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Table of Contents
Vol. 82, No. 2, 2008
Issue release date: August 2008
Section title: Review
Free Access
Pharmacology 2008;82:83–88
(DOI:10.1159/000134943)

Mechanisms of Zidovudine-Induced Mitochondrial Toxicity and Myopathy

Scruggs E.R. · Dirks Naylor A.J.
Wingate University School of Pharmacy, Wingate, N.C., USA
email Corresponding Author

Abstract

Zidovudine (3-azido-3′-deoxythymidine), also referred to as azidothymidine (AZT), has become an integral component in highly active antiretroviral therapy, and has also been used in the treatment of cancer. The clinical effectiveness of AZT is constrained due to its association with increased adverse effects, such as myopathy. There are numerous potential mechanisms that may contribute to AZT-induced myopathy. The first hypothesized mechanism to explain AZT-induced toxicity was mtDNA depletion due to inhibition of DNA polymerase γ. Although mtDNA depletion is present in patients with myopathy, current data suggests that alternative mechanisms may play a more direct role in the myotoxicity. These mechanisms include AZT-induced oxidative stress, direct inhibition of mitochondrial bioenergetic machinery, and mitochondrial depletion of L-carnitine. Furthermore, we hypothesize that apoptosis may play a role in AZT-induced myopathy.

© 2008 S. Karger AG, Basel


  

Key Words

  • Azidothymidine
  • Zidovudine
  • Skeletal muscle
  • Apoptosis
  • Oxidative stress

References

  1. Georges B, Galland S, Rigault C, Le Borgne F, Demarquoy J: Beneficial effects of L-carnitine in myoblastic C2C12 cells: interaction with zidovudine. Biochem Pharmacol 2003;65:1483–1488.
  2. Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL: Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 1990;322:1098–1105.
  3. Owczarek J, Jasinska M, Orszulak-Michalak D: Drug-induced myopathies: an overview of the possible mechanisms. Pharmacol Rep 2005;57:23–34.
  4. Masanes F, Barrientos A, Cebrian M, Pedrol E, Miro O, Casademont J, Grau JM: Clinical, histological and molecular reversibility of zidovudine myopathy. J Neurol Sci 1998;159:226–228.
  5. Arnaudo E, Dalakas M, Shanske S, Moraes CT, DiMauro S, Schon EA: Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet 1991;337:508–510.
  6. Lewis W, Copeland WC, Day BJ: Mitochondrial DNA depletion, oxidative stress, and mutation: mechanisms of dysfunction from nucleoside reverse transcriptase inhibitors. Lab Invest 2001;81:777–790.
  7. Tolomeo M, Mancuso S, Todaro M, Stassi G, Catalano M, Arista S, Cannizzo G, Barbusca E, Abbadessa V: Mitochondrial disruption and apoptosis in lymphocytes of an HIV infected patient affected by lactic acidosis after treatment with highly active antiretroviral therapy. J Clin Pathol 2003;56:147–151.
  8. Cote HC, Brumme ZL, Craib KJ, Alexander CS, Wynhoven B, Ting L, Wong H, Harris M, Harrigan PR, O’Shaughnessy MV, Montaner JS: Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 2002;346:811–820.
  9. Martin JL, Brown CE, Matthews-Davis N, Reardon JE: Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob Agents Chemother 1994;38:2743–2749.
  10. Lynx MD, McKee EE: 3′-Azido-3′-deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondria. Biochem Pharmacol 2006;72:239–243.
  11. Rylova SN, Albertioni F, Flygh G, Eriksson S: Activity profiles of deoxynucleoside kinases and 5′-nucleotidases in cultured adipocytes and myoblastic cells: insights into mitochondrial toxicity of nucleoside analogs. Biochem Pharmacol 2005;69:951–960.
  12. Lebrecht D, Deveaud C, Beauvoit B, Bonnet J, Kirschner J, Walker UA: Uridine supplementation antagonizes zidovudine-induced mitochondrial myopathy and hyperlactatemia in mice. Arthritis Rheum 2008;58:318–326.
  13. Modica-Napolitano JS: AZT causes tissue-specific inhibition of mitochondrial bioenergetic function. Biochem Biophys Res Commun 1993;194:170–177.
  14. Yamaguchi T, Katoh I, Kurata S: Azidothymidine causes functional and structural destruction of mitochondria, glutathione deficiency and HIV-1 promoter sensitization. Eur J Biochem 2002;269:2782–2788.
  15. Cazzalini O, Lazze MC, Iamele L, Stivala LA, Bianchi L, Vaghi P, Cornaglia A, Calligaro A, Curti D, Alessandrini A, Prosperi E, Vannini V: Early effects of AZT on mitochondrial functions in the absence of mitochondrial DNA depletion in rat myotubes. Biochem Pharmacol 2001;62:893–902.
  16. de la Asuncion JG, del Olmo ML, Sastre J, Millan A, Pellin A, Pallardo FV, Vina J: AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria: prevention by antioxidant vitamins. J Clin Invest 1998;102:4–9.
  17. Wheeler S, Maxwell-Bawden A, Herb RA, Gallagher GE, Coast JR: Zidovudine-induced diaphragmatic contractile dysfunction: impact of an antioxidant diet. Respirology 2005;10:171–176.
  18. Linnane AW, Degli Esposti M, Generowicz M, Luff AR, Nagley P: The universality of bioenergetic disease and amelioration with redox therapy. Biochim Biophys Acta 1995;1271:191–194.

