title: Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects?
abstract: This "Controversies in Cardiovascular Research" article evaluates the evidence for and against the hypothesis that the circulating blood level of growth differentiation factor 11 (GDF11) decreases in old age and that restoring normal GDF11 levels in old animals rejuvenates their skeletal muscle and reverses pathological cardiac hypertrophy and cardiac dysfunction. Studies supporting the original GDF11 hypothesis in skeletal and cardiac muscle have not been validated by several independent groups. These new studies have either found no effects of restoring normal GDF11 levels on cardiac structure and function or have shown that increasing GDF11 or its closely related family member growth differentiation factor 8 actually impairs skeletal muscle repair in old animals. One possible explanation for what seems to be mutually exclusive findings is that the original reagent used to measure GDF11 levels also detected many other molecules so that age-dependent changes in GDF11 are still not well known. The more important issue is whether increasing blood [GDF11] repairs old skeletal muscle and reverses age-related cardiac pathologies. There are substantial new and existing data showing that GDF8/11 can exacerbate rather than rejuvenate skeletal muscle injury in old animals. There is also new evidence disputing the idea that there is pathological hypertrophy in old C57bl6 mice and that GDF11 therapy can reverse cardiac pathologies. Finally, high [GDF11] causes reductions in body and heart weight in both young and old animals, suggestive of a cachexia effect. Our conclusion is that elevating blood levels of GDF11 in the aged might cause more harm than good.
authors.affiliation: From the Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (S.C.H., S.R.H.); Eli and Edythe Broad Center of Stem Cell Research and Regeneration Medicine, Department of Orthopaedic Surgery, University of California, San Francisco (A.B.); Department of Cardiovascular Research (S.M.), and Department of Research Beyond Borders (M.F.), Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT (S.M., M.F.); Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (B.B.O.); Department of Biology, Ursinus College, Collegeville, PA (B.A.B.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada (M.A.R.); and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (M.A.R.).
authors.forename: Shavonn C
authors.initials: SC
authors.lastname: Harper
authors.affiliation: From the Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (S.C.H., S.R.H.); Eli and Edythe Broad Center of Stem Cell Research and Regeneration Medicine, Department of Orthopaedic Surgery, University of California, San Francisco (A.B.); Department of Cardiovascular Research (S.M.), and Department of Research Beyond Borders (M.F.), Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT (S.M., M.F.); Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (B.B.O.); Department of Biology, Ursinus College, Collegeville, PA (B.A.B.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada (M.A.R.); and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (M.A.R.).
authors.forename: Andrew
authors.initials: A
authors.lastname: Brack
authors.affiliation: From the Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (S.C.H., S.R.H.); Eli and Edythe Broad Center of Stem Cell Research and Regeneration Medicine, Department of Orthopaedic Surgery, University of California, San Francisco (A.B.); Department of Cardiovascular Research (S.M.), and Department of Research Beyond Borders (M.F.), Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT (S.M., M.F.); Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (B.B.O.); Department of Biology, Ursinus College, Collegeville, PA (B.A.B.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada (M.A.R.); and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (M.A.R.).
authors.forename: Scott
authors.initials: S
authors.lastname: MacDonnell
authors.affiliation: From the Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (S.C.H., S.R.H.); Eli and Edythe Broad Center of Stem Cell Research and Regeneration Medicine, Department of Orthopaedic Surgery, University of California, San Francisco (A.B.); Department of Cardiovascular Research (S.M.), and Department of Research Beyond Borders (M.F.), Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT (S.M., M.F.); Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (B.B.O.); Department of Biology, Ursinus College, Collegeville, PA (B.A.B.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada (M.A.R.); and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (M.A.R.).
authors.forename: Michael
authors.initials: M
authors.lastname: Franti
authors.affiliation: From the Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (S.C.H., S.R.H.); Eli and Edythe Broad Center of Stem Cell Research and Regeneration Medicine, Department of Orthopaedic Surgery, University of California, San Francisco (A.B.); Department of Cardiovascular Research (S.M.), and Department of Research Beyond Borders (M.F.), Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT (S.M., M.F.); Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (B.B.O.); Department of Biology, Ursinus College, Collegeville, PA (B.A.B.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada (M.A.R.); and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (M.A.R.).
authors.forename: Bradley B
authors.initials: BB
authors.lastname: Olwin
authors.affiliation: From the Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (S.C.H., S.R.H.); Eli and Edythe Broad Center of Stem Cell Research and Regeneration Medicine, Department of Orthopaedic Surgery, University of California, San Francisco (A.B.); Department of Cardiovascular Research (S.M.), and Department of Research Beyond Borders (M.F.), Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT (S.M., M.F.); Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (B.B.O.); Department of Biology, Ursinus College, Collegeville, PA (B.A.B.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada (M.A.R.); and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (M.A.R.).
authors.forename: Beth A
authors.initials: BA
authors.lastname: Bailey
authors.affiliation: From the Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (S.C.H., S.R.H.); Eli and Edythe Broad Center of Stem Cell Research and Regeneration Medicine, Department of Orthopaedic Surgery, University of California, San Francisco (A.B.); Department of Cardiovascular Research (S.M.), and Department of Research Beyond Borders (M.F.), Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT (S.M., M.F.); Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (B.B.O.); Department of Biology, Ursinus College, Collegeville, PA (B.A.B.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada (M.A.R.); and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (M.A.R.).
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rudnicki
authors.affiliation: From the Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (S.C.H., S.R.H.); Eli and Edythe Broad Center of Stem Cell Research and Regeneration Medicine, Department of Orthopaedic Surgery, University of California, San Francisco (A.B.); Department of Cardiovascular Research (S.M.), and Department of Research Beyond Borders (M.F.), Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT (S.M., M.F.); Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (B.B.O.); Department of Biology, Ursinus College, Collegeville, PA (B.A.B.); Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada (M.A.R.); and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (M.A.R.). srhouser@temple.edu.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
mesh_terms: D000375:Aging / Q000097:blood / Q000473:pathology*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000097:blood / Q000172:deficiency / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D002100:Cachexia / Q000139:chemically induced; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D055412:Growth Differentiation Factors / Q000097:blood / Q000172:deficiency / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D006321:Heart / Q000187:drug effects; D006801:Humans; D006984:Hypertrophy; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000293:injuries / Q000502:physiology; D009132:Muscles / Q000473:pathology; D009135:Muscular Diseases / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D055435:Myostatin / Q000502:physiology / Q000627:therapeutic use / Q000633:toxicity; D010227:Parabiosis; D011994:Recombinant Proteins / Q000627:therapeutic use / Q000633:toxicity; D012038:Regeneration / Q000187:drug effects; D015203:Reproducibility of Results; D015398:Signal Transduction; D016037:Single-Blind Method; D051899:Smad2 Protein / Q000502:physiology; D051900:Smad3 Protein / Q000502:physiology
chemical_list: D019485:Bone Morphogenetic Proteins; C492266:GDF11 protein, human; C119153:Gdf11 protein, mouse; D055412:Growth Differentiation Factors; D055435:Myostatin; D011994:Recombinant Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein
keywords: aging; growth factors; myocardium; myokines; pathological hypertrophy