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PMID: 21111239 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging.

Cell ·Vol. 143 ·No. 5 ·2010-11-24 ·Pages 813-25

Demontis F, Perrimon N

Abstract

The progressive loss of muscle strength during aging is a common degenerative event of unclear pathogenesis. Although muscle functional decline precedes age-related changes in other tissues, its contribution to systemic aging is unknown. Here, we show that muscle aging is characterized in Drosophila by the progressive accumulation of protein aggregates that associate with impaired muscle function. The transcription factor FOXO and its target 4E-BP remove damaged proteins at least in part via the autophagy/lysosome system, whereas foxo mutants have dysfunctional proteostasis. Both FOXO and 4E-BP delay muscle functional decay and extend life span. Moreover, FOXO/4E-BP signaling in muscles decreases feeding behavior and the release of insulin from producing cells, which in turn delays the age-related accumulation of protein aggregates in other tissues. These findings reveal an organism-wide regulation of proteostasis in response to muscle aging and a key role of FOXO/4E-BP signaling in the coordination of organismal and tissue aging.

MeSH Terms
Aging Animals Autophagy Drosophila Proteins/metabolism Drosophila melanogaster/metabolism Forkhead Transcription Factors/metabolism Humans Intracellular Signaling Peptides and Proteins/metabolism Lysosomes/metabolism Models, Animal Muscle Proteins/metabolism Muscles/metabolism Peptide Initiation Factors/metabolism Signal Transduction
Chemicals
Drosophila Proteins FOXO protein, Drosophila Forkhead Transcription Factors Intracellular Signaling Peptides and Proteins Muscle Proteins Peptide Initiation Factors Thor protein, Drosophila
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Demontis Fabio
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. [email protected]
Perrimon Norbert
References (48)
48 references, click to expand
  1. Autophagy is required to maintain muscle mass.
    Cell Metab. 2009 Dec;10(6):507-15 PMID: 19945408
  2. The roles of intracellular protein-degradation pathways in neurodegeneration.
    Nature. 2006 Oct 19;443(7113):780-6 PMID: 17051204
  3. Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated Type I (slow twitch/red muscle) fiber genes, and impaired glycemic control.
    J Biol Chem. 2004 Sep 24;279(39):41114-23 PMID: 15272020
  4. Association of muscle strength with the risk of Alzheimer disease and the rate of cognitive decline in community-dwelling older persons.
    Arch Neurol. 2009 Nov;66(11):1339-44 PMID: 19901164
  5. Hsps and aging.
    Trends Endocrinol Metab. 2009 Jul;20(5):216-22 PMID: 19394247
  6. Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain.
    J Cell Biol. 2008 Mar 24;180(6):1065-71 PMID: 18347073
  7. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body.
    Nature. 2004 Jun 3;429(6991):562-6 PMID: 15175753
  8. Skeletal muscle development and regeneration.
    Stem Cells Dev. 2007 Oct;16(5):857-68 PMID: 17999606
  9. Prandiology of Drosophila and the CAFE assay.
    Proc Natl Acad Sci U S A. 2007 May 15;104(20):8253-6 PMID: 17494737
  10. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans.
    Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10417-22 PMID: 12122205
  11. Invertebrate models of age-related muscle degeneration.
    Biochim Biophys Acta. 2009 Oct;1790(10):1084-94 PMID: 19563864
  12. Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates.
    Mol Cell. 2009 Feb 27;33(4):517-27 PMID: 19250912
  13. Remote control of insulin secretion by fat cells in Drosophila.
    Cell Metab. 2009 Sep;10(3):199-207 PMID: 19723496
  14. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles.
    FASEB J. 2002 Sep;16(11):1335-47 PMID: 12205025
  15. Genetic and environmental factors impact age-related impairment of negative geotaxis in Drosophila by altering age-dependent climbing speed.
    Exp Gerontol. 2008 Aug;43(8):739-48 PMID: 18515028
  16. Physical activity and the risk of Parkinson disease.
    Neurology. 2005 Feb 22;64(4):664-9 PMID: 15728289
  17. The plasticity of aging: insights from long-lived mutants.
    Cell. 2005 Feb 25;120(4):449-60 PMID: 15734678
  18. Cytokines and Feeding.
    News Physiol Sci. 1998 Dec;13:298-304 PMID: 11390808