    External Resources

  19. Rosenfeldt FL, Mijch A, McCrystal G, Sweeney C, Pepe S, Nicholls M, Dennett X: Skeletal myopathy associated with nucleoside reverse transcriptase inhibitor therapy: potential benefit of coenzyme Q10 therapy. Int J STD AIDS 2005;16:827–829.
  20. Dalakas MC, Leon-Monzon ME, Bernardini I, Gahl WA, Jay CA: Zidovudine-induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage. Ann Neurol 1994;35:482–487.
  21. Semino-Mora MC, Leon-Monzon ME, Dalakas MC: Effect of L-carnitine on the zidovudine-induced destruction of human myotubes. I. L-carnitine prevents the myotoxicity of AZT in vitro. Lab Invest 1994;71:102–112.
  22. Kokoszka JE, Coskun P, Esposito LA, Wallace DC: Increased mitochondrial oxidative stress in the Sod2 (+/–) mouse results in the age-related decline of mitochondrial function culminating in increased apoptosis. Proc Natl Acad Sci USA 2001;98:2278–2283.
  23. Liu CY, Lee CF, Hong CH, Wei YH: Mitochondrial DNA mutation and depletion increase the susceptibility of human cells to apoptosis. Ann NY Acad Sci 2004;1011:133–145.
  24. Ratan RR, Murphy TH, Baraban JM: Oxidative stress induces apoptosis in embryonic cortical neurons. J Neurochem 1994;62:376–379.
  25. Unger RH, Orci L: Lipoapoptosis: its mechanism and its diseases. Biochim Biophys Acta 2002;1585:202–212.
  26. Mirabella M, Di Giovanni S, Silvestri G, Tonali P, Servidei S: Apoptosis in mitochondrial encephalomyopathies with mitochondrial DNA mutations: a potential pathogenic mechanism. Brain 2000;123(pt 1):93–104.
  27. Ikezoe K, Nakagawa M, Yan C, Kira J, Goto Y, Nonaka I: Apoptosis is suspended in muscle of mitochondrial encephalomyopathies. Acta Neuropathol (Berl) 2002;103:531–540.
  28. Umaki Y, Mitsui T, Endo I, Akaike M, Matsumoto T: Apoptosis-related changes in skeletal muscles of patients with mitochondrial diseases. Acta Neuropathol (Berl) 2002;103:163–170.
  29. Formichi P, Battisti C, Bianchi S, Cardaioli E, Federico A: Evidence of apoptosis via TUNEL staining in muscle biopsy from patients with mitochondrial encephaloneuromyopathies. J Submicrosc Cytol Pathol 2003;35:29–34.
  30. Sandri M, Carraro U, Podhorska-Okolov M, Rizzi C, Arslan P, Monti D, Franceschi C: Apoptosis, DNA damage and ubiquitin expression in normal and mdx muscle fibers after exercise. FEBS Lett 1995;373:291–295.
  31. Adams V, Jiang H, Yu J, Mobius-Winkler S, Fiehn E, Linke A, Weigl C, Schuler G, Hambrecht R: Apoptosis in skeletal myocytes of patients with chronic heart failure is associated with exercise intolerance. J Am Coll Cardiol 1999;33:959–965.
  32. Belizario JE, Lorite MJ, Tisdale MJ: Cleavage of caspases-1, -3, -6, -8 and -9 substrates by proteases in skeletal muscles from mice undergoing cancer cachexia. Br J Cancer 2001;84:1135–1140.
  33. Alway SE, Degens H, Krishnamurthy G, Chaudhrai A: Denervation stimulates apoptosis but not Id2 expression in hindlimb muscles of aged rats. J Gerontol A Biol Sci Med Sci 2003;58:687–697.
