F., R.T.L.); Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA (J.O., S.W., A.J.W.); Division of Cardiology, Universitäres Herzzentrum, Zürich, Switzerland (B.H.); Department of Medicine, University of California, San Francisco (B.H., P.G.); and Division of Cardiology, San Francisco General Hospital, CA (P.G.).
authors.forename: Tommaso
authors.initials: T
authors.lastname: Poggioli
authors.affiliation: From the Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., L.K., S.M.B., J.O., S.W., L.L.R., A.J.W., R.T.L.); Department of Neuroscience, Institut Pasteur, Paris, France (L.K.); Cardiovascular Division (T.P.), Department of Medicine, Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (Y.W.F., R.T.L.); Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA (J.O., S.W., A.J.W.); Division of Cardiology, Universitäres Herzzentrum, Zürich, Switzerland (B.H.); Department of Medicine, University of California, San Francisco (B.H., P.G.); and Division of Cardiology, San Francisco General Hospital, CA (P.G.).
authors.forename: Lida
authors.initials: L
authors.lastname: Katsimpardi
authors.affiliation: From the Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., L.K., S.M.B., J.O., S.W., L.L.R., A.J.W., R.T.L.); Department of Neuroscience, Institut Pasteur, Paris, France (L.K.); Cardiovascular Division (T.P.), Department of Medicine, Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (Y.W.F., R.T.L.); Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA (J.O., S.W., A.J.W.); Division of Cardiology, Universitäres Herzzentrum, Zürich, Switzerland (B.H.); Department of Medicine, University of California, San Francisco (B.H., P.G.); and Division of Cardiology, San Francisco General Hospital, CA (P.G.).
authors.forename: Sean M
authors.initials: SM
authors.lastname: Buchanan
authors.affiliation: From the Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., L.K., S.M.B., J.O., S.W., L.L.R., A.J.W., R.T.L.); Department of Neuroscience, Institut Pasteur, Paris, France (L.K.); Cardiovascular Division (T.P.), Department of Medicine, Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (Y.W.F., R.T.L.); Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA (J.O., S.W., A.J.W.); Division of Cardiology, Universitäres Herzzentrum, Zürich, Switzerland (B.H.); Department of Medicine, University of California, San Francisco (B.H., P.G.); and Division of Cardiology, San Francisco General Hospital, CA (P.G.).
authors.forename: Juhyun
authors.initials: J
authors.lastname: Oh
authors.affiliation: From the Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., L.K., S.M.B., J.O., S.W., L.L.R., A.J.W., R.T.L.); Department of Neuroscience, Institut Pasteur, Paris, France (L.K.); Cardiovascular Division (T.P.), Department of Medicine, Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (Y.W.F., R.T.L.); Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA (J.O., S.W., A.J.W.); Division of Cardiology, Universitäres Herzzentrum, Zürich, Switzerland (B.H.); Department of Medicine, University of California, San Francisco (B.H., P.G.); and Division of Cardiology, San Francisco General Hospital, CA (P.G.).
authors.forename: Sam
authors.initials: S
authors.lastname: Wattrus
authors.affiliation: From the Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., L.K., S.M.B., J.O., S.W., L.L.R., A.J.W., R.T.L.); Department of Neuroscience, Institut Pasteur, Paris, France (L.K.); Cardiovascular Division (T.P.), Department of Medicine, Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (Y.W.F., R.T.L.); Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA (J.O., S.W., A.J.W.); Division of Cardiology, Universitäres Herzzentrum, Zürich, Switzerland (B.H.); Department of Medicine, University of California, San Francisco (B.H., P.G.); and Division of Cardiology, San Francisco General Hospital, CA (P.G.).
authors.forename: Bettina
authors.initials: B
authors.lastname: Heidecker
authors.affiliation: From the Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., L.K., S.M.B., J.O., S.W., L.L.R., A.J.W., R.T.L.); Department of Neuroscience, Institut Pasteur, Paris, France (L.K.); Cardiovascular Division (T.P.), Department of Medicine, Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (Y.W.F., R.T.L.); Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA (J.O., S.W., A.J.W.); Division of Cardiology, Universitäres Herzzentrum, Zürich, Switzerland (B.H.); Department of Medicine, University of California, San Francisco (B.H., P.G.); and Division of Cardiology, San Francisco General Hospital, CA (P.G.).
authors.forename: Yick W
authors.initials: YW
authors.lastname: Fong
authors.affiliation: From the Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., L.K., S.M.B., J.O., S.W., L.L.R., A.J.W., R.T.L.); Department of Neuroscience, Institut Pasteur, Paris, France (L.K.); Cardiovascular Division (T.P.), Department of Medicine, Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (Y.W.F., R.T.L.); Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA (J.O., S.W., A.J.W.); Division of Cardiology, Universitäres Herzzentrum, Zürich, Switzerland (B.H.); Department of Medicine, University of California, San Francisco (B.H., P.G.); and Division of Cardiology, San Francisco General Hospital, CA (P.G.).
