Targeting mitochondrial function and proteostasis to mitigate dynapenia

Abstract

Traditionally, interventions to treat skeletal muscle aging have largely targeted sarcopenia—the age-related loss of skeletal muscle mass. Dynapenia refers to the age-related loss in skeletal muscle function due to factors outside of muscle mass, which helps to inform treatment strategies for aging skeletal muscle. There is evidence that mechanisms to maintain protein homeostasis and proteostasis, deteriorate with age. One key mechanism to maintain proteostasis is protein turnover, which is an energetically costly process. When there is a mismatch between cellular energy demands and energy provision, inelastic processes related to metabolism are maintained, but there is competition for the remaining energy between the elastic processes of somatic maintenance and growth. With aging, mitochondrial dysfunction reduces ATP generation capacity, constraining the instantaneous supply of energy, thus compromising growth and somatic maintenance processes. Further, with age the need for somatic maintenance increases because of the accumulation of protein damage. In this review, we highlight the significant role mitochondria have in maintaining skeletal muscle proteostasis through increased energy provision, protein turnover, and substrate flux. In addition, we provide evidence that improving mitochondrial function could promote a cellular environment that is conducive to somatic maintenance, and consequently for mitigating dynapenia. Finally, we highlight interventions, such as aerobic exercise, that could be used to improve mitochondrial function and improve outcomes related to dynapenia.

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Fig. 1
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Abbreviations

AGE:

Advanced glycation end-product

AMPK:

5′ adenosine monophosphate-activated protein kinase

ATP:

Adenosine triphosphate

DAG:

Diacylglyceride

mTOR:

Mechanistic target of rapamycin

NADH:

Reduced nicotinamide adenine dinucleotide

ROS:

Reactive oxygen species

References

  1. Amara CE, Shankland EG, Jubrias SA et al (2007) Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivo. Proc Natl Acad Sci 104:1057–1062. doi:10.1073/pnas.0610131104

    CAS  Article  PubMed  Google Scholar 

  2. Anderson EJ, Lustig ME, Boyle KE et al (2009) Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest 119:573–581. doi:10.1172/JCI37048

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Ayyadevara S, Balasubramaniam M, Suri P et al (2016) Proteins that accumulate with age in human skeletal-muscle aggregates contribute to declines in muscle mass and function in Caenorhabditis elegans. Aging 8:3486–3497. doi:10.18632/aging.101141

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Balch WE, Morimoto RI, Dillin A, Kelly JW (2008) Adapting proteostasis for disease intervention. Science 319:916–919. doi:10.1126/science.1141448

    CAS  Article  PubMed  Google Scholar 

  5. Barreiro E, Hussain SNA a (2010) Protein carbonylation in skeletal muscles: impact on function. Antioxid Redox Signal 12:417–429. doi:10.1089/ars.2009.2808

    CAS  Article  PubMed  Google Scholar 

  6. Batsis JA, Mackenzie TA, Lopez-Jimenez F, Bartels SJ (2015) Sarcopenia, sarcopenic obesity, and functional impairments in older adults: National Health and Nutrition Examination Surveys 1999–2004. Nutr Res 35:1031–1039. doi:10.1016/j.nutres.2015.09.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Baumgartner RN, Koehler KM, Gallagher D et al (1998) Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol 147:755–763

    CAS  Article  Google Scholar 

  8. Befroy DE, Petersen KF, Dufour S et al (2008) Increased substrate oxidation and mitochondrial uncoupling in skeletal muscle of endurance-trained individuals. Proc Natl Acad Sci U S A 105:16701–16706. doi:10.1073/pnas.0808889105

    Article  PubMed  PubMed Central  Google Scholar 

  9. Berthon P, Freyssenet D, Chatard J-C et al (1995) Mitochondrial ATP production rate in 55 to 73-year-old men: effect of endurance training. Acta Physiol Scand 154:269–274. doi:10.1111/j.1748-1716.1995.tb09908.x

    CAS  Article  PubMed  Google Scholar 

  10. Bhatti JS, Bhatti GK, Reddy PH (2016) Mitochondrial dysfunction and oxidative stress in metabolic disorders—A step towards mitochondria based therapeutic strategies. Biochim Biophys Acta Mol Basis Dis. doi:10.1016/j.bbadis.2016.11.010