  34. Allen DL, Linderman JK, Roy RR, Bigbee AJ, Grindeland RE, Mukku V, Edgerton VR: Apoptosis: a mechanism contributing to remodeling of skeletal muscle in response to hindlimb unweighting. Am J Physiol 1997;273:C579–C587.
  35. 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–C76.
  36. Dirks A, Leeuwenburgh C: Apoptosis in skeletal muscle with aging. Am J Physiol Regul Integr Comp Physiol 2002;282:R519–R527.
  37. Dirks AJ, Leeuwenburgh C: Aging and lifelong calorie restriction result in adaptations of skeletal muscle apoptosis repressor, apoptosis-inducing factor, X-linked inhibitor of apoptosis, caspase-3, and caspase-12. Free Radic Biol Med 2004;36:27–39.
  38. Dirks AJ, Jones KM: Statin-induced apoptosis and skeletal myopathy. Am J Physiol Cell Physiol 2006;291:C1208–C1212.
  39. Lee MC, Wee GR, Kim JH: Apoptosis of skeletal muscle on steroid-induced myopathy in rats. J Nutr 2005;135:S1806–S1808.
  40. Collier AC, Helliwell RJ, Keelan JA, Paxton JW, Mitchell MD, Tingle MD: 3′-azido-3′-deoxythymidine (AZT) induces apoptosis and alters metabolic enzyme activity in human placenta. Toxicol Appl Pharmacol 2003;192:164–173.
  41. Falchetti A, Franchi A, Bordi C, Mavilia C, Masi L, Cioppi F, Recenti R, Picariello L, Marini F, Del Monte F, Ghinoi V, Martineti V, Tanini A, Brandi ML: Azidothymidine induces apoptosis and inhibits cell growth and telomerase activity of human parathyroid cancer cells in culture. J Bone Miner Res 2005;20:410–418.
  42. Sun YQ, Guo TK, Xi YM, Chen C, Wang J, Wang ZR: Effects of AZT and RNA-protein complex (FA-2-b-beta) extracted from Liang Jin mushroom on apoptosis of gastric cancer cells. World J Gastroenterol 2007;13:4185–4191.
  43. Ji HJ, Rha SY, Jeung HC, Yang SH, An SW, Chung HC: Cyclic induction of senescence with intermittent AZT treatment accelerates both apoptosis and telomere loss. Breast Cancer Res Treat 2005;93:227–236.
  44. Zhou FX, Liao ZK, Dai J, Xiong J, Xie CH, Luo ZG, Liu SQ, Zhou YF: Radiosensitization effect of zidovudine on human malignant glioma cells. Biochem Biophys Res Commun 2007;354:351–356.
  45. Purevjav E, Nelson DP, Varela JJ, Jimenez S, Kearney DL, Sanchez XV, Defreitas G, Carabello B, Taylor MD, Vatta M, Shearer WT, Towbin JA, Bowles NE: Myocardial Fas Ligand Expression Increases Susceptibility to AZT-Induced Cardiomyopathy. Cardiovasc Toxicol 2007;7:255–263.

  

Author Contacts

Amie J. Dirks Naylor, PhD
School of Pharmacy, Wingate University
316 N. Main Street
Wingate, NC 28174 (USA)
Tel. +1 704 233 8341, Fax +1 704 233 8332, E-Mail adirks@wingate.edu

  

Article Information

Received: January 7, 2008
Accepted: February 22, 2008
Published online: May 27, 2008
Number of Print Pages : 6
Number of Figures : 1, Number of Tables : 0, Number of References : 45

  

Publication Details

Pharmacology (International Journal of Experimental and Clinical Pharmacology)

Vol. 82, No. 2, Year 2008 (Cover Date: August 2008)

Journal Editor: Donnerer J. (Graz), Billingsley M.L. (Hershey, Pa.), Maeyama K. (Matsuyama)
ISSN: 0031–7012 (Print), eISSN: 1423–0313 (Online)

