Mitochondrial theory of skeletal muscle ageing –new facts, new doubts

Open access


For many years, scientists have been pursuing research on skeletal muscle ageing both in humans and animals. Studies on animal models have extended our knowledge of this mechanism in humans. Most researchers agree that the major processes of muscle ageing occur in the mitochondria as the major energy production centres in muscle cells. It is believed that decisive changes occur at the enzymatic activity level as well as in protein synthesis and turnover ability. Deregulation of ion channels and oxidative stress also play significant roles. In particular, in recent years the free radical theory of ageing has undergone considerable modification; researchers are increasingly highlighting the partly positive effects of free radicals on processes occurring in cells. In addition, the influence of diet and physical activity on the rate of muscle cell ageing is widely debated as well as the possibility of delaying it through appropriate physical exercise and diet programmes. Numerous studies, especially those related to genetic processes, are still being conducted, and in the near future the findings could provide valuable information on muscle ageing. The results of ongoing research could answer the perennial question of whether and how we can influence the rate of ageing both in animals and humans.

1. Altun M., Besche H.C., Overkleeft H.S., Piccirillo R., Edelmann M.J., Kessler B.M., Goldberg A.L., Ulfhake B.: Muscle wasting in aged, sarcopenic rats is associated with enhanced activity of the ubiquitin proteasome pathway. J Biol Chem 2010, 285, 39597–39608.

2. Amara C.E., Shankland E.G., Jubrias S.A., Marcinek D.J., Kushmerick M.J., Conley K.E.: Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivo. Proc Natl Acad Sci USA 2007, 104, 1057–1062.

3. Barazzoni R., Short K.R., Nair K.S.: Effects of aging on mitochondria DNA copy number and cytochrome c oxidase gene expression in rat skeletal muscle, liver, and heart. J Biol Chem 2000, 275, 3343–3347.

4. Barrciro E., Cornell C., Lavina B., Ramirez-Sarmiento A., Orozco-Levi M., Gea J.: Aging sex differences and oxidative stress in human respiratory and limb muscles. Free Radic Biol Med 2006, 41, 797–809.

5. Barrientos A., Casademont J., Cardellach F.: Qualitative and quantitative changes in skeletal muscle mtDNA and expression of mitochondrial-encoded genes in the human aging process. Biochem Mol Med 1997, 62, 165–171.

6. Bevilacqua L., Ramsey J.J., Hagopian K., Weindruch R., Harper M.E.: Long-term caloric restriction increases UCP3 content but decreases proton leak and reactive oxygen species production in rat skeletal muscle mitochondria. Am J Physiol Endocrinol Metab 2005, 289, E429–E438.

7. Bjelakovic G., Nikolova D., Gluud L.I., Simonetti R.G., Gluud C.: Mortality in randomized trials of antioxidant supplements for primary and secondary prevention, systematic review and meta-analysis. J Am Med Assoc 2007, 297, 842–857.

8. Bua E., Johnson J., Herbst A., Delong B., McKenzie D., Salamat S., Aiken J.M.: Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers. Am J Hum Genet 2006, 79, 469–480.

9. Capel F., Rimbert V., Lioger D., Diot A., Rousset P., Mirand P.P., Boirie Y., Morio B., Mosoni L.: Due to reverse electron transfer, mitochondrial H2O2 release increases with age in human vastus lateralis muscle although oxidative capacity is preserved. Mech Ageing Dev 2005, 126, 505–511.

10. Cipolat S., Rudka T., Hartmann D., Costa V., Serneels L., Craessaerts K., Metzger K., Frezza C., Annaert W., D'Adamio L., Derks C., Dejaegere T., Pellegrini L., D'Hooge R., Scorrano L., De Strooper B.: Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodelling. Cell 2006, 126, 1, 163–175.

11. Conley K.E., Marcinek D.J., Villarin J.: Mitochondrial dysfunction and age. Curr Opin Nutr Metab Care 2007, 10, 688–692.

12. Crane J.D., Devries M.C., Safdar A., Hamadeh M.J., Tarnopolsky M.A.: The effect of aging on human skeletal muscle mitochondrial and intramyocellular lipid ultrastructure. J Gerontol A Biol Sci Med Sci 2010, 65, 119–128.

13. Cuervo A.M., Bergamini E., Brunk U.T., Droge W., Ffrench M., Terman A.: Autophagy and aging, the importance of maintaining “clean cells”. Autophagy 2005, 1, 131–140.

14. Chabi B., Ljubicic V., Menzies K.J., Huang J.H., Saleem A., Hood D.A.: Mitochondrial function and apoptotic susceptibility in aging skeletal muscle. Aging Cell 2008, 7, 2–12.