    Article  PubMed  Google Scholar 

  11. Bitto A, Ito TK, Pineda VV et al (2016) Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife 5:1–17. doi:10.7554/eLife.16351

    Article  Google Scholar 

  12. Brand MD (1990) The contribution of the leak of protons across the mitochondrial inner membrane to standard metabolic rate. J Theor Biol 145:267–286. doi:10.1016/S0022-5193(05)80131-6

    CAS  Article  PubMed  Google Scholar 

  13. Brand MD (1997) Regulation analysis of energy metabolism. J Exp Biol 200:193–202

    CAS  PubMed  Google Scholar 

  14. Brocca L, McPhee JS, Longa E et al (2017) Structure and function of human muscle fibres and muscle proteome in physically active older men. J Physiol 0:1–22. doi:10.1113/JP274148

    CAS  Article  Google Scholar 

  15. Buttgereit F, Brand MD (1995) A hierarchy of ATP-consuming processes in mammalian cells. Biochem J 312(Pt 1):163–167. doi:10.1210/er.2008-0019

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Civitarese AE, Carling S, Heilbronn LK et al (2007) Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 4:e76. doi:10.1371/journal.pmed.0040076

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Clark BC, Manini TM (2008) Sarcopenia != dynapenia. J Gerontol Ser A Biol Sci Med Sci 63:829–834. doi:10.1093/gerona/63.8.829

    Article  Google Scholar 

  18. Clark BC, Manini TM (2012) What is dynapenia? Nutrition 28:495–503. doi:10.1016/j.nut.2011.12.002

    Article  PubMed  PubMed Central  Google Scholar 

  19. Coen PM, Dubé JJ, Amati F et al (2010) Insulin resistance is associated with higher intramyocellular triglycerides in type I but not type II myocytes concomitant with higher ceramide content. Diabetes 59:80–88. doi:10.2337/db09-0988

    CAS  Article  PubMed  Google Scholar 

  20. Conley KE, Jubrias SA, Esselman PC (2000) Oxidative capacity and ageing in human muscle. J Physiol 526:203–210. doi:10.1111/j.1469-7793.2000.t01-1-00203.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Corcoran MP, Lamon-Fava S, Fielding RA (2007) Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise. Am J Clin Nutr 85:662–677

    CAS  PubMed  Google Scholar 

  22. Cruz-Jentoft AJ, Baeyens JP, Bauer JM et al (2010) Sarcopenia: European consensus on definition and diagnosis. Age Ageing 39:412–423. doi:10.1093/ageing/afq034

    Article  PubMed  PubMed Central  Google Scholar 

  23. Cruz-Jentoft AJ, Landi F, Schneider SM et al (2014) Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing 43:748–759. doi:10.1093/ageing/afu115

    Article  PubMed  PubMed Central  Google Scholar 

  24. Dai D-F, Chiao YA, Marcinek DJ et al (2014) Mitochondrial oxidative stress in aging and healthspan. Longev Heal 3:6. doi:10.1186/2046-2395-3-6

    Article  Google Scholar 

  25. Dalal M, Ferrucci L, Sun K et al (2009) Elevated serum advanced glycation end products and poor grip strength in older community-dwelling women. J Gerontol Ser A Biol Sci Med Sci 64A:132–137. doi:10.1093/gerona/gln018

    CAS  Article  Google Scholar 

  26. Dennis M, Bier (1999) The energy costs of protein metabolism: lean and mean on Uncle Sam’s team. In: Research Institute of Medicine (US) Committee on Military Nutrition (ed) The role of protein and amino acids in sustaining and enhancing performance. National Academies, Washington, D.C.