For additional information: http://www.karger.com/PHA


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Zidovudine (3-azido-3′-deoxythymidine), also referred to as azidothymidine (AZT), has become an integral component in highly active antiretroviral therapy, and has also been used in the treatment of cancer. The clinical effectiveness of AZT is constrained due to its association with increased adverse effects, such as myopathy. There are numerous potential mechanisms that may contribute to AZT-induced myopathy. The first hypothesized mechanism to explain AZT-induced toxicity was mtDNA depletion due to inhibition of DNA polymerase γ. Although mtDNA depletion is present in patients with myopathy, current data suggests that alternative mechanisms may play a more direct role in the myotoxicity. These mechanisms include AZT-induced oxidative stress, direct inhibition of mitochondrial bioenergetic machinery, and mitochondrial depletion of L-carnitine. Furthermore, we hypothesize that apoptosis may play a role in AZT-induced myopathy.

© 2008 S. Karger AG, Basel


  

Author Contacts

Amie J. Dirks Naylor, PhD
School of Pharmacy, Wingate University
316 N. Main Street
Wingate, NC 28174 (USA)
Tel. +1 704 233 8341, Fax +1 704 233 8332, E-Mail adirks@wingate.edu

  

Article Information

Received: January 7, 2008
Accepted: February 22, 2008
Published online: May 27, 2008
Number of Print Pages : 6
Number of Figures : 1, Number of Tables : 0, Number of References : 45

  

Publication Details

Pharmacology (International Journal of Experimental and Clinical Pharmacology)

Vol. 82, No. 2, Year 2008 (Cover Date: August 2008)

Journal Editor: Donnerer J. (Graz), Billingsley M.L. (Hershey, Pa.), Maeyama K. (Matsuyama)
ISSN: 0031–7012 (Print), eISSN: 1423–0313 (Online)

For additional information: http://www.karger.com/PHA


Article / Publication Details

First-Page Preview
Abstract of Review

Received: 1/7/2008
Accepted: 2/22/2008
Published online: 5/27/2008
Issue release date: August 2008

Number of Print Pages: 6
Number of Figures: 1
Number of Tables: 0

ISSN: 0031-7012 (Print)
eISSN: 1423-0313 (Online)

For additional information: http://www.karger.com/PHA


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Georges B, Galland S, Rigault C, Le Borgne F, Demarquoy J: Beneficial effects of L-carnitine in myoblastic C2C12 cells: interaction with zidovudine. Biochem Pharmacol 2003;65:1483–1488.
  2. Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL: Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 1990;322:1098–1105.
  3. Owczarek J, Jasinska M, Orszulak-Michalak D: Drug-induced myopathies: an overview of the possible mechanisms. Pharmacol Rep 2005;57:23–34.
  4. Masanes F, Barrientos A, Cebrian M, Pedrol E, Miro O, Casademont J, Grau JM: Clinical, histological and molecular reversibility of zidovudine myopathy. J Neurol Sci 1998;159:226–228.
  5. Arnaudo E, Dalakas M, Shanske S, Moraes CT, DiMauro S, Schon EA: Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet 1991;337:508–510.
  6. Lewis W, Copeland WC, Day BJ: Mitochondrial DNA depletion, oxidative stress, and mutation: mechanisms of dysfunction from nucleoside reverse transcriptase inhibitors. Lab Invest 2001;81:777–790.
  7. Tolomeo M, Mancuso S, Todaro M, Stassi G, Catalano M, Arista S, Cannizzo G, Barbusca E, Abbadessa V: Mitochondrial disruption and apoptosis in lymphocytes of an HIV infected patient affected by lactic acidosis after treatment with highly active antiretroviral therapy. J Clin Pathol 2003;56:147–151.
  8. Cote HC, Brumme ZL, Craib KJ, Alexander CS, Wynhoven B, Ting L, Wong H, Harris M, Harrigan PR, O’Shaughnessy MV, Montaner JS: Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 2002;346:811–820.
  9. Martin JL, Brown CE, Matthews-Davis N, Reardon JE: Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob Agents Chemother 1994;38:2743–2749.
  10. Lynx MD, McKee EE: 3′-Azido-3′-deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondria. Biochem Pharmacol 2006;72:239–243.
  11. Rylova SN, Albertioni F, Flygh G, Eriksson S: Activity profiles of deoxynucleoside kinases and 5′-nucleotidases in cultured adipocytes and myoblastic cells: insights into mitochondrial toxicity of nucleoside analogs. Biochem Pharmacol 2005;69:951–960.
  12. Lebrecht D, Deveaud C, Beauvoit B, Bonnet J, Kirschner J, Walker UA: Uridine supplementation antagonizes zidovudine-induced mitochondrial myopathy and hyperlactatemia in mice. Arthritis Rheum 2008;58:318–326.
  13. Modica-Napolitano JS: AZT causes tissue-specific inhibition of mitochondrial bioenergetic function. Biochem Biophys Res Commun 1993;194:170–177.
  14. Yamaguchi T, Katoh I, Kurata S: Azidothymidine causes functional and structural destruction of mitochondria, glutathione deficiency and HIV-1 promoter sensitization. Eur J Biochem 2002;269:2782–2788.
  15. Cazzalini O, Lazze MC, Iamele L, Stivala LA, Bianchi L, Vaghi P, Cornaglia A, Calligaro A, Curti D, Alessandrini A, Prosperi E, Vannini V: Early effects of AZT on mitochondrial functions in the absence of mitochondrial DNA depletion in rat myotubes. Biochem Pharmacol 2001;62:893–902.
  16. de la Asuncion JG, del Olmo ML, Sastre J, Millan A, Pellin A, Pallardo FV, Vina J: AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria: prevention by antioxidant vitamins. J Clin Invest 1998;102:4–9.
  17. Wheeler S, Maxwell-Bawden A, Herb RA, Gallagher GE, Coast JR: Zidovudine-induced diaphragmatic contractile dysfunction: impact of an antioxidant diet. Respirology 2005;10:171–176.
  18. Linnane AW, Degli Esposti M, Generowicz M, Luff AR, Nagley P: The universality of bioenergetic disease and amelioration with redox therapy. Biochim Biophys Acta 1995;1271:191–194.

    External Resources

  19. Rosenfeldt FL, Mijch A, McCrystal G, Sweeney C, Pepe S, Nicholls M, Dennett X: Skeletal myopathy associated with nucleoside reverse transcriptase inhibitor therapy: potential benefit of coenzyme Q10 therapy. Int J STD AIDS 2005;16:827–829.
  20. Dalakas MC, Leon-Monzon ME, Bernardini I, Gahl WA, Jay CA: Zidovudine-induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage. Ann Neurol 1994;35:482–487.
  21. Semino-Mora MC, Leon-Monzon ME, Dalakas MC: Effect of L-carnitine on the zidovudine-induced destruction of human myotubes. I. L-carnitine prevents the myotoxicity of AZT in vitro. Lab Invest 1994;71:102–112.
  22. Kokoszka JE, Coskun P, Esposito LA, Wallace DC: Increased mitochondrial oxidative stress in the Sod2 (+/–) mouse results in the age-related decline of mitochondrial function culminating in increased apoptosis. Proc Natl Acad Sci USA 2001;98:2278–2283.
  23. Liu CY, Lee CF, Hong CH, Wei YH: Mitochondrial DNA mutation and depletion increase the susceptibility of human cells to apoptosis. Ann NY Acad Sci 2004;1011:133–145.
  24. Ratan RR, Murphy TH, Baraban JM: Oxidative stress induces apoptosis in embryonic cortical neurons. J Neurochem 1994;62:376–379.
  25. Unger RH, Orci L: Lipoapoptosis: its mechanism and its diseases. Biochim Biophys Acta 2002;1585:202–212.
  26. Mirabella M, Di Giovanni S, Silvestri G, Tonali P, Servidei S: Apoptosis in mitochondrial encephalomyopathies with mitochondrial DNA mutations: a potential pathogenic mechanism. Brain 2000;123(pt 1):93–104.
  27. Ikezoe K, Nakagawa M, Yan C, Kira J, Goto Y, Nonaka I: Apoptosis is suspended in muscle of mitochondrial encephalomyopathies. Acta Neuropathol (Berl) 2002;103:531–540.
  28. Umaki Y, Mitsui T, Endo I, Akaike M, Matsumoto T: Apoptosis-related changes in skeletal muscles of patients with mitochondrial diseases. Acta Neuropathol (Berl) 2002;103:163–170.
  29. Formichi P, Battisti C, Bianchi S, Cardaioli E, Federico A: Evidence of apoptosis via TUNEL staining in muscle biopsy from patients with mitochondrial encephaloneuromyopathies. J Submicrosc Cytol Pathol 2003;35:29–34.
  30. Sandri M, Carraro U, Podhorska-Okolov M, Rizzi C, Arslan P, Monti D, Franceschi C: Apoptosis, DNA damage and ubiquitin expression in normal and mdx muscle fibers after exercise. FEBS Lett 1995;373:291–295.
  31. Adams V, Jiang H, Yu J, Mobius-Winkler S, Fiehn E, Linke A, Weigl C, Schuler G, Hambrecht R: Apoptosis in skeletal myocytes of patients with chronic heart failure is associated with exercise intolerance. J Am Coll Cardiol 1999;33:959–965.
