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Vol. 58, No. 2, 2012
Issue release date: February 2012
Free Access
Gerontology 2012;58:99–106
(DOI:10.1159/000330064)

Apoptosis in Skeletal Myocytes: A Potential Target for Interventions against Sarcopenia and Physical Frailty – A Mini-Review

Marzetti E.a · Calvani R.b · Bernabei R.b · Leeuwenburgh C.c
Departments of aOrthopaedics and Traumatology, and bGerontology, Geriatrics and Physiatrics, University Hospital Agostino Gemelli, Catholic University of the Sacred Heart, Rome, Italy; cDepartment of Aging and Geriatric Research, Institute on Aging, University of Florida, Gainesville, Fla., USA
email Corresponding Author

Abstract

Background: Sarcopenia, the age-related loss of muscle mass and function, represents a relevant public health issue due to its high prevalence and detrimental consequences. While the exact mechanisms underlying the pathogenesis of sarcopenia are not clear, growing experimental evidence indicates that progressive myonuclear elimination over the course of aging via an apoptosis-like process may represent a converging mechanism through which muscle atrophy and loss of physical function develop. Notably, the proapoptotic environment taking place in aged muscle appears amenable to interventions. Objective: We aimed at providing (1) an overview of signaling pathways of apoptosis relevant to sarcopenia, and (2) a review of the literature supporting myocyte apoptosis as a target for interventions against muscle aging. Methods: We summarized findings from studies focused on skeletal myocyte apoptosis as a mechanism in the development of sarcopenia and reports supporting myonuclear apoptosis as a target for interventions against age-related muscle loss. Results: Advanced age is associated with increased signaling through extrinsic and intrinsic apoptotic pathways in skeletal myocytes. In contrast, downregulation of myocyte apoptosis through calorie restriction, exercise training, hormonal supplementation, drugs (e.g. angiotensin-converting enzyme inhibitors, acetaminophen, antimyostatin antibodies), nutraceuticals or genetic interventions (e.g. PGC-1α overexpression) is linked with preservation of muscle integrity and improved physical performance in late life. Preliminary data also indicate that skeletal myocyte apoptotic signaling may be downregulated by compounds, such as resveratrol, with calorie restriction-mimicking properties. Whether exercise mimetics exert a similar effect has not yet been investigated. Conclusions: Available evidence suggests that targeting myonuclear apoptosis might provide novel and effective therapeutic tools to combat sarcopenia. Further research is required to definitely establish if downregulating myonuclear apoptosis is effective in maintaining muscle mass and function in late life, identify the most relevant apoptotic pathway(s) to target, and determine the optimal timing for intervening.


 goto top of outline Key Words

  • Muscle
  • Mitochondria
  • Calorie restriction
  • Exercise
  • Resveratrol
  • Angiotensin-converting enzyme inhibitors
  • Hormones

 goto top of outline Abstract

Background: Sarcopenia, the age-related loss of muscle mass and function, represents a relevant public health issue due to its high prevalence and detrimental consequences. While the exact mechanisms underlying the pathogenesis of sarcopenia are not clear, growing experimental evidence indicates that progressive myonuclear elimination over the course of aging via an apoptosis-like process may represent a converging mechanism through which muscle atrophy and loss of physical function develop. Notably, the proapoptotic environment taking place in aged muscle appears amenable to interventions. Objective: We aimed at providing (1) an overview of signaling pathways of apoptosis relevant to sarcopenia, and (2) a review of the literature supporting myocyte apoptosis as a target for interventions against muscle aging. Methods: We summarized findings from studies focused on skeletal myocyte apoptosis as a mechanism in the development of sarcopenia and reports supporting myonuclear apoptosis as a target for interventions against age-related muscle loss. Results: Advanced age is associated with increased signaling through extrinsic and intrinsic apoptotic pathways in skeletal myocytes. In contrast, downregulation of myocyte apoptosis through calorie restriction, exercise training, hormonal supplementation, drugs (e.g. angiotensin-converting enzyme inhibitors, acetaminophen, antimyostatin antibodies), nutraceuticals or genetic interventions (e.g. PGC-1α overexpression) is linked with preservation of muscle integrity and improved physical performance in late life. Preliminary data also indicate that skeletal myocyte apoptotic signaling may be downregulated by compounds, such as resveratrol, with calorie restriction-mimicking properties. Whether exercise mimetics exert a similar effect has not yet been investigated. Conclusions: Available evidence suggests that targeting myonuclear apoptosis might provide novel and effective therapeutic tools to combat sarcopenia. Further research is required to definitely establish if downregulating myonuclear apoptosis is effective in maintaining muscle mass and function in late life, identify the most relevant apoptotic pathway(s) to target, and determine the optimal timing for intervening.