    Google Scholar 

  27. Distefano G, Standley RA, Dubé JJ et al (2016) Chronological age does not influence ex-vivo mitochondrial respiration and quality control in skeletal muscle. J Gerontol Ser A Biol Sci Med Sci 0:glw102. doi:10.1093/gerona/glw102

    CAS  Article  Google Scholar 

  28. Doherty TJ (2003) Invited review: aging and sarcopenia. J Appl Physiol 95:1717–1727. doi:10.1152/japplphysiol.00347.2003

    CAS  Article  PubMed  Google Scholar 

  29. Drake JC, Bruns DR, Peelor FF et al (2014) Long-lived crowded-litter mice have an age-dependent increase in protein synthesis to DNA synthesis ratio and mTORC1 substrate phosphorylation. Am J Physiol Endocrinol Metab 307:E813–E821. doi:10.1152/ajpendo.00256.2014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Drake JC, Wilson RJ, Yan Z (2016) Molecular mechanisms for mitochondrial adaptation to exercise training in skeletal muscle. FASEB J 30:13–22. doi:10.1096/fj.15-276337

    CAS  Article  PubMed  Google Scholar 

  31. Drenth H, Zuidema S, Bunt S et al (2016) The contribution of advanced glycation end product (AGE) accumulation to the decline in motor function. A systematic review. Eur Rev Aging Phys Act. doi:10.1186/s11556-016-0163-1

    Article  PubMed  PubMed Central  Google Scholar 

  32. Drew B, Dirks PA, Selman C et al (2003) Effects of aging and caloric restriction on mitochondrial energy production in gastrocnemius muscle and heart. Am J Physiol Regul Integr Comp Physiol 284:R474–R480. doi:10.1152/ajpregu.00455.2002

    CAS  Article  PubMed  Google Scholar 

  33. Dumitru CA, Zhang Y, Li X, Gulbins E (2007) Ceramide: a novel player in reactive oxygen species-induced signaling? Antioxid Redox Signal 9:1535–1540. doi:10.1089/ars.2007.1692

    CAS  Article  PubMed  Google Scholar 

  34. European Commission Directorate-General for Economic and Financial Affairs (2015) The 2015 Ageing Report Economic and budgetary projections for the 28 EU Member States (2013–2060)

  35. Fielding RA, Vellas B, Evans WJ et al (2011) Sarcopenia: an undiagnosed condition in older adults. Current Consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. J Am Med Dir Assoc 12:249–256. doi:10.1016/j.jamda.2011.01.003

    Article  PubMed  Google Scholar 

  36. Figueiredo PA, Powers SK, Ferreira RM et al (2009) Aging impairs skeletal muscle mitochondrial bioenergetic function. J Gerontol Ser A Biol Sci Med Sci 64:21–33. doi:10.1093/gerona/gln048

    CAS  Article  Google Scholar 

  37. Fischer KE, Gelfond JAL, Soto VY et al (2015) Health effects of long-term rapamycin treatment: the impact on mouse health of enteric rapamycin treatment from four months of age throughout life. PLoS One 10:1–18. doi:10.1371/journal.pone.0126644

    CAS  Article  Google Scholar 

  38. Gavrilov LA, Gavrilova NS (2002) Evolutionary theories of aging and longevity. Sci World J 2:339–356. doi:10.1100/tsw.2002.96

    Article  Google Scholar 

  39. Gomez-Cabrera M-C, Domenech E, Viña J (2008) Moderate exercise is an antioxidant: upregulation of antioxidant genes by training. Free Radic Biol Med 44:126–131. doi:10.1016/j.freeradbiomed.2007.02.001

    CAS  Article  PubMed  Google Scholar 

  40. Gonzalez-Freire M, De Cabo R, Bernier M et al (2015) Reconsidering the role of mitochondria in aging. J Gerontol Ser A Biol Sci Med Sci 70:1334–1342. doi:10.1093/gerona/glv070

    CAS  Article  Google Scholar 

  41. Goodpaster BH, He J, Watkins S, Kelley DE (2001) Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 86:5755–5761. doi:10.1210/jcem.86.12.8075

    CAS  Article  PubMed  Google Scholar 

  42. Greggio C, Jha P, Kulkarni SS et al (2017) Enhanced respiratory chain supercomplex formation in response to exercise in human skeletal muscle. Cell Metab 25:301–311. doi:10.1016/j.cmet.2016.11.004

    CAS  Article  PubMed  Google Scholar 

  43. Gregory TR (2001) Coincidence, coevolution, or causation? DNA content, cellsize, and the C-value enigma. Biol Rev 76:65–101. doi:10.1111/j.1469-185X.2000.tb00059.x