  32. Belizario JE, Lorite MJ, Tisdale MJ: Cleavage of caspases-1, -3, -6, -8 and -9 substrates by proteases in skeletal muscles from mice undergoing cancer cachexia. Br J Cancer 2001;84:1135–1140.
  33. Alway SE, Degens H, Krishnamurthy G, Chaudhrai A: Denervation stimulates apoptosis but not Id2 expression in hindlimb muscles of aged rats. J Gerontol A Biol Sci Med Sci 2003;58:687–697.
  34. Allen DL, Linderman JK, Roy RR, Bigbee AJ, Grindeland RE, Mukku V, Edgerton VR: Apoptosis: a mechanism contributing to remodeling of skeletal muscle in response to hindlimb unweighting. Am J Physiol 1997;273:C579–C587.
  35. 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–C76.
  36. Dirks A, Leeuwenburgh C: Apoptosis in skeletal muscle with aging. Am J Physiol Regul Integr Comp Physiol 2002;282:R519–R527.
  37. Dirks AJ, Leeuwenburgh C: Aging and lifelong calorie restriction result in adaptations of skeletal muscle apoptosis repressor, apoptosis-inducing factor, X-linked inhibitor of apoptosis, caspase-3, and caspase-12. Free Radic Biol Med 2004;36:27–39.
  38. Dirks AJ, Jones KM: Statin-induced apoptosis and skeletal myopathy. Am J Physiol Cell Physiol 2006;291:C1208–C1212.
  39. Lee MC, Wee GR, Kim JH: Apoptosis of skeletal muscle on steroid-induced myopathy in rats. J Nutr 2005;135:S1806–S1808.
  40. Collier AC, Helliwell RJ, Keelan JA, Paxton JW, Mitchell MD, Tingle MD: 3′-azido-3′-deoxythymidine (AZT) induces apoptosis and alters metabolic enzyme activity in human placenta. Toxicol Appl Pharmacol 2003;192:164–173.
  41. Falchetti A, Franchi A, Bordi C, Mavilia C, Masi L, Cioppi F, Recenti R, Picariello L, Marini F, Del Monte F, Ghinoi V, Martineti V, Tanini A, Brandi ML: Azidothymidine induces apoptosis and inhibits cell growth and telomerase activity of human parathyroid cancer cells in culture. J Bone Miner Res 2005;20:410–418.
  42. Sun YQ, Guo TK, Xi YM, Chen C, Wang J, Wang ZR: Effects of AZT and RNA-protein complex (FA-2-b-beta) extracted from Liang Jin mushroom on apoptosis of gastric cancer cells. World J Gastroenterol 2007;13:4185–4191.
  43. Ji HJ, Rha SY, Jeung HC, Yang SH, An SW, Chung HC: Cyclic induction of senescence with intermittent AZT treatment accelerates both apoptosis and telomere loss. Breast Cancer Res Treat 2005;93:227–236.
  44. Zhou FX, Liao ZK, Dai J, Xiong J, Xie CH, Luo ZG, Liu SQ, Zhou YF: Radiosensitization effect of zidovudine on human malignant glioma cells. Biochem Biophys Res Commun 2007;354:351–356.
  45. Purevjav E, Nelson DP, Varela JJ, Jimenez S, Kearney DL, Sanchez XV, Defreitas G, Carabello B, Taylor MD, Vatta M, Shearer WT, Towbin JA, Bowles NE: Myocardial Fas Ligand Expression Increases Susceptibility to AZT-Induced Cardiomyopathy. Cardiovasc Toxicol 2007;7:255–263.