GDF11

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
GDF11
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGDF11, BMP-11, BMP11, growth differentiation factor 11
External IDsOMIM: 603936 MGI: 1338027 HomoloGene: 21183 GeneCards: GDF11
Gene location (Human)
Chromosome 12 (human)
Chr.Chromosome 12 (human)[1]
Chromosome 12 (human)
Genomic location for GDF11
Genomic location for GDF11
Band12q13.2Start55,743,280 bp[1]
End55,757,278 bp[1]
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005811

NM_010272

RefSeq (protein)

NP_005802

NP_034402

Location (UCSC)Chr 12: 55.74 – 55.76 MbChr 10: 128.88 – 128.89 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Growth differentiation factor 11 (GDF11) also known as bone morphogenetic protein 11 (BMP-11) is a protein that in humans is encoded by the growth differentiation factor 11 gene.[5]

GDF11 acts as a cytokine and its molecular structure is identical in humans, mice and rats.[6]The bone morphogenetic protein group is characterized by a polybasic proteolytic processing site, which is cleaved to produce a protein containing seven conserved cysteine residues.[7]

Systemic GDF11 treatment improves vasculature in the hippocampus and cortex of old mice resulting in enhanced neurogenesis.[8] Also, systematic replenishment of GDF11 improved the survival and morphology of β-cells and improved glucose metabolism in both non genetic and genetic mouse models of type 2 diabetes.[9]

GDF11 is a regulator of skin biology and has significant effects on the production of procollagen I and hyaluronic acid. GDF11 also activates the Smad2/3 phosphorylation pathway in skin endothelial cells and improves skin vasculature.[10]

Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity. [11]

Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.[12]

GDF11 has been found to reduce oxidative stress and was able to reduce the levels of AGEs, protein oxidation and lipid peroxidation, and to slow down the accumulation of age-related histological markers. GDF11 significantly prevented the decrease in CAT, GPX and SOD activities, [13]

Enhanced GDF11 expression promoted apoptosis and down-regulated GDF11 expression inhibited apoptosis in pancreatic cancer cell lines. These findings suggested that GDF11 acted as a tumor suppressor for pancreatic cancer.[14]

In 2014, GDF11 was described as a life extension factor in two publications based on the results of a parabiosis experiments with mice [11][15] that were chosen as Science's scientific breakthrough of the year.[16] Later studies questioned these findings.[17][18][19][20] Researchers disagree on the selectivity of the tests used to measure GDF11 and on the activity of GDF11 from various commercially available sources.[21] The full relationship of GDF11 to aging—and any possible differences in the action of GDF11 in mice, rats, and humans—is unclear and continues to be researched.

Effects on cell growth and differentiation[edit]

GDF11 belongs to the transforming growth factor beta superfamily that controls anterior-posterior patterning by regulating the expression of Hox genes.[22] It determines Hox gene expression domains and rostrocaudal identity in the caudal spinal cord.[23]

During mouse development, GDF11 expression begins in the tail bud and caudal neural plate region. GDF knock-out mice display skeletal defects as a result of patterning problems with anterior-posterior positioning.[24]

In the mouse adult central nervous system, GDF11 alone can improve the cerebral vasculature and enhance neurogenesis.[15]

This cytokine also inhibits the proliferation of olfactory receptor neuron progenitors to regulate the number of olfactory receptor neurons occurring in the olfactory epithelium,[25] and controls the competence of progenitor cells to regulate numbers of retinal ganglionic cells developing in the retina.[26]

Other studies in mice suggest that GDF11 is involved in mesodermal formation and neurogenesis during embryonic development. The members of this TGF-β superfamily are involved in the regulation of cell growth and differentiation not only in embryonic tissues, but adult tissues as well.[27]

GDF11 can bind type I TGF-beta superfamily receptors ACVR1B (ALK4), TGFBR1 (ALK5) and ACVR1C (ALK7), but predominantly uses ALK4 and ALK5 for signal transduction.[22]

GDF11 is closely related to myostatin, a negative regulator of muscle growth.[28][29] Both myostatin and GDF11 are involved in the regulation of cardiomyocyte proliferation.