    CAS  Article  PubMed  Google Scholar 

  44. Hamilton KL, Miller BF (2017) Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation. J Physiol. doi:10.1113/JP274335

    Article  PubMed  PubMed Central  Google Scholar 

  45. Hancock CR, Han DH, Higashida K et al (2011) Does calorie restriction induce mitochondrial biogenesis? A reevaluation. FASEB J 25:785–791. doi:10.1096/fj.10-170415

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Harber MP, Konopka AR, Douglass MD et al (2009) Aerobic exercise training improves whole muscle and single myofiber size and function in older women. AJP Regul Integr Comp Physiol 297:R1452–R1459. doi:10.1152/ajpregu.00354.2009

    CAS  Article  Google Scholar 

  47. Harber MP, Konopka AR, Undem MK et al (2012) Aerobic exercise training induces skeletal muscle hypertrophy and age-dependent adaptations in myofiber function in young and older men. J Appl Physiol 113:1495–1504. doi:10.1152/japplphysiol.00786.2012

    Article  PubMed  PubMed Central  Google Scholar 

  48. Haus JM, Carrithers JA, Trappe SW, Trappe TA (2007) Collagen, cross-linking, and advanced glycation end products in aging human skeletal muscle. J Appl Physiol 47306:2068–2076. doi:10.1152/japplphysiol.00670.2007

    CAS  Article  Google Scholar 

  49. Heeman B, Van den Haute C, Aelvoet S-AS-A et al (2011) Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy maintenance. J Cell Sci 124:1115–1125. doi:10.1242/jcs.078303

    CAS  Article  PubMed  Google Scholar 

  50. Holloszy JO (1967) Biochemical adaptations in muscle. J Biol Chem 242:2278–2282

    CAS  Article  Google Scholar 

  51. Hou C (2013) The energy trade-off between growth and longevity. Mech Ageing Dev 134:373–380. doi:10.1016/j.mad.2013.07.001

    Article  PubMed  Google Scholar 

  52. Hou C, Zuo W, Moses ME et al (2008) Energy uptake and allocation during ontogeny. Science 322:736–739. doi:10.1126/science.1162302

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Jacobs RA, Boushel R, Wright-Paradis C et al (2013) Mitochondrial function in human skeletal muscle following high-altitude exposure. Exp Physiol 98:245–255. doi:10.1113/expphysiol.2012.066092

    CAS  Article  PubMed  Google Scholar 

  54. Janssen I, Shepard DS, Katzmarzyk PT, Roubenoff R (2004) The healthcare costs of sarcopenia in the United S… [J Am Geriatr Soc. 2004]—PubMed result. J Am Geriatr Soc 52:80–85. doi:10.1111/j.1532-5415.2004.52014.x

    Article  PubMed  Google Scholar 

  55. Jensen MB, Jasper H (2014) Mitochondrial proteostasis in the control of aging and longevity. Cell Metab 20:214–225

    CAS  Article  Google Scholar 

  56. Kapahi P (2010) Protein synthesis and the antagonistic pleiotropy hypothesis of aging. Adv Exp Med Biol 694:30–37

    CAS  Article  Google Scholar 

  57. Kent JA, Fitzgerald LF (2016) In vivo mitochondrial function in aging skeletal muscle: capacity, flux, and patterns of use. J Appl Physiol 121:996–1003. doi:10.1152/japplphysiol.00583.2016

    CAS  Article  PubMed  Google Scholar 

  58. Konopka AR, Harber MP (2014) Skeletal muscle hypertrophy after aerobic exercise training. Exerc Sport Sci Rev 42:53–61. doi:10.1249/JES.0000000000000007

    Article  PubMed  PubMed Central  Google Scholar 

  59. Konopka AR, Trappe TA, Jemiolo B et al (2011) Myosin heavy chain plasticity in aging skeletal muscle with aerobic exercise training. J Gerontol Ser A Biol Sci Med Sci 66A:835–841. doi:10.1093/gerona/glr088

    CAS  Article  Google Scholar 

  60. Kruse SE, Karunadharma PP, Basisty N et al (2016) Age modifies respiratory complex I and protein homeostasis in a muscle type-specific manner. Aging Cell 15:89–99. doi:10.1111/acel.12412

