Aging Clinical and Experimental Research

, Volume 23, Issue 3, pp 170–174

Differential gene expression of FoxO1, ID1, and ID3 between young and older men and associations with muscle mass and function

  • Thomas W. Buford
  • Matthew B. Cooke
  • Brian D. Shelmadine
  • Geoffrey M. Hudson
  • Liz L. Redd
  • Darryn S. Willoughby
Original Article

Abstract

Background and aims: Aging is associated with significant losses of skeletal muscle mass and function. Numerous biochemical molecules have been implicated in the development of these age-related changes, however evidence from human models is sparse. Assessment of transcript expression is useful as it requires minimal tissue and may potentially be used in clinical trials. This study aimed to compare mRNA expression of proteolytic genes in skeletal muscle of young (18–35 yrs) and older (55–75 yrs) men. Methods: Muscle tissue was obtained from young (n=14, 21.35±01.03 yrs) and older (n=13, 63.85±1.83 yrs) men using percutaneous biopsy, and transcript expression was quantified using real-time polymerase chain reaction. Lower limb muscle mass was assessed using DEXA while concentric peak torque (PT) and power were assessed via isokinetic dynamometer. When age-related differences in mRNA expression were observed, Pearson correlation coefficients were obtained to examine the relationship of transcripts to muscle mass and function. Results: Older muscle contained significantly more transcript for Forkhead Box O 1 (FoxO1, p=0.001), Inhibitor of DNA binding 1 (ID1, p=0.009), and Inhibitor of DNA Binding 3 (ID3, p=0.043) than young muscle. FoxO1 was significantly correlated with lean mass (R=−0.44, p=0.023) and PT (R=−0.40, p=0.046) while ID3 was significantly correlated with PT (R=−0.58, p=0.001) and power (R=−0.65, p<0.001). Moreover, ID1 was significantly correlated with all assessed measures of muscle function - mass (R=−0.39, p=0.046), PT (R=−0.53, p=0.005), and power (R=−0.520, p=0.005). Conclusion: These data suggest that FoxO1, ID1, and ID3 are potentially useful as clinical biomarkers of age-related muscle atrophy and dysfunction.