Copyright © 2011 S. Karger AG, Basel


 goto top of outline References
  1. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP, Rolland Y, Schneider SM, Topinkova E, Vandewoude M, Zamboni M: Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010;39:412–423.

    External Resources

  2. Roubenoff R: Sarcopenia: a major modifiable cause of frailty in the elderly. J Nutr Health Aging 2000;4:140–142.
  3. Marzetti E, Privitera G, Simili V, Wohlgemuth SE, Aulisa L, Pahor M, Leeuwenburgh C: Multiple pathways to the same end: mechanisms of myonuclear apoptosis in sarcopenia of aging. Scientific World J 2010;10:340–349.
  4. Marzetti E, Hwang JC, Lees HA, Wohlgemuth SE, Dupont-Versteegden EE, Carter CS, Bernabei R, Leeuwenburgh C: Mitochondrial death effectors: relevance to sarcopenia and disuse muscle atrophy. Biochim Biophys Acta 2010;1800:235–244.
  5. Walston J, Fedarko N, Yang H, Leng S, Beamer B, Espinoza S, Lipton A, Zheng H, Becker K: The physical and biological characterization of a frail mouse model. J Gerontol A Biol Sci Med Sci 2008;63:391–398.

    External Resources

  6. Marzetti E, Wohlgemuth SE, Lees HA, Chung HY, Giovannini S, Leeuwenburgh C: Age-related activation of mitochondrial caspase-independent apoptotic signaling in rat gastrocnemius muscle. Mech Ageing Dev 2008;129:542–549.
  7. Phillips T, Leeuwenburgh C: Muscle fiber specific apoptosis and TNF-alpha signaling in sarcopenia are attenuated by life-long calorie restriction. FASEB J 2005;19:668–670.
  8. Marzetti E, Carter CS, Wohlgemuth SE, Lees HA, Giovannini S, Anderson B, Quinn LS, Leeuwenburgh C: Changes in IL-15 expression and death-receptor apoptotic signaling in rat gastrocnemius muscle with aging and life-long calorie restriction. Mech Ageing Dev 2009;130:272–280.
  9. Turpin SM, Lancaster GI, Darby I, Febbraio MA, Watt MJ: Apoptosis in skeletal muscle myotubes is induced by ceramides and is positively related to insulin resistance. Am J Physiol Endocrinol Metab 2006;291:E1341–E1350.
  10. Kerr JF, Wyllie AH, Currie AR: Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239–257.
  11. Zimmermann KC, Bonzon C, Green DR: The machinery of programmed cell death. Pharmacol Ther 2001;92:57–70.
  12. Parsons MJ, Green DR: Mitochondria in cell death. Essays Biochem 2010;47:99–114.
  13. Du J, Wang X, Miereles C, Bailey JL, Debigare R, Zheng B, Price SR, Mitch WE: Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. J Clin Invest 2004;113:115–123.
  14. Argiles JM, Lopez-Soriano FJ, Busquets S: Apoptosis signalling is essential and precedes protein degradation in wasting skeletal muscle during catabolic conditions. Int J Biochem Cell Biol 2008;40:1674–1678.
  15. Marzetti E, Lees HA, Wohlgemuth SE, Leeuwenburgh C: Sarcopenia of aging: underlying cellular mechanisms and protection by calorie restriction. Bio Factors 2009;35:28–35.
  16. 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.
  17. Ekhterae D, Lin Z, Lundberg MS, Crow MT, Brosius FC, III, Nunez G: ARC inhibits cytochrome c release from mitochondria and protects against hypoxia-induced apoptosis in heart-derived H9c2 cells. Circ Res 1999;85:e70–e77.
  18. Landi F, Zuccala G, Gambassi G, Incalzi RA, Manigrasso L, Pagano F, Carbonin P, Bernabei R: Body mass index and mortality among older people living in the community. J Am Geriatr Soc 1999;47:1072–1076.
  19. Chung S, Yao H, Caito S, Hwang JW, Arunachalam G, Rahman I: Regulation of SIRT1 in cellular functions: role of polyphenols. Arch Biochem Biophys 2010;501:79–90.
  20. Siddiqui MA, Kashyap MP, Kumar V, Al-Khedhairy AA, Musarrat J, Pant AB: Protective potential of trans-resveratrol against 4-hydroxynonenal induced damage in PC12 cells. Toxicol In Vitro 2010;24:1592–1598.
  21. Jackson JR, Ryan MJ, Hao Y, Alway SE: Mediation of endogenous antioxidant enzymes and apoptotic signaling by resveratrol following muscle disuse in the gastrocnemius muscles of young and old rats. Am J Physiol Regul Integr Comp Physiol 2010;299:R1572–R1581.
  22. Frankel JE, Bean JF, Frontera WR: Exercise in the elderly: research and clinical practice. Clin Geriatr Med 2006;22:239–256.