    CAS  Article  PubMed  Google Scholar 

  61. Lanza IR, Zabielski P, Klaus KA et al (2012) Chronic caloric restriction preserves mitochondrial function in senescence without increasing mitochondrial biogenesis. Cell Metab 16:777–788. doi:10.1016/j.cmet.2012.11.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. Larsen S, Nielsen J, Hansen CN et al (2012) Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. J Physiol 590:3349–3360. doi:10.1113/jphysiol.2012.230185

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. Levine RL, Stadtman ER (2001) Oxidative modification of proteins during aging. Exp Gerontol 36:1495–1502 pii]

    CAS  Article  Google Scholar 

  64. Long DE, Peck BD, Martz JL et al (2017) Metformin to augment strength training effective response in seniors (MASTERS): study protocol for a randomized controlled trial. Trials 18:192. doi:10.1186/s13063-017-1932-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Lynch M, Marinov GK (2015) The bioenergetic costs of a gene. Proc Natl Acad Sci 112:201514974. doi:10.1073/pnas.1514974112

    CAS  Article  Google Scholar 

  66. Madeira VMC (2012) Overview of mitochondrial bioenergetics. Methods Mol Biol 810:1–6

    CAS  Article  Google Scholar 

  67. Marcinek DJ, Schenkman K a, Ciesielski W a et al (2005) Reduced mitochondrial coupling in vivo alters cellular energetics in aged mouse skeletal muscle. J Physiol 569:467–473. doi:10.1113/jphysiol.2005.097782

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Martin BT, Zimmer EI, Grimm V, Jager T (2012) Dynamic energy budget theory meets individual-based modelling: a generic and accessible implementation. Methods Ecol Evol 3:445–449. doi:10.1111/j.2041-210X.2011.00168.x

    Article  Google Scholar 

  69. Menshikova EV, Ritov VB, Fairfull L et al (2006) Effects of exercise on mitochondrial content and function in aging human skeletal muscle. J Gerontol A Biol Sci Med Sci 61:534–540

    Article  Google Scholar 

  70. Miller BF, Robinson MM, Bruss MD et al (2012a) A comprehensive assessment of mitochondrial protein synthesis and cellular proliferation with age and caloric restriction. Aging Cell 11:150–161. doi:10.1111/j.1474-9726.2011.00769.x

    CAS  Article  PubMed  Google Scholar 

  71. Miller BF, Robinson MM, Reuland DJ et al (2012b) Calorie restriction does not increase short-term or long-term protein synthesis. J Gerontol A Biol Sci Med Sci 68:1–9. doi:10.1093/gerona/gls219

    CAS  Article  Google Scholar 

  72. Miller BF, Drake JC, Naylor B et al (2014) The measurement of protein synthesis for assessing proteostasis in studies of slowed aging. Ageing Res Rev 18:106–111. doi:10.1016/j.arr.2014.09.005

    CAS  Article  PubMed  Google Scholar 

  73. Moghaddas S, Hoppel CL, Lesnefsky EJ (2003) Aging defect at the QO site of complex III augments oxyradical production in rat heart interfibrillar mitochondria. Arch Biochem Biophys 414:59–66

    CAS  Article  Google Scholar 

  74. Morrow RM, Picard M, Derbeneva O et al (2017) Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity. Proc Natl Acad Sci. doi:10.1073/pnas.1700997114

    Article  PubMed  Google Scholar 

  75. Mortimore GE, Pösö a R (1987) Intracellular protein catabolism and its control during nutrient deprivation and supply. Annu Rev Nutr 7:539–564. doi:10.1146/annurev.nutr.7.1.539

    CAS  Article  PubMed  Google Scholar 

  76. Murton AJ (2015) Muscle protein turnover in the elderly and its potential contribution to the development of sarcopenia. Proc Nutr Soc 74:1–10. doi:10.1017/S0029665115000130

    CAS  Article  Google Scholar 

  77. Nair KS (2005) Aging muscle. Am J Clin Nutr 81:953–963

    CAS  Article  Google Scholar 

  78. Nisbet RM, Jusup M, Klanjscek T, Pecquerie L (2012) Integrating dynamic energy budget (DEB) theory with traditional bioenergetic models. J Exp Biol 215:892–902. doi:10.1242/jeb.059675