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.affiliation: From the Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., L.K., S.M.B., J.O., S.W., L.L.R., A.J.W., R.T.L.); Department of Neuroscience, Institut Pasteur, Paris, France (L.K.); Cardiovascular Division (T.P.), Department of Medicine, Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (Y.W.F., R.T.L.); Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA (J.O., S.W., A.J.W.); Division of Cardiology, Universitäres Herzzentrum, Zürich, Switzerland (B.H.); Department of Medicine, University of California, San Francisco (B.H., P.G.); and Division of Cardiology, San Francisco General Hospital, CA (P.G.).
authors.forename: Peter
authors.initials: P
authors.lastname: Ganz
authors.affiliation: From the Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., L.K., S.M.B., J.O., S.W., L.L.R., A.J.W., R.T.L.); Department of Neuroscience, Institut Pasteur, Paris, France (L.K.); Cardiovascular Division (T.P.), Department of Medicine, Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (Y.W.F., R.T.L.); Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA (J.O., S.W., A.J.W.); Division of Cardiology, Universitäres Herzzentrum, Zürich, Switzerland (B.H.); Department of Medicine, University of California, San Francisco (B.H., P.G.); and Division of Cardiology, San Francisco General Hospital, CA (P.G.).
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Thompson
authors.affiliation: From the Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., L.K., S.M.B., J.O., S.W., L.L.R., A.J.W., R.T.L.); Department of Neuroscience, Institut Pasteur, Paris, France (L.K.); Cardiovascular Division (T.P.), Department of Medicine, Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (Y.W.F., R.T.L.); Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA (J.O., S.W., A.J.W.); Division of Cardiology, Universitäres Herzzentrum, Zürich, Switzerland (B.H.); Department of Medicine, University of California, San Francisco (B.H., P.G.); and Division of Cardiology, San Francisco General Hospital, CA (P.G.). RLee@bwh.harvard.edu amy_wagers@harvard.edu.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.affiliation: From the Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., L.K., S.M.B., J.O., S.W., L.L.R., A.J.W., R.T.L.); Department of Neuroscience, Institut Pasteur, Paris, France (L.K.); Cardiovascular Division (T.P.), Department of Medicine, Brigham Regenerative Medicine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (Y.W.F., R.T.L.); Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA (J.O., S.W., A.J.W.); Division of Cardiology, Universitäres Herzzentrum, Zürich, Switzerland (B.H.); Department of Medicine, University of California, San Francisco (B.H., P.G.); and Division of Cardiology, San Francisco General Hospital, CA (P.G.). RLee@bwh.harvard.edu amy_wagers@harvard.edu.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
mesh_terms: D000328:Adult; D000375:Aging / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*; D001921:Brain / Q000254:growth & development / Q000502:physiology; D019281:Dimerization; D005260:Female; D038681:Follistatin / Q000378:metabolism; D038702:Follistatin-Related Proteins / Q000378:metabolism; D055412:Growth Differentiation Factors / Q000737:chemistry / Q000172:deficiency / Q000502:physiology* / Q000627:therapeutic use; D006321:Heart / Q000502:physiology; D006331:Heart Diseases / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009132:Muscles / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D055435:Myostatin / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*; D009928:Organ Specificity; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D019485:Bone Morphogenetic Proteins; C503233:FST protein, human; D038681:Follistatin; D038702:Follistatin-Related Proteins; C000606403:Fstl3 protein, human; C492266:GDF11 protein, human; C119153:Gdf11 protein, mouse; C492267:Gdf11 protein, rat; D055412:Growth Differentiation Factors; C525911:MSTN protein, human; C525912:Mstn protein, mouse; D055435:Myostatin
keywords: heart disease; ligands; muscle; myocardium