GDF11 is a regulator of kidney organogenesis,[30] pancreatic development,[31] the rostro-caudal patterning in the development of spinal cords,[23] and of chondrogenesis.[32]

Due to the similarities between myostatin and GDF11, the actions of GDF11 are likely regulated by WFIKKN2, a large extracellular multidomain protein consisting of follistatin, immunoglobulin, protease inhibitor, and NTR domains.[33] WFIKKN2 has a high affinity for GDF11, and previously has been found to inhibit the biological activities of myostatin.[34]

Effect on cardiac and skeletal muscle aging[edit]

GDF11 has been identified as a blood circulating factor that has the ability to reverse age-related cardiac hypertrophy in mice. GDF11 gene expression and protein abundance decreases with age, and it shows differential abundance between young and old mice in parabiosis procedures, causing youthful regeneration of cardiomyocytes, a reduction in the brain natriuretic peptide (BNP) and in the atrial natriuretic peptide (ANP). GDF11 also causes an increase in expression of SERCA-2, an enzyme necessary for relaxation during diastolic functions.[12] GDF11 activates the TGF-β pathway in cardiomyocytes derived from pluripotent hematopoietic stem cells and suppresses the phosphorylation of Forkhead (FOX proteins) transcription factors. These effects suggest an "anti-hypertrophic effect", aiding in the reversal process of age-related hypertrophy, on the cardiomyocytes.[12] In 2014, peripheral supplementation of GDF11 protein (in mice) was shown to ameliorate the age-related dysfunction of skeletal muscle by rescuing the function of aged muscle stem cells. In humans, older males who had been chronically active over their lives show higher concentrations of GDF11 than inactive older men, and the concentration of circulating GDF11 correlated with leg power output when cycling.[35] These results have led to claims that GDF11 may be an anti-aging rejuvenation factor.[11]

These previous findings have been disputed since another publication has demonstrated the contrary, concluding that GDF11 increases with age and has deleterious effects on skeletal muscle regeneration,[17] being a pro-aging factor, with very high levels in some aged individuals. However, in October 2015, a Harvard study showed these contrary results to be the result of a flawed assay that was detecting immunoglobulin and not GDF11. The Harvard study claimed GDF11 does in fact reverse age-related cardiac hypertrophy.[21] However the Harvard study both ignored the GDF11-specific assay that was developed, establishing that GDF11 in mice is undetectable, and that the factor measured was in fact myostatin.[17] Also, the Harvard study combined the measure of GDF11 and GDF8 (myostatin), using a non-specific antibody, further confusing matters.