    Article  PubMed  Google Scholar 

  79. Nisoli E, Tonello C, Cardile A et al (2005) Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310:314–317. doi:10.1126/science.1117728

    CAS  Article  PubMed  Google Scholar 

  80. Paddon-Jones D, Rasmussen BB (2009) Dietary protein recommendations and the prevention of sarcopenia. Curr Opin Clin Nutr Metab Care 12:86–90. doi:10.1097/MCO.0b013e32831cef8b

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. Picard M, Ritchie D, Wright KJ et al (2010) Mitochondrial functional impairment with aging is exaggerated in isolated mitochondria compared to permeabilized myofibers. Aging Cell 9:1032–1046. doi:10.1111/j.1474-9726.2010.00628.x

    CAS  Article  PubMed  Google Scholar 

  82. Pikosky MA, Gaine PC, Martin WF et al (2006) Aerobic exercise training increases skeletal muscle protein turnover in healthy adults at rest. J Nutr 136:379–383

    CAS  Article  Google Scholar 

  83. Poppek D, Grune T (2005) Protein repair and degradation. In: Grune T (ed) Reactions, processes: oxidants and antioxidant defense systems. Springer Berlin Heidelberg, Berlin, pp 177–201

    Google Scholar 

  84. Porter C, Wall BT (2012) Skeletal muscle mitochondrial function: is it quality or quantity that makes the difference in insulin resistance? J Physiol 590:5935–5936. doi:10.1113/jphysiol.2012.241083

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. Rivas DA, Morris EP, Haran PH et al (2012) Increased ceramide content and NFκB signaling may contribute to the attenuation of anabolic signaling after resistance exercise in aged males

  86. Rivas DA, Mcdonald DJ, Rice NP et al (2016) Diminished anabolic signaling response to insulin induced by intramuscular lipid accumulation is associated with inflammation in aging but not obesity. Am J Physiol Regul Integr Comp Physiol ajpregu. doi:10.1152/ajpregu.00198.2015

    Article  Google Scholar 

  87. Robinson MM, Dasari S, Konopka AR et al (2017) Enhanced protein translation underlies improved metabolic and physical adaptations to different exercise training modes in young and old humans clinical and translational report enhanced protein translation underlies improved metabolic and physical adapta. Cell Metab 25:581–592. doi:10.1016/j.cmet.2017.02.009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Rolfe DF, Brown GC (1997) Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev 77(3):731–758

    CAS  Article  Google Scholar 

  89. Romanello V, Sandri M (2015) Mitochondrial quality control and muscle mass maintenance. Front Physiol 6:422. doi:10.3389/fphys.2015.00422

    Article  PubMed  Google Scholar 

  90. Ryu D, Mouchiroud L, Andreux PA et al (2016) Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med 22:879–888. doi:10.1038/nm.4132

    CAS  Article  PubMed  Google Scholar 

  91. Salminen A, Ojala J, Kaarniranta K, Kauppinen A (2012) Mitochondrial dysfunction and oxidative stress activate inflammasomes: impact on the aging process and age-related diseases. Cell Mol Life Sci 69:2999–3013. doi:10.1007/s00018-012-0962-0

    CAS  Article  PubMed  Google Scholar 

  92. Scalzo RL, Peltonen GL, Binns SE et al (2014) Greater muscle protein synthesis and mitochondrial biogenesis in males compared with females during sprint interval training. FASEB J 28:2705–2714. doi:10.1096/fj.13-246595

    CAS  Article  PubMed  Google Scholar 

  93. Semba RD, Nicklett EJ, Ferrucci L (2010) Does Accumulation of advanced glycation end products contribute to the aging phenotype? J Gerontol Ser A Biol Sci Med Sci 65A:963–975. doi:10.1093/gerona/glq074

    CAS  Article  Google Scholar 

  94. Shanley DP, Kirkwood TB (2000) Calorie restriction and aging: a life-history analysis. Evol Int J Org Evol 54:740–750

    CAS  Article  Google Scholar 

  95. Siegel MP, Kruse SE, Percival JM et al (2013) Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell 12:763–771. doi:10.1111/acel.12102

