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Contributions of the ubiquitin–proteasome pathway and apoptosis to human skeletal muscle wasting with age

  • Skeletal Muscle
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Abstract

The primary mechanism that contributes to decreasing skeletal muscle strength and size with healthy aging is not presently known. This study examined the contribution of the ubiquitin–proteasome pathway and apoptosis to skeletal muscle wasting in older adults (n = 21; mean age = 72.76 ± 8.31 years) and young controls (n = 21; mean age = 21.48 ± 2.93 years). Subjects underwent a percutaneous muscle biopsy of the vastus lateralis to determine: (1) ubiquitin ligase gene expression (MAFbx and MuRF1); (2) frequency of apoptosis; and (3) individual fiber type and cross-sectional area. In addition, a whole muscle strength test was also performed. A one-way ANOVA revealed significant increases in the number of positive TUNEL cells in older adults (87%; p < 0.05), although no significant increase in caspase-3/7 activity was detected. Additionally, ubiquitin ligase gene expression, individual muscle fiber type and CSA were not different between old and young subjects. Muscle strength was also significantly lower in old compared to young subjects (p < 0.05). In conclusion, this study indicates a preferential role for apoptosis contributing to decreases in muscle function with age.

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References

  1. Allen DL, Linderman JK, Roy RR, Bigbee AJ, Grindeland RE, Mukku V, Edgerton VR (1997) Apoptosis: a mechanism contributing to remodeling of skeletal muscle in response to hindlimb unweighting. Am J Physiol Cell Physiol 273:C579–C587

    CAS  Google Scholar 

  2. Argiles JM, Lopez-Soriano FJ (1996) The ubiquitin-dependent proteolytic pathway in skeletal muscle: its role in pathological states. Trends Pharmacol Sci 17:223–226

    Article  CAS  PubMed  Google Scholar 

  3. Bergstrom J (1962) Muscle electrolytes in man. Scand J Clin Lab Invest 14:511–513

    Google Scholar 

  4. Bodine SC, Latres E, Baumhueter S, Lai V, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan Z, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–1708

    Article  CAS  PubMed  Google Scholar 

  5. Borisov AB, Carlson BM (2000) Cell death in denervated skeletal muscle is distinct from classical apoptosis. Anat Rec 258:305–318

    Article  CAS  PubMed  Google Scholar 

  6. Bossola M, Muscaritoli M, Costelli P, Bellantone R, Pacelli F, Busquets S, Argiles J, Lopez-Soriano FJ, Civello IM, Baccino FM, Fanelli FR, Doglietto GB (2001) Increased muscle ubiquitin mRNA levels in gastric cancer patients. Am J Physiol Regul Integr Comp Physiol 280:R1518–R1523

    CAS  PubMed  Google Scholar 

  7. Brooke MH, Kaiser KK (1970) Muscle fiber types: how many and what kind? Arch Neurol 23:369–379

    CAS  PubMed  Google Scholar 

  8. D’Antona G, Pellegrino MA, Adami R, Rossi R, Carlizzi CN, Canepari M, Saltin B, Bottinelli R (2003) The effect of ageing and immobilization on structure and function of human skeletal muscle fibres. J Physiol (Lond) 552:499–511

    Google Scholar 

  9. Deas O, Dumont C, MacFarlane M, Rouleau M, Hebib C, Harper F, Hirsch F, Charpentier B, Cohen CM, Senik A (1998) Caspase-independent cell death induced by anti-cd2 or staurosporine in activated human peripheral t lymphocytes. J Immunol 161:3375–3383

    CAS  PubMed  Google Scholar 

  10. DeMartino G, Ordway GA (1998) Ubiquitin–proteasome pathway of intracellular protein degradation: implications for muscle atrophy during unloading. Exerc Sport Sci Rev 26:219–252

    CAS  PubMed  Google Scholar 

  11. Dipietro L, Caspersen CJ, Ostfeld AM, Nadel ER (1993) A survey for assessing physical activity among older adults. Med Sci Sports Exerc 25:628–642

    CAS  PubMed  Google Scholar 

  12. Dirks A, Leeuwenburgh C (2002) Apoptosis in skeletal muscle with aging. Am J Physiol Regul Integr Comp Physiol 282(2):R519–R527

    CAS  PubMed  Google Scholar 

  13. Frontera WR, Hughes VA, Fielding RA, Fiatarone MA, Evans WJ, Roubenoff R (2000) Aging of skeletal muscle: a 12-yr longitudinal study. J Appl Physiol 88:1321–1326

    CAS  PubMed  Google Scholar 

  14. Hill RJ, Rouillard DB, Chin ER, Ibebunjo C, Wang X, Layfield R, Oleynek JJ (2004) Age-related muscle atrophy is associated with both in increase in poly ubiquitination and expression of the muscle-specific ubiquitin E3 ligase, MAFbx (abstract). FASEB J 18:227–214

    Article  PubMed  Google Scholar 

  15. Hughes VA, Frontera WR, Wood M, Evans WJ, Dallal GE, Roubenoff R, Singh MAF (2001) Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health. J Gerontol A Biol Sci Med Sci 56:B209–B217

    CAS  PubMed  Google Scholar 

  16. Imai Y, Soda M, Takahashi R (2000) Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin–protein ligase activity. J Biol Chem 275:35661–35664

    CAS  PubMed  Google Scholar 

  17. Janssen I, Shepard DS, Katzmarzyk PT, Roubenoff R (2004) The healthcare costs of sarcopenia in the united states. J Am Geriatr Soc 52:80–85

    Article  PubMed  Google Scholar 

  18. Jones SW, Hill RJ, Krasney PA, O’Conner B, Peirce N, Greenhaff PL (2004) Disuse atrophy and exercise rehabilitation in humans profoundly affects the expression of genes associated with the regulation of skeletal muscle mass. FASEB J 18(9):1025–1027

    CAS  PubMed  Google Scholar 

  19. Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li C-Y, Sasaki T, Eila AJ, Cheng HY, Ravagnan L, Ferri KF, Zamzami N, Wakeham A, Hakem R, Yoshida H, Kong Y, Mak TW, Zuniga-Pflucker JC, Kroemer G, Penninger J (2001) Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 410:549–554

    Article  CAS  PubMed  Google Scholar 

  20. Larsson L, Edstrom L (1986) Effects of age on enzyme-histochemical fibre spectra and contractile properties of fast- and slow-twitch skeletal muscles in the rat. J Neurol Sci 76:69–89

    Article  CAS  PubMed  Google Scholar 

  21. Larsson L, Grimby G, Karlsson J (1979) Muscle strength and speed of movement in relation to age and muscle morphology. J Appl Physiol 46:451–456

    CAS  PubMed  Google Scholar 

  22. Larsson L, Li X, Frontera WR (1997) Effects of aging on shortening velocity and myosin isoform composition in single human skeletal muscle cells. Am J Physiol 272:C638–C649

    CAS  PubMed  Google Scholar 

  23. Lexell J, Taylor CC, Sjostrom M (1988) What is the cause of the ageing atrophy? total number, size, and proportion of different fiber types studied in whole vastus lateralis muscle from 15- to 83-year-old men. J Neurol Sci 84:275–294

    Article  CAS  PubMed  Google Scholar 

  24. Mansoor O, Beaufrere B, Boirie Y, Ralliere C, Taillandier D, Aurousseau E, Schoeffler P, Arnal M, Attaix D (1996) Increased mRNA levels for components of the lysosomal, ca2+ -activated, and ATP–ubiquitin-dependent proteolytic pathways in skeletal muscle from head trauma patients. Proc Natl Acad Sci USA 93:2714–2718

    Article  CAS  PubMed  Google Scholar 

  25. McCarthy NJ, Whyte MKB, Gilbert CS, Evan GI (1997) Inhibition of ced-3/ice-related proteases does not prevent cell death induced by oncogenes, DNA damage, or the bcl-2 homologue bak. J Cell Biol 136:215–227

    Article  CAS  PubMed  Google Scholar 

  26. Medina R, Wing SS, Goldberg AL (1995) Increase in levels of polyubiquitin and proteasome mRNA in skeletal muscle during starvation and denervation atrophy. Biochem J 307:631–637

    CAS  PubMed  Google Scholar 

  27. Newman AB, Haggerty CL, Goodpaster B, Harris T, Kritchevsky S, Nevitt M, Miles TP, Visser M, Health A, and Body Composition Research Group (2003) Strength and muscle quality in a well-functioning cohort of older adults: the health, aging and body composition study. J Am Geriatr Soc 51:323–330