Key words

Aging atrophy peak torque proteolysis RNA sarcopenia 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Newman AB, Kupelian V, Visser M et al. Strength, but not muscle mass, is associated with mortality in the health, aging and body composition study cohort. J Gerontol A Biol Sci Med Sci 2006; 61: 72–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Visser M, Goodpaster BH, Kritchevsky SB et al. Muscle mass, muscle strength, and muscle fat infiltration as predictors of incident mobility limitations in well-functioning older persons. J Gerontol A Biol Sci Med Sci 2005; 60: 324–33.PubMedCrossRefGoogle Scholar
  3. 3.
    Federal Interagency Forum on Aging-Related Statistics. Statistical Data of Older Americans [www.agingstats.gov].
  4. 4.
    de Palma L, Marinelli M, Pavan M, Orazi A. Ubiquitin ligases MuRF1 and MAFbx in human skeletal muscle atrophy. Joint Bone Spine 2008; 75: 53–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Cao PR, Kim HJ, Lecker SH. Ubiquitin-protein ligases in muscle wasting. Int J Biochem Cell Biol 2005; 37: 2088–97.PubMedCrossRefGoogle Scholar
  6. 6.
    Attaix D, Ventadour S, Codran A, Bechet D, Taillandier D, Combaret L. The ubiquitin-proteasome system and skeletal muscle wasting. Essays Biochem 2005; 41: 173–86.PubMedCrossRefGoogle Scholar
  7. 7.
    Huang J, Forsberg NE. Role of calpain in skeletal-muscle protein degradation. Proc Natl Acad Sci USA 1998; 95: 12100–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Costelli P, Reffo P, Penna F, Autelli R, Bonelli G, Baccino FM. Ca(2+)-dependent proteolysis in muscle wasting. Int J Biochem Cell Biol 2005; 37: 2134–46.PubMedCrossRefGoogle Scholar
  9. 9.
    Dargelos E, Brule C, Combaret L et al. Involvement of the calcium- dependent proteolytic system in skeletal muscle aging. Exp Gerontol 2007; 42: 1088–98.PubMedCrossRefGoogle Scholar
  10. 10.
    Gilson H, Schakman O, Combaret L et al. Myostatin gene deletion prevents glucocorticoid-induced muscle atrophy. Endocrinology 2007; 148: 452–60.PubMedCrossRefGoogle Scholar
  11. 11.
    Baumann AP, Ibebunjo C, Grasser WA, Paralkar VM. Myostatin expression in age and denervation-induced skeletal muscle atrophy. J Musculoskelet Neuronal Interact 2003; 3: 8–16.PubMedGoogle Scholar
  12. 12.
    McCroskery S, Thomas M, Maxwell L, Sharma M, Kambadur R. Myostatin negatively regulates satellite cell activation and self-renewal. J Cell Biol 2003; 162: 1135–47.PubMedCrossRefGoogle Scholar
  13. 13.
    Alway SE, Degens H, Krishnamurthy G, Smith CA. Potential role for Id myogenic repressors in apoptosis and attenuation of hypertrophy in muscles of aged rats. Am J Physiol Cell Physiol 2002; 283: C66–76.PubMedCrossRefGoogle Scholar
  14. 14.
    Alway SE, Degens H, Lowe DA, Krishnamurthy G. Increased myogenic repressor Id mRNA and protein levels in hindlimb muscles of aged rats. Am J Physiol Regul Integr Comp Physiol 2002; 282: R411–22.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Sun L, Trausch-Azar JS, Muglia LJ, Schwartz AL. Glucocorticoids differentially regulate degradation of MyoD and Id1 by N-terminal ubiquitination to promote muscle protein catabolism. Proc Natl Acad Sci USA 2008; 105: 3339–44.PubMedCrossRefGoogle Scholar
  16. 16.
    Leger B, Derave W, De Bock K, Hespel P, Russell AP. Human sarcopenia reveals an increase in SOCS-3 and myostatin and a reduced efficiency of akt phosphorylation. Rejuvenation Res 2008; 11: 163–75B.PubMedCrossRefGoogle Scholar
  17. 17.
    Williamson DL, Raue U, Slivka DR, Trappe S. Resistance exercise, skeletal muscle FOXO3A, and 85-year-old women. J Gerontol A Biol Sci Med Sci 2010; 65: 335–43.PubMedCrossRefGoogle Scholar
  18. 18.
    Whitman SA, Wacker MJ, Richmond SR, Godard MP. Contributions of the ubiquitin-proteasome pathway and apoptosis to human skeletal muscle wasting with age. Pflugers Arch 2005; 450: 437–46.PubMedCrossRefGoogle Scholar
  19. 19.
    Raue U, Slivka D, Jemiolo B, Hollon C, Trappe S. Proteolytic gene expression differs at rest and after resistance exercise between young and old women. J Gerontol A Biol Sci Med Sci 2007; 62: 1407–12.PubMedCrossRefGoogle Scholar
  20. 20.
    Giresi PG, Stevenson EJ, Theilhaber J et al. Identification of a molecular signature of sarcopenia. Physiol Genomics 2005; 21: 253–63.PubMedCrossRefGoogle Scholar
  21. 21.
    Buford TW, Cooke MB, Manini TM, Leeuwenburgh C, Willoughby DS. Effects of age and sedentary lifestyle on skeletal muscle NF-{kappa}B signaling in men. J Gerontol A Biol Sci Med Sci 2010; 65: 532–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Buford TW, Cooke MB, Shelmadine BD, Hudson GM, Redd L, Willoughby DS. Effects of eccentric treadmill exercise on inflammatory gene expression in human skeletal muscle. Appl Physiol Nutr Metab 2009; 34: 745–53.PubMedCrossRefGoogle Scholar
  23. 23.
    Buford TW, Cooke MB, Willoughby DS. Resistance exercise-induced changes of inflammatory gene expression within human skeletal muscle. Eur J Appl Physiol 2009; 107: 463–71.PubMedCrossRefGoogle Scholar
  24. 24.
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 2001; 25: 402–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Sandri M, Sandri C, Gilbert A et al. FoxO transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 2004; 117: 399–412.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Zhao J, Brault JJ, Schild A et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 2007; 6: 472–83.PubMedCrossRefGoogle Scholar
  27. 27.
    Zhao J, Brault JJ, Schild A, Goldberg AL. Coordinate activation of autophagy and the proteasome pathway by FoxO transcription factor. Autophagy 2008; 4: 378–80.PubMedGoogle Scholar
  28. 28.
    Allen DL, Unterman TG. Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors. Am J Physiol Cell Physiol 2007; 292: C188–99.PubMedCrossRefGoogle Scholar
  29. 29.
    Attaix D, Baracos VE. MAFbx/Atrogin-1 expression is a poor index of muscle proteolysis. Curr Opin Clin Nutr Metab Care 2010; 13: 223–4.PubMedCrossRefGoogle Scholar
  30. 30.
    Cai D, Frantz JD, Tawa NE Jr et al. IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 2004; 119: 285–98.PubMedCrossRefGoogle Scholar
  31. 31.
    Mourkioti F, Kratsios P, Luedde T et al. Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration. J Clin Invest 2006; 116: 2945–54.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Navarro M, Valentinis B, Belletti B, Romano G, Reiss K, Baserga R. Regulation of Id2 gene expression by the type 1 IGF receptor and the insulin receptor substrate-1. Endocrinology 2001; 142: 5149–57.PubMedGoogle Scholar
  33. 33.
    Kumar D, Shadrach JL, Wagers AJ, Lassar AB. Id3 is a direct transcriptional target of Pax7 in quiescent satellite cells. Mol Biol Cell 2009; 20: 3170–7.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Internal Publishing Switzerland 2011

Authors and Affiliations

  • Thomas W. Buford
    • 1
  • Matthew B. Cooke
    • 2
  • Brian D. Shelmadine
    • 3
  • Geoffrey M. Hudson
    • 4
  • Liz L. Redd
    • 3
  • Darryn S. Willoughby
    • 3
  1. 1.Department of Aging and Geriatric ResearchUniversity of FloridaGainesvilleUSA
  2. 2.Schools of Medicine and Human Movement StudiesUniversity of QueenslandQueenslandAustralia
  3. 3.Department of Health, Human Performance and RecreationBaylor UniversityWacoUSA
  4. 4.School of Human Performance and RecreationUniversity of Southern MississippiHattiesburgUSA

Personalised recommendations