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. Snow LM, Fugere NA, Thompson LV (2007) Advanced glycation end-product accumulation and associated protein modification in type II skeletal muscle. With Aging 62:1204–1210

    Google Scholar 

  97. Stadtman ER, Oliver CN, Levine RL et al (1988) Implication of protein oxidation in protein turnover, aging, and oxygen toxicity. Basic Life Sci 49:331–339

    CAS  PubMed  Google Scholar 

  98. Stern M (2017) Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy. Aging Cell 16:1–9. doi:10.1111/acel.12579

    CAS  Article  Google Scholar 

  99. Suarez RK (1998) Oxygen and the upper limits to animal design and performance. J Exp Biol 1072:1065–1072

    Google Scholar 

  100. Suarez RK, Suarez KR (2012) Energy and metabolism. In: Comprehensive physiology. Wiley, Hoboken

    Google Scholar 

  101. Toyama BH, Hetzer MW (2013) Protein homeostasis: live long, won’t prosper. Nat Rev Mol Cell Biol 14:55–61. doi:10.1038/nrm3496

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. Valdez G, Tapia JC, Kang H et al (2010) Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise. Proc Natl Acad Sci USA 107:14863–14868. doi:10.1073/pnas.1002220107

    Article  PubMed  Google Scholar 

  103. van Leeuwen IMM, Vera J, Wolkenhauer O (2010) Dynamic energy budget approaches for modelling organismal ageing. Philos Trans R Soc B Biol Sci 365:3443–3454. doi:10.1098/rstb.2010.0071

    Article  Google Scholar 

  104. Wanagat J, Cao Z, Pathare P, Aiken JM (2001) Mitochondrial DNA deletion mutations colocalize with segmental electron transport system abnormalities, muscle fiber atrophy, fiber splitting, and oxidative damage in sarcopenia. FASEB J 15:322–332. doi:10.1096/fj.00-0320com

    CAS  Article  PubMed  Google Scholar 

  105. Waterlow JC (1984) Protein turnover with special reference to man. Q J Exp Physiol 69:409–438. doi:10.1113/expphysiol.1984.sp002829

    CAS  Article  PubMed  Google Scholar 

  106. Wibom R, Hultman E, Johansson M (1992) Adaptation of mitochondrial ATP production in human skeletal muscle to endurance training and detraining. J Appl Physiol 73:2004–2010

    CAS  Article  Google Scholar 

  107. Wiley CD, Velarde MC, Lecot P et al (2016) Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab 23:303–314. doi:10.1016/j.cmet.2015.11.011

    CAS  Article  PubMed  Google Scholar 

  108. Xue Q-L, Leng S (2016) Rapamycin increases grip strength and attenuates age-related decline in maximal running distance in old low capacity runner rats. Aging 8:1–8. doi:10.18632/aging.100929

    Article  Google Scholar 

  109. Zampieri S, Pietrangelo L, Loefler S et al (2015) Lifelong physical exercise delays age-associated skeletal muscle decline. J Gerontol Ser A Biol Sci Med Sci 70:163–173. doi:10.1093/gerona/glu006

    CAS  Article  Google Scholar 

  110. Zangarelli A, Chanseaume E, Morio B et al (2006) Synergistic effects of caloric restriction with maintained protein intake on skeletal muscle performance in 21-month-old rats: a mitochondria-mediated pathway. FASEB J 20:2439–2450. doi:10.1096/fj.05-4544com

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank members of the Translational Research on Aging and Chronic Disease lab for their collective contributions that have led to the ideas and knowledge presented in this review.

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Correspondence to Benjamin F. Miller.

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The authors declare that they have no conflict of interest.

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Karyn L. Hamilton and Benjamin F. Miller: Co-Senior Authors.

Communicated by Michael Lindinger.

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Musci, R.V., Hamilton, K.L. & Miller, B.F. Targeting mitochondrial function and proteostasis to mitigate dynapenia. Eur J Appl Physiol 118, 1–9 (2018). https://doi.org/10.1007/s00421-017-3730-x

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Keywords

  • Mitochondria
  • Dynapenia
  • Proteostasis
  • Aging