    External Resources

  23. Fiatarone MA, O’Neill EF, Ryan ND, Clements KM, Solares GR, Nelson ME, Roberts SB, Kehayias JJ, Lipsitz LA, Evans WJ: Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med 1994;330:1769–1775.
  24. Song W, Kwak HB, Lawler JM: Exercise training attenuates age-induced changes in apoptotic signaling in rat skeletal muscle. Antioxid Redox Signal 2006;8:517–528.
  25. Marzetti E, Groban L, Wohlgemuth SE, Lees HA, Lin M, Jobe H, Giovannini S, Leeuwenburgh C, Carter CS: Effects of short-term GH supplementation and treadmill exercise training on physical performance and skeletal muscle apoptosis in old rats. Am J Physiol Regul Integr Comp Physiol 2008;294: R558–R567.
  26. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM: AMPK and PPARdelta agonists are exercise mimetics. Cell 2008;134:405–415.
  27. Carter CS, Giovaninni S, Seo DO, Dupree J, Morgan D, Chung HY, Lees H, Daniels M, Hubbard GB, Lee S, Ikeno Y, Foster TC, Buford TW, Marzetti E: Differential effects of enalapril and losartan on body composition and indices of muscle quality in aged male Fischer 344 × Brown Norway rats. Age (Dordr) 2011;33:167–183.
  28. Wu M, Katta A, Gadde MK, Liu H, Kakarla SK, Fannin J, Paturi S, Arvapalli RK, Rice KM, Wang Y, Blough ER: Aging-associated dysfunction of Akt/protein kinase B: S-nitrosylation and acetaminophen intervention. PLoS One 2009;4:e6430.

    External Resources

  29. Murphy KT, Koopman R, Naim T, Leger B, Trieu J, Ibebunjo C, Lynch GS: Antibody-directed myostatin inhibition in 21-mo-old mice reveals novel roles for myostatin signaling in skeletal muscle structure and function. FASEB J 2010;24:4433–4442.
  30. Xu J, Seo AY, Vorobyeva DA, Carter CS, Anton SD, Lezza AM, Leeuwenburgh C: Beneficial effects of a Q-ter based nutritional mixture on functional performance, mitochondrial function, and oxidative stress in rats. PLoS One 2010;5:e10572.

    External Resources

  31. Kovacheva EL, Hikim AP, Shen R, Sinha I, Sinha-Hikim I: Testosterone supplementation reverses sarcopenia in aging through regulation of myostatin, c-Jun NH2-terminal kinase, Notch, and Akt signaling pathways. Endocrinology 2010;151:628–638.
  32. Pistilli EE, Alway SE: Systemic elevation of interleukin-15 in vivo promotes apoptosis in skeletal muscles of young adult and aged rats. Biochem Biophys Res Commun 2008;373:20–24.
  33. Kujoth GC, Leeuwenburgh C, Prolla TA: Mitochondrial DNA mutations and apoptosis in mammalian aging. Cancer Res 2006;66:7386–7389.
  34. Safdar A, Bourgeois JM, Ogborn DI, Little JP, Hettinga BP, Akhtar M, Thompson JE, Melov S, Mocellin NJ, Kujoth GC, Prolla TA, Tarnopolsky MA: Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc Natl Acad Sci USA 2011;108:4135–4140.
  35. Jang YC, Lustgarten MS, Liu Y, Muller FL, Bhattacharya A, Liang H, Salmon AB, Brooks SV, Larkin L, Hayworth CR, Richardson A, Van RH: Increased superoxide in vivo accelerates age-associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration. FASEB J 2010;24:1376–1390.
  36. Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT: Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci USA 2009;106:20405–20410.