  19. Muscle as an endocrine organ: focus on muscle-derived interleukin-6.
    Physiol Rev. 2008 Oct;88(4):1379-406 PMID: 18923185
  20. Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation.
    Genetics. 2002 Jul;161(3):1101-12 PMID: 12136014
  21. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice.
    Nature. 2006 Jun 15;441(7095):885-9 PMID: 16625204
  22. Differential patterns of apoptosis in response to aging in Drosophila.
    Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12083-8 PMID: 16099837
  23. Chaperone-assisted selective autophagy is essential for muscle maintenance.
    Curr Biol. 2010 Jan 26;20(2):143-8 PMID: 20060297
  24. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss.
    Nat Neurosci. 2009 Sep;12(9):1129-35 PMID: 19684592
  25. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin.
    Nature. 2006 Jun 29;441(7097):1157-61 PMID: 16672980
  26. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo.
    Nat Cell Biol. 2001 Nov;3(11):1014-9 PMID: 11715023
  27. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling.
    J Biol. 2003;2(3):20 PMID: 12908874
  28. Opposing activities protect against age-onset proteotoxicity.
    Science. 2006 Sep 15;313(5793):1604-10 PMID: 16902091
  29. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells.
    Cell Metab. 2007 Dec;6(6):472-83 PMID: 18054316
  30. Sporadic inclusion body myositis: a continuing puzzle.
    Neuromuscul Disord. 2008 Jan;18(1):6-16 PMID: 18160291
  31. Long-lived Drosophila with overexpressed dFOXO in adult fat body.
    Science. 2004 Jul 16;305(5682):361 PMID: 15192154
  32. Integration of Insulin receptor/Foxo signaling and dMyc activity during muscle growth regulates body size in Drosophila.
    Development. 2009 Mar;136(6):983-93 PMID: 19211682
  33. Regulation of C. elegans life-span by insulinlike signaling in the nervous system.
    Science. 2000 Oct 6;290(5489):147-50 PMID: 11021802
  34. Aging muscle.
    Am J Clin Nutr. 2005 May;81(5):953-63 PMID: 15883415
  35. Insulin regulation of heart function in aging fruit flies.
    Nat Genet. 2004 Dec;36(12):1275-81 PMID: 15565107
  36. FoxO3 controls autophagy in skeletal muscle in vivo.
    Cell Metab. 2007 Dec;6(6):458-71 PMID: 18054315
  37. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.
    Cell. 2004 Apr 30;117(3):399-412 PMID: 15109499
  38. Regulation of feeding and metabolism by neuronal and peripheral clocks in Drosophila.
    Cell Metab. 2008 Oct;8(4):289-300 PMID: 18840359
  39. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling.
    Cell. 2005 Apr 8;121(1):115-25 PMID: 15820683
  40. Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway.
    Dev Cell. 2004 Aug;7(2):179-92 PMID: 15296715
  41. Endocrine regulation of ageing.
    Nat Rev Mol Cell Biol. 2007 Sep;8(9):681-91 PMID: 17684529
  42. FoxO transcription factors in the maintenance of cellular homeostasis during aging.
    Curr Opin Cell Biol. 2008 Apr;20(2):126-36 PMID: 18394876
  43. Regulation of aging and age-related disease by DAF-16 and heat-shock factor.
    Science. 2003 May 16;300(5622):1142-5 PMID: 12750521
  44. Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans.
    Nature. 2002 Oct 24;419(6909):808-14 PMID: 12397350
  45. Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan.
    Cell. 2003 Nov 14;115(4):489-502 PMID: 14622602
  46. DILP-producing median neurosecretory cells in the Drosophila brain mediate the response of lifespan to nutrition.
    Aging Cell. 2010 Jun;9(3):336-46 PMID: 20156206
  47. A SAGE approach to discovery of genes involved in autophagic cell death.
    Curr Biol. 2003 Feb 18;13(4):358-63 PMID: 12593804
  48. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila.
    Autophagy. 2008 Feb;4(2):176-84 PMID: 18059160
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2010.10.007
Email
[email protected]
Published
2010-11-24
Pages
813-25
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3066043
Subset
IM
Grants
NCI NIH HHS · P01 CA120964 · United States
NIAMS NIH HHS · R01 AR057352 · United States
NIDDK NIH HHS · R01 DK088718 · United States
NCI NIH HHS · 1P01CA120964-01A1 · United States
NCI NIH HHS · P01 CA120964-05 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2010.10.007 PMC Full Text View journal details
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