15. Chen H., Vermulst M., Wang Y.E., Chomyn A., Prolla T.A., McCaffery J.M., Chan D.C.: Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 2010, 141, 280–289.

16. Diaz F., Bayona-Bafaluy M.P., Rana M., Mora M., Hao H., Moraes C.T.: Human mitochondrial DNA with large deletions repopulates organelles faster than full-length genomes under relaxed copy number control. Nucleic Acids Res 2002, 30, 4626–4633.

17. Drew B., Phaneuf S., Dirks A., Selman C., Gredilla R., Lezza A,. Barja G., Leeuwenburgh C.: Effects of aging and caloric restriction on mitochondrial energy production in gastrocnemius muscle and heart. Am J Physiol 2003, 284, 474–480.

18. Figueiredo P.A., Powers S.K., Ferreira R.M., Amado F., Appell H.J., Duarte J.A.: Impact of lifelong sedentary behaviour on mitochondrial function of mice skeletal muscle. J Gerontol A Biol Sci Med Sci 2009, 64, 927–939.

19. Fink S.L., Cookson B.T.: Apoptosis, pyroptosis, and necrosis: Mechanistic Description of Dead and Dying Eukaryotic Cells. Infect Immun 2005, 73, 1907–1916.

20. Gelfi C., Vigano A., Ripamonti M., Pontoglio A., Begum S., Pellegrino M.A., Grassi B., Bottinelli R., Wait R., Cerretelli P.: The human muscle proteome in aging. J Proteome Res 2006, 5, 1344–1353.

21. Giorgi C., Marchi S., Simoes I.C.M., Ren Z., Morciano G., Perrone M., Patalas-Krawczyk P., Borchard S., Jędrak P., Pierzynowska K., Szymański J., Wang D.Q., Portincasa P., Węgrzyn G., Zischka H., Dobrzyn P., Bonora M., Duszynski J., Rimessi A., Karkucińska-Wieckowska A., Dobrzyn A., Szabadkai G., Zavan B., Oliveira P.J., Sardao V.A., Pinton P., Wieckowski M.R.: Mitochondria and reactive oxygen species in aging and age-related diseases. Int Rev Cell Mol Biol 2018, 340, 209–344.

22. Hayashi J.I., Hashizume O., Ishikawa K., Shimizu A.: Mutations in mitochondrial DNA regulate mitochondrial diseases and metastasis but do not regulate aging. Curr Opin Genet Dev 2016, 38, 63–67.

23. Hepple R.T., Baker D.J., Kaczor J.J., Krause D.J.: Long-term caloric restriction abrogates the age-related decline in skeletal muscle aerobic function. FASEB J 2005, 19, 1320–1322.

24. Holloszy J.O.: Skeletal muscle “mitochondrial deficiency” does not mediate insulin resistance. Am J Clin Nutr 2009, 89, 463–466.

25. Jackson J.R., Ryan M.J., Always S.E.: Long-term supplementation with resveratrol alleviates oxidative stress but does not attenuate sarcopenia in aged mice. J Gerontol A Biol Sci Med Sci 2011, 66, 751–764.

26. Jo E.K., Kim J.K., Shin D.M., Sasakawa C.: Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol 2016, 13, 148–159.

27. Johannsen D.L., Conley K.E., Bajpeyi S., Punyanitya M., Gallagher D., Zhang Z., Covington J., Smith S.R., Ravussin E.: Ectopic lipid accumulation and reduced glucose tolerance in elderly adults are accompanied by altered skeletal muscle mitochondrial activity. J Clin Endocrinol Metab 2012, 97, 242–250.

28. Johannsen D.L., DeLany J.P., Frisard M.I., Welsch M.A., Rowley C.K., Fang X., Jazwinski S.M., Ravussin E.: Physical activity in aging: comparison among young, aged, and nonagenarian individuals. J Appl Physiol 2008, 105, 495–501.

29. Khrapko K.: The timing of mitochondrial DNA mutations in aging. Nat Genet 2011, 43, 726–727.

30. Khrapko K., Vijg J.: Mitochondrial DNA mutations and aging: devils in the details? Trends Genet 2009, 25, 91–98.

31. Kirkwood T.B.L.: A systematic look at an old problem. Nature 2008, 451, 644–647.

32. Kowald A., Kirkwood T.B.L.: Evolution of the mitochondrial fusion-fission cycle and its role in aging. Proc Natl Acad Sci USA 2011, 108, 10237–10242.

33. Krishnan K.J., Reeve A.K., Samuels D.C., Chinnery P.F., Blackwood J.K., Taylor R.W., Wanrooij S., Spelbrink J.N, Lightowlers R.N., Turnbull D.M.: What causes mitochondrial DNA deletions in human cells? Nat Genet 2008, 40, 275–279.