 goto top of outline Author Contacts

Emanuele Marzetti, MD, PhD
Department of Orthopaedics and Traumatology, University Hospital Agostino Gemelli
Catholic University of the Sacred Heart, Largo A. Gemelli 1
IT–00168 Rome (Italy)
Tel. +39 06 3015 5669, E-Mail emarzetti@live.com


 goto top of outline Article Information

Received: April 7, 2011
Accepted: June 9, 2011
Published online: September 23, 2011
Number of Print Pages : 8
Number of Figures : 1, Number of Tables : 1, Number of References : 36


 goto top of outline Publication Details

Gerontology (International Journal of Experimental, Clinical, Behavioural and Technological Gerontology)

Vol. 58, No. 2, Year 2012 (Cover Date: February 2012)

Journal Editor: Wick G. (Innsbruck)
ISSN: 0304-324X (Print), eISSN: 1423-0003 (Online)

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


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

Background: Sarcopenia, the age-related loss of muscle mass and function, represents a relevant public health issue due to its high prevalence and detrimental consequences. While the exact mechanisms underlying the pathogenesis of sarcopenia are not clear, growing experimental evidence indicates that progressive myonuclear elimination over the course of aging via an apoptosis-like process may represent a converging mechanism through which muscle atrophy and loss of physical function develop. Notably, the proapoptotic environment taking place in aged muscle appears amenable to interventions. Objective: We aimed at providing (1) an overview of signaling pathways of apoptosis relevant to sarcopenia, and (2) a review of the literature supporting myocyte apoptosis as a target for interventions against muscle aging. Methods: We summarized findings from studies focused on skeletal myocyte apoptosis as a mechanism in the development of sarcopenia and reports supporting myonuclear apoptosis as a target for interventions against age-related muscle loss. Results: Advanced age is associated with increased signaling through extrinsic and intrinsic apoptotic pathways in skeletal myocytes. In contrast, downregulation of myocyte apoptosis through calorie restriction, exercise training, hormonal supplementation, drugs (e.g. angiotensin-converting enzyme inhibitors, acetaminophen, antimyostatin antibodies), nutraceuticals or genetic interventions (e.g. PGC-1α overexpression) is linked with preservation of muscle integrity and improved physical performance in late life. Preliminary data also indicate that skeletal myocyte apoptotic signaling may be downregulated by compounds, such as resveratrol, with calorie restriction-mimicking properties. Whether exercise mimetics exert a similar effect has not yet been investigated. Conclusions: Available evidence suggests that targeting myonuclear apoptosis might provide novel and effective therapeutic tools to combat sarcopenia. Further research is required to definitely establish if downregulating myonuclear apoptosis is effective in maintaining muscle mass and function in late life, identify the most relevant apoptotic pathway(s) to target, and determine the optimal timing for intervening.



 goto top of outline Author Contacts

Emanuele Marzetti, MD, PhD
Department of Orthopaedics and Traumatology, University Hospital Agostino Gemelli
Catholic University of the Sacred Heart, Largo A. Gemelli 1
IT–00168 Rome (Italy)
Tel. +39 06 3015 5669, E-Mail emarzetti@live.com


 goto top of outline Article Information

Received: April 7, 2011
Accepted: June 9, 2011
Published online: September 23, 2011
Number of Print Pages : 8
Number of Figures : 1, Number of Tables : 1, Number of References : 36


 goto top of outline Publication Details

Gerontology (International Journal of Experimental, Clinical, Behavioural and Technological Gerontology)

Vol. 58, No. 2, Year 2012 (Cover Date: February 2012)

Journal Editor: Wick G. (Innsbruck)
ISSN: 0304-324X (Print), eISSN: 1423-0003 (Online)

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


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. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP, Rolland Y, Schneider SM, Topinkova E, Vandewoude M, Zamboni M: Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010;39:412–423.