In 2016 conflicting reviews from different research teams were published concerning the effects of GDF11 on skeletal and cardiac muscle.[36] [37] One of the reviews reported an anti-hypertrophic effect in aging mice,[36] but the other team denied that cardiac hypertrophy occurs in old mice, asserting that GDF11 causes muscle wasting.[37] Both teams agreed that whether GDF11 increases or decreases with age had not been established.[36][37] A 2017 study found that super-physiological levels of GDF11 induced muscle wasting in the skeletal muscle of mice.[38]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000135414 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025352 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:".
  4. ^ "Mouse PubMed Reference:".
  5. ^ Ge G, Hopkins DR, Ho WB, Greenspan DS (July 2005). "GDF11 forms a bone morphogenetic protein 1-activated latent complex that can modulate nerve growth factor-induced differentiation of PC12 cells". Molecular and Cellular Biology. 25 (14): 5846–58. doi:10.1128/MCB.25.14.5846-5858.2005. PMC 1168807. PMID 15988002.
  6. ^ Jamaiyar A, Wan W, Janota DM, Enrick MK, Chilian WM, Yin L (July 2017). "The versatility and paradox of GDF 11". Pharmacology & Therapeutics. 175: 28–34. doi:10.1016/j.pharmthera.2017.02.032. PMC 6319258. PMID 28223232.
  7. ^ "Gene GDF11". Genecards. Retrieved 25 May 2013.
  8. ^ Ozek C, Krolewski RC, Buchanan SM, Rubin LL (November 2018). "Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice". Scientific Reports. 8 (1): 17293. doi:10.1038/s41598-018-35716-6. PMC 6251885. PMID 30470794.
  9. ^ Harmon EB, Apelqvist AA, Smart NG, Gu X, Osborne DH, Kim SK (December 2004). "GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development". Development. 131 (24): 6163–74. doi:10.1242/dev.01535. PMID 15548585.
  10. ^ Lyga, John; Rubin, Lee L.; Pfaff, Kathleen Lindahl; Buchanan, Sean M.; Santhanam, Uma; Idkowiak-Baldys, Jolanta (2019-06-10). "Growth differentiation factor 11 (GDF11) has pronounced effects on skin biology". PLOS ONE. 14 (6): e0218035. doi:10.1371/journal.pone.0218035. ISSN 1932-6203.
  11. ^ a b c Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, Miller C, Regalado SG, Loffredo FS, Pancoast JR, Hirshman MF, Lebowitz J, Shadrach JL, Cerletti M, Kim MJ, Serwold T, Goodyear LJ, Rosner B, Lee RT, Wagers AJ (May 2014). "Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle". Science. 344 (6184): 649–52. doi:10.1126/science.1251152. PMC 4104429. PMID 24797481.
  12. ^ a b c Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, Sinha M, Dall'Osso C, Khong D, Shadrach JL, Miller CM, Singer BS, Stewart A, Psychogios N, Gerszten RE, Hartigan AJ, Kim MJ, Serwold T, Wagers AJ, Lee RT (May 2013). "Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy". Cell. 153 (4): 828–39. doi:10.1016/j.cell.2013.04.015. PMC 3677132. PMID 23663781.
  13. ^ Zhou, Yang; Song, Lili; Ni, Shousheng; Zhang, Yu; Zhang, Shicui (2019-08-01). "Administration of rGDF11 retards the aging process in male mice via action of anti-oxidant system". Biogerontology. 20 (4): 433–443. doi:10.1007/s10522-019-09799-1. ISSN 1573-6768.
  14. ^ Liu Y, Shao L, Chen K, Wang Z, Wang J, Jing W, Hu M (2018-11-27). "GDF11 restrains tumor growth by promoting apoptosis in pancreatic cancer". OncoTargets and Therapy. 11: 8371–8379. doi:10.2147/OTT.S181792. PMC 6267626. PMID 30568460.
  15. ^ a b Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL (May 2014). "Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors". Science. 344 (6184): 630–4. doi:10.1126/science.1251141. PMC 4123747. PMID 24797482.
  16. ^ "'Young blood' reverses aging – the breakthrough of 2014 #GDF11". 2015-01-05.
  17. ^ a b c Egerman MA, Cadena SM, Gilbert JA, Meyer A, Nelson HN, Swalley SE, Mallozzi C, Jacobi C, Jennings LL, Clay I, Laurent G, Ma S, Brachat S, Lach-Trifilieff E, Shavlakadze T, Trendelenburg AU, Brack AS, Glass DJ (July 2015). "GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration". Cell Metabolism. 22 (1): 164–74. doi:10.1016/j.cmet.2015.05.010. PMC 4497834. PMID 26001423.
  18. ^ Age-reversal effects of 'young blood' molecule GDF-11 called into question, retrieved 20 May 2015
  19. ^ Reardon, Sara (2015), "'Young blood' anti-ageing mechanism called into question", Nature, doi:10.1038/nature.2015.17583, retrieved 20 May 2015