34. Kujoth G.C., Hiona A., Pugh T.D., Someya S., Panzer K., Wohlgemuth S.E., Hofer T., Seo A.Y., Sullivan R., Jobling W.A., Morrow J.D., Van Remmen H., Sedivy J.M., Yamasoba T., Tanokura M., Weindruch R., Leeuwenburgh C., Prolla T.A.: Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 2005, 309, 481–484.

35. Kushnareva Y., Murphy A.N., Andreyev A.: Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation-reduction state. Biochem J 2002, 368, 545–553.

36. Lam J., McKeague M., Dietary modulation of mitochondrial DNA damage: implications in aging and associated diseases. J Nutr Biochem 2018, 63, 1–10.

37. Lanza I.R., Larsen R.G., Kent-Braun J.A.: Effects of old age on human skeletal muscle energetics during fatiguing contractions with and without blood flow. J Physiol 2007, 583, 1093–1105.

38. Lanza I.R., Short D.K., Short K.R., Raghavakaimal S., Basu R., Joyner M.J.: Endurance exercise as a countermeasure for aging. Diabetes 2008, 57, 2933–2942.

39. Larsson N.G.: Somatic mitochondrial DNA mutations in mammalian aging. Annu Rev Biochem 2010, 79, 683–706.

40. Lee H.Y., Choi C.S., Birkenfeld A.L., Alves T.C., Jonayvaz F.R., Jurczak M.J., Zhang D., Woo D.K., Shadel G.S., Ladiges W., Rabinovitch P.S.., Santos J.H., Petersen K.F., Samuel V.T., Shulman G.I.: Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab 2010, 12, 668–674.

41. Leeuwenburgh C., Gurley C.M., Strotman B.A., Dupont-Versteegden E.E.: Age-related differences in apoptosis with disuse atrophy in soleus muscle. Am J Physiol 2005, 288, R1288–R1296.

42. Lodi R., Tonon C., Valentino M.L., Iotti S., Clementi V., Malucelli E., Barboni P., Longanesi L., Schimpf S., Wissinger B., Baruzzi A., Barbiroli B., Carelli V.: Deficit of in vivo mitochondrial ATP production in OPA1-related dominant optic atrophy. Ann Neurol 2004, 56, 719–723.

43. Low P.: The role of ubiquitin-proteasome system in ageing. Gen Comp Endocrinol 2011, 172, 39–43.

44. Marcinek D.J., Schenkman K.A., Ciesielski W.A., Lee D., Conley K.E.: Reduced mitochondrial coupling in vivo alters cellular energetics in aged mouse skeletal muscle. J Physiol 2005, 569, 467–473.

45. Marzetti E., Hwang J.C., Lees H.A., Wohlgemuth S.E., Dupont-Versteegden E.E., Carter C.S., Bernabei R., Leeuwenburgh C.: Mitochondrial death effectors: relevance to sarcopenia and disuse muscle atrophy. Biochim Biophys Acta 2010, 1800, 235–244.

46. Melov S., Tarnopolsky M.A,. Beckman K., Felkey K., Hubbard A.: Resistance exercise reverses aging in human skeletal muscle. PLoS ONE 2007, 2, e465.

47. Miller B.F., Robinson M.M., Bruss M.D., Hellerstein M., Hamilton K.L.: A comprehensive assessment of mitochondrial protein synthesis and cellular proliferation with age and caloric restriction. Aging Cell 2012, 11, 150–161.

48. Molnar R.I., Bartelmes G., Dinkelacker I., Witte H, Sommer R.J.: Mutation rates and intraspecific divergence of the mitochondrial genome of pristionchus pacificus. Mol Biol Evol 2011, 28, 2317–2326.

49. Murase T., Haramizu S., Ota N., Hase T.: Suppression of the aging-associated decline in physical performance by a combination of resveratrol intake and habitual exercise in senescence-accelerated mice. Biogerontology 2009, 10, 423–434.

50. Nakamura S., Takamura T., Matsuzawa-Nagata N., Takayama H., Misu H., Noda H., Nabemoto S., Kurita S., Ota T., Ando H., Miyamoto K., Kaneko S.: Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria. J Biol Chem 2009, 284, 14809–14818.

51. O’Connell K., Ohlendieck K.: Proteomic DIGE analysis of the mitochondria-enriched fraction from aged rat skeletal muscle. Proteomics 2009, 9, 5509–5524.

52. Okamoto K., Kondo-Okamoto N., Ohsumi Y.: Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy. Dev Cell 2009, 17, 87–97.