    External Resources

  2. Roubenoff R: Sarcopenia: a major modifiable cause of frailty in the elderly. J Nutr Health Aging 2000;4:140–142.
  3. Marzetti E, Privitera G, Simili V, Wohlgemuth SE, Aulisa L, Pahor M, Leeuwenburgh C: Multiple pathways to the same end: mechanisms of myonuclear apoptosis in sarcopenia of aging. Scientific World J 2010;10:340–349.
  4. Marzetti E, Hwang JC, Lees HA, Wohlgemuth SE, Dupont-Versteegden EE, Carter CS, Bernabei R, Leeuwenburgh C: Mitochondrial death effectors: relevance to sarcopenia and disuse muscle atrophy. Biochim Biophys Acta 2010;1800:235–244.
  5. Walston J, Fedarko N, Yang H, Leng S, Beamer B, Espinoza S, Lipton A, Zheng H, Becker K: The physical and biological characterization of a frail mouse model. J Gerontol A Biol Sci Med Sci 2008;63:391–398.

    External Resources

  6. Marzetti E, Wohlgemuth SE, Lees HA, Chung HY, Giovannini S, Leeuwenburgh C: Age-related activation of mitochondrial caspase-independent apoptotic signaling in rat gastrocnemius muscle. Mech Ageing Dev 2008;129:542–549.
  7. Phillips T, Leeuwenburgh C: Muscle fiber specific apoptosis and TNF-alpha signaling in sarcopenia are attenuated by life-long calorie restriction. FASEB J 2005;19:668–670.
  8. Marzetti E, Carter CS, Wohlgemuth SE, Lees HA, Giovannini S, Anderson B, Quinn LS, Leeuwenburgh C: Changes in IL-15 expression and death-receptor apoptotic signaling in rat gastrocnemius muscle with aging and life-long calorie restriction. Mech Ageing Dev 2009;130:272–280.
  9. Turpin SM, Lancaster GI, Darby I, Febbraio MA, Watt MJ: Apoptosis in skeletal muscle myotubes is induced by ceramides and is positively related to insulin resistance. Am J Physiol Endocrinol Metab 2006;291:E1341–E1350.
  10. Kerr JF, Wyllie AH, Currie AR: Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239–257.
  11. Zimmermann KC, Bonzon C, Green DR: The machinery of programmed cell death. Pharmacol Ther 2001;92:57–70.
  12. Parsons MJ, Green DR: Mitochondria in cell death. Essays Biochem 2010;47:99–114.
  13. Du J, Wang X, Miereles C, Bailey JL, Debigare R, Zheng B, Price SR, Mitch WE: Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. J Clin Invest 2004;113:115–123.
  14. Argiles JM, Lopez-Soriano FJ, Busquets S: Apoptosis signalling is essential and precedes protein degradation in wasting skeletal muscle during catabolic conditions. Int J Biochem Cell Biol 2008;40:1674–1678.
  15. Marzetti E, Lees HA, Wohlgemuth SE, Leeuwenburgh C: Sarcopenia of aging: underlying cellular mechanisms and protection by calorie restriction. Bio Factors 2009;35:28–35.
  16. 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.
  17. Ekhterae D, Lin Z, Lundberg MS, Crow MT, Brosius FC, III, Nunez G: ARC inhibits cytochrome c release from mitochondria and protects against hypoxia-induced apoptosis in heart-derived H9c2 cells. Circ Res 1999;85:e70–e77.
  18. Landi F, Zuccala G, Gambassi G, Incalzi RA, Manigrasso L, Pagano F, Carbonin P, Bernabei R: Body mass index and mortality among older people living in the community. J Am Geriatr Soc 1999;47:1072–1076.
  19. Chung S, Yao H, Caito S, Hwang JW, Arunachalam G, Rahman I: Regulation of SIRT1 in cellular functions: role of polyphenols. Arch Biochem Biophys 2010;501:79–90.
  20. Siddiqui MA, Kashyap MP, Kumar V, Al-Khedhairy AA, Musarrat J, Pant AB: Protective potential of trans-resveratrol against 4-hydroxynonenal induced damage in PC12 cells. Toxicol In Vitro 2010;24:1592–1598.
  21. Jackson JR, Ryan MJ, Hao Y, Alway SE: Mediation of endogenous antioxidant enzymes and apoptotic signaling by resveratrol following muscle disuse in the gastrocnemius muscles of young and old rats. Am J Physiol Regul Integr Comp Physiol 2010;299:R1572–R1581.
  22. Frankel JE, Bean JF, Frontera WR: Exercise in the elderly: research and clinical practice. Clin Geriatr Med 2006;22:239–256.