    Article  PubMed  Google Scholar 

  28. Oleynek JJ, Rouillard OB, O’Malley JP, Ibebunjo C, Wang X, Layfield R, Hill RJ (2004) Activation of the ubiquitin–proteasome system in models of muscle wasting (abstract). FASEB J 18:476–478

    Google Scholar 

  29. Sandri M, Carraro U, Podhorska-Okolov M, Rizzi C, Arslan P, Monti D, Franceshi C (1995) Apoptosis, DNA damage and ubiquitin expression in normal and mdx muscle fibers after exercise. FEBS Lett 373:291–295

    Article  CAS  PubMed  Google Scholar 

  30. Smith K, Winegard K, Hicks A, McCartney N (2003) Two years of resistance training in older men and women: the effects of three years of detraining on the retention of dynamic strength. Can J Appl Physiol 28:462–474

    PubMed  Google Scholar 

  31. Tiao G, Hobler S, Wang JJ, Meyer TA, Luchette FA, Fischer JE, Hasselgren P-O (1997) Sepsis is associated with increased mRNAs of the ubiquitin–proteasome proteolytic pathway in human skeletal muscle. J Clin Invest 99:163–168

    CAS  PubMed  Google Scholar 

  32. Trappe S, Trappe T, Gallagher P, Harber M, Alkner B, Tesch P (2004) Human single muscle fibre function with 84 day bed-rest and resistance exercise. J Physiol (Lond) 557:501–513

    Google Scholar 

  33. Vescovo G, Volteranni M, Zennaro R (2000) Apoptosis in the skeletal muscle of patients with heart failure: investigation of clinical and biochemical changes. Heart 84:431–437

    Article  CAS  PubMed  Google Scholar 

  34. Vescovo G, Zennaro R, Sandri M (1998) Apoptosis of skeletal muscle myofibers and interstitial cells in experimental heart failure. J Mol Cell Cardiol 30:2449–2459

    Article  CAS  PubMed  Google Scholar 

  35. Wagner K-D, Wagner N, Wellmann S, Schley G, Bondke A, Theres H, Scholz H (2003) Oxygen-regulated expression of the Wilms tumor suppressor WT1 involves hypoxia-inducible factor-1 (HIF-1). FASEB J 17(10):1364–1366

    CAS  PubMed  Google Scholar 

  36. Welle S, Brooks AI, Delehanty JM, Needler N, Thornton CA (2003) Gene expression profile of aging in human muscle. Physiol Genomics 14:149–159

    CAS  PubMed  Google Scholar 

  37. Widrick JJ, Knuth ST, Norenberg KM, Romatowski JG, Bain JLW, Riley DA, Karhanek M, Trappe SW, Trappe TA, Costill DL, Fitts RH (1999) Effect of a 17 day spaceflight on contractile properties of human soleus muscle fibres. J Physiol (Lond) 516:915–930

    Article  CAS  Google Scholar 

  38. Williamson DL, Godard MP, Porter DA, Costill DL, Trappe SW (2000) Progressive resistance training reduces myosin heavy chain coexpression in single muscle fibers from older men. J Appl Physiol 88:627–633

    CAS  PubMed  Google Scholar 

  39. Willoughby DS, Priest JW, Nelson M (2002) Expression of the stress proteins, ubiquitin, heat shock protein 72, and myofibrillar protein content after 12 weeks of leg cycling in person with spinal cord injury. Arch Phys Med Rehabil 83:649–654

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Applied Physiology Laboratory, University of Kansas, 1301 Sunnyside Ave, Robinson Center Room 101DJ, Lawrence, KS, 66045, USA

    Samantha A. Whitman, Michael J. Wacker, Scott R. Richmond & Michael P. Godard

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  1. Samantha A. Whitman
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  2. Michael J. Wacker
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  3. Scott R. Richmond
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  4. Michael P. Godard
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Correspondence to Michael P. Godard.

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Whitman, S.A., Wacker, M.J., Richmond, S.R. et al. Contributions of the ubiquitin–proteasome pathway and apoptosis to human skeletal muscle wasting with age. Pflugers Arch - Eur J Physiol 450, 437–446 (2005). https://doi.org/10.1007/s00424-005-1473-8

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  • DOI: https://doi.org/10.1007/s00424-005-1473-8

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