  20. ^ Smith SC, Zhang X, Zhang X, Gross P, Starosta T, Mohsin S, Franti M, Gupta P, Hayes D, Myzithras M, Kahn J, Tanner J, Weldon SM, Khalil A, Guo X, Sabri A, Chen X, MacDonnell S, Houser SR (November 2015). "GDF11 does not rescue aging-related pathological hypertrophy". Circulation Research. 117 (11): 926–32. doi:10.1161/CIRCRESAHA.115.307527. PMC 4636963. PMID 26383970.
  21. ^ a b Kaiser J (Oct 2015). "Antiaging protein is the real deal, Harvard team claims". Science. doi:10.1126/science.aad4748.
  22. ^ a b Andersson O, Reissmann E, Ibáñez CF (August 2006). "Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis". EMBO Reports. 7 (8): 831–7. doi:10.1038/sj.embor.7400752. PMC 1525155. PMID 16845371.
  23. ^ a b Liu JP (August 2006). "The function of growth/differentiation factor 11 (Gdf11) in rostrocaudal patterning of the developing spinal cord". Development. 133 (15): 2865–74. doi:10.1242/dev.02478. PMID 16790475.
  24. ^ McPherron AC, Lawler AM, Lee SJ (July 1999). "Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11". Nature Genetics. 22 (3): 260–4. doi:10.1038/10320. PMID 10391213.
  25. ^ Wu HH, Ivkovic S, Murray RC, Jaramillo S, Lyons KM, Johnson JE, Calof AL (January 2003). "Autoregulation of neurogenesis by GDF11". Neuron. 37 (2): 197–207. doi:10.1016/S0896-6273(02)01172-8. PMID 12546816.
  26. ^ Kim J, Wu HH, Lander AD, Lyons KM, Matzuk MM, Calof AL (June 2005). "GDF11 controls the timing of progenitor cell competence in developing retina". Science. 308 (5730): 1927–30. doi:10.1126/science.1110175. PMID 15976303.
  27. ^ "GDF11". Genecards.
  28. ^ McPherron AC, Lee SJ (November 1997). "Double muscling in cattle due to mutations in the myostatin gene". Proceedings of the National Academy of Sciences of the United States of America. 94 (23): 12457–61. doi:10.1073/pnas.94.23.12457. PMC 24998. PMID 9356471.
  29. ^ Lee SJ, McPherron AC (October 1999). "Myostatin and the control of skeletal muscle mass". Current Opinion in Genetics & Development. 9 (5): 604–7. doi:10.1016/S0959-437X(99)00004-0. PMID 10508689.
  30. ^ Esquela AF, Lee SJ (May 2003). "Regulation of metanephric kidney development by growth/differentiation factor 11". Developmental Biology. 257 (2): 356–70. doi:10.1016/s0012-1606(03)00100-3. PMID 12729564.
  31. ^ Dichmann DS, Yassin H, Serup P (November 2006). "Analysis of pancreatic endocrine development in GDF11-deficient mice". Developmental Dynamics. 235 (11): 3016–25. doi:10.1002/dvdy.20953. PMID 16964608.
  32. ^ Gamer LW, Cox KA, Small C, Rosen V (January 2001). "Gdf11 is a negative regulator of chondrogenesis and myogenesis in the developing chick limb". Developmental Biology. 229 (2): 407–20. doi:10.1006/dbio.2000.9981. PMID 11203700.
  33. ^ Kondás K, Szláma G, Trexler M, Patthy L (August 2008). "Both WFIKKN1 and WFIKKN2 have high affinity for growth and differentiation factors 8 and 11". The Journal of Biological Chemistry. 283 (35): 23677–84. doi:10.1074/jbc.M803025200. PMC 3259755. PMID 18596030.
  34. ^ "WJIKKN2". Geneards. Retrieved 25 May 2013.
  35. ^ Elliott BT, Herbert P, Sculthorpe N, Grace FM, Stratton D, Hayes LD (July 2017). "Lifelong exercise, but not short-term high-intensity interval training, increases GDF11, a marker of successful aging: a preliminary investigation". Physiological Reports. 5 (13): e13343. doi:10.14814/phy2.13343. PMC 5506528. PMID 28701523.
  36. ^ a b c Walker RG, Poggioli T, Katsimpardi L, Buchanan SM, Oh J, Wattrus S, Heidecker B, Fong YW, Rubin LL, Ganz P, Thompson TB, Wagers AJ, Lee RT (April 2016). "Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation". Circulation Research. 118 (7): 1125–41, discussion 1142. doi:10.1161/CIRCRESAHA.116.308391. PMC 4818972. PMID 27034275.
  37. ^ a b c Harper SC, Brack A, MacDonnell S, Franti M, Olwin BB, Bailey BA, Rudnicki MA, Houser SR (April 2016). "Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects?". Circulation Research. 118 (7): 1143–50, discussion 1150. doi:10.1161/CIRCRESAHA.116.307962. PMC 4829942. PMID 27034276.
  38. ^ Hammers DW, Merscham-Banda M, Hsiao JY, Engst S, Hartman JJ, Sweeney HL (April 2017). "Supraphysiological levels of GDF11 induce striated muscle atrophy". EMBO Molecular Medicine. 9 (4): 531–544. doi:10.15252/emmm.201607231. PMC 5376753. PMID 28270449.

Further reading[edit]

External links[edit]