    External Resources

  23. Fiatarone MA, O’Neill EF, Ryan ND, Clements KM, Solares GR, Nelson ME, Roberts SB, Kehayias JJ, Lipsitz LA, Evans WJ: Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med 1994;330:1769–1775.
  24. Song W, Kwak HB, Lawler JM: Exercise training attenuates age-induced changes in apoptotic signaling in rat skeletal muscle. Antioxid Redox Signal 2006;8:517–528.
  25. Marzetti E, Groban L, Wohlgemuth SE, Lees HA, Lin M, Jobe H, Giovannini S, Leeuwenburgh C, Carter CS: Effects of short-term GH supplementation and treadmill exercise training on physical performance and skeletal muscle apoptosis in old rats. Am J Physiol Regul Integr Comp Physiol 2008;294: R558–R567.
  26. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM: AMPK and PPARdelta agonists are exercise mimetics. Cell 2008;134:405–415.
  27. Carter CS, Giovaninni S, Seo DO, Dupree J, Morgan D, Chung HY, Lees H, Daniels M, Hubbard GB, Lee S, Ikeno Y, Foster TC, Buford TW, Marzetti E: Differential effects of enalapril and losartan on body composition and indices of muscle quality in aged male Fischer 344 × Brown Norway rats. Age (Dordr) 2011;33:167–183.
  28. Wu M, Katta A, Gadde MK, Liu H, Kakarla SK, Fannin J, Paturi S, Arvapalli RK, Rice KM, Wang Y, Blough ER: Aging-associated dysfunction of Akt/protein kinase B: S-nitrosylation and acetaminophen intervention. PLoS One 2009;4:e6430.

    External Resources

  29. Murphy KT, Koopman R, Naim T, Leger B, Trieu J, Ibebunjo C, Lynch GS: Antibody-directed myostatin inhibition in 21-mo-old mice reveals novel roles for myostatin signaling in skeletal muscle structure and function. FASEB J 2010;24:4433–4442.
  30. Xu J, Seo AY, Vorobyeva DA, Carter CS, Anton SD, Lezza AM, Leeuwenburgh C: Beneficial effects of a Q-ter based nutritional mixture on functional performance, mitochondrial function, and oxidative stress in rats. PLoS One 2010;5:e10572.

    External Resources

  31. Kovacheva EL, Hikim AP, Shen R, Sinha I, Sinha-Hikim I: Testosterone supplementation reverses sarcopenia in aging through regulation of myostatin, c-Jun NH2-terminal kinase, Notch, and Akt signaling pathways. Endocrinology 2010;151:628–638.
  32. Pistilli EE, Alway SE: Systemic elevation of interleukin-15 in vivo promotes apoptosis in skeletal muscles of young adult and aged rats. Biochem Biophys Res Commun 2008;373:20–24.
  33. Kujoth GC, Leeuwenburgh C, Prolla TA: Mitochondrial DNA mutations and apoptosis in mammalian aging. Cancer Res 2006;66:7386–7389.
  34. Safdar A, Bourgeois JM, Ogborn DI, Little JP, Hettinga BP, Akhtar M, Thompson JE, Melov S, Mocellin NJ, Kujoth GC, Prolla TA, Tarnopolsky MA: Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc Natl Acad Sci USA 2011;108:4135–4140.
  35. Jang YC, Lustgarten MS, Liu Y, Muller FL, Bhattacharya A, Liang H, Salmon AB, Brooks SV, Larkin L, Hayworth CR, Richardson A, Van RH: Increased superoxide in vivo accelerates age-associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration. FASEB J 2010;24:1376–1390.
  36. Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT: Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci USA 2009;106:20405–20410.