53. Park S.Y., Kim H.Y., Lee J.H., Yoon K.H., Chang M.S., Park S.K.: The age-dependent induction of apoptosis-inducing factor (AIF) in the human semitendinosus skeletal muscle. Cell Mol Biol Lett 2010, 15, 1–2.

54. Payne B.A., Wilson I.J., Yu-Wai-Man P., Coxhead J., Deehan D., Horvath R., Taylor R.W., Samuels D.C., Santibanez-Koref M., Chinnery P.F.: Universal heteroplasmy of human mitochondrial DNA. Hum Mol Genet 2013, 22, 384–390.

55. Petersen K.F., Befroy D., Dufour S.: Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003, 300, 5622, 1140–1142.

56. Peterson C.M., Johannsen D.L., Ravussin E.: Skeletal muscle mitochondria and aging: A review. J Aging Res 2012, 2012: 194821, doi: 10.1155/2012/194821.

57. Ren J., Li Q., Wu S., Li S.Y., Babcock S.A.: Cardiac overexpression of antioxidant catalase attenuates aging-induced cardiomyocyte relaxation dysfunction. Mech Ageing Dev 2007, 128, 276–285.

58. Reznick R.M., Zong H., Li J.: Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab 2007, 5, 151–156.

59. Romanello V., Guadagnin E., Gomes L.: Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J 2010, 29, 1774–1785.

60. Ross J.M., Stewart J.B., Hagstrom E., Brene S., Mouries A., Coppotelli G., Freyer C., Lagouge M., Hoffer B.J., Olson L., Larsson N.G.: Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 2013, 501, 412–415.

61. Safdar S., Hamadeh M.J., Kaczor J.J., Raha S., Debeer J., Tarnopolsky M.A.: Aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults. PLoS ONE 2010, 5, e10778.

62. Scheckhuber C.Q., Wanger R.A., Mignat C.A., Osiewacz H.D.: Unopposed mitochondrial fission leads to severe lifespan shortening. Cell Cycle 2011, 10, 3105–3110.

63. Schunk K., Pitton M., Duber C., Kersjes W., Schadmand-Fischer S., Thelen M.: Dynamic phosphorus-31 magnetic resonance spectroscopy of the quadriceps muscle: effects of age and sex on spectroscopic results. Invest Radiol 1999, 34, 116–125.

64. Seirafi M., Kozlov G., Gehring K.: Parkin structure and function. FEBS J 2015, 282, 2076–2088.

65. Short K.R., Vittone J.L., Bigelow M.L., Proctor D.N., Nair K.S.: Age and aerobic exercise training effects on whole body and muscle protein metabolism. Am J Physiol 2004, 286, 92–101.

66. Shulman G.I.: Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab 2010, 12, 668–674.

67. Song S., Pursell Z.F., Copeland W.C., Longley M.J., Kunkel T.A., Mathews C.K.: DNA precursor asymmetries in mammalian tissue mitochondria and possible contribution to mutagenesis through reduced replication fidelity. Proc Natl Acad Sci USA 2005, 102, 4990–4995.

68. Speakman J.R., Mitchell S.E.: Caloric restriction. Mol Aspects Med 2011, 32, 159–221.

69. Stumpf J.D., Saneto R.P., Copeland W.C.: Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harb Perspect Biol 2013, 5, a011395.

70. Taylor E.B., Rutter J.: Mitochondrial quality control by the ubiquitin-proteasome system. Biochem Soc Trans 2011, 39, 1509–1513.

71. Twig G., Hyde B., Shirihai O.S.: Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta 2008, 1777, 1092–1097.

72. Um J.H., Park S.J., Kang H., Yang S., Foretz M., McBurney M.W., Kim M.K., Viollet B., Chung J.H.: AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 2010, 59, 554–563.

73. Wenz T., Rossi S.G., Rotundo R.L., Spiegelman B.M., Moraes C.T.: Increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci U S A. 2009, 106, 20405–20410.

74. Whitman S.A., Wacker M.J., Richmond S.R., Godard M.P.: Contributions of the ubiquitin-proteasome pathway and apoptosis to human skeletal muscle wasting with age. Pflugers Arch 2005, 450, 437–446.

75. Wohlgemuth S.E., Seo A.Y., Marzetti E., Lees H.A., Leeuwenburgh C.: Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise. Exp Gerontol 2010, 45, 138–148.

76. Wolff J.N., Camus M.F., Dowling D.K., Rogell B.: Mitochondrial genome variation affects the mutation rate of the nuclear genome in Drosophila melanogaster. BioRXiV 2017, doi: 10.1101/122234.

77. Zainal T.A., Oberley T.D., Allison D.B., Szweda L.I., Weindruch R.: Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle. FASEB J 2000, 14, 1825–1836.

78. Zarse K., Schmeisser S., Groth M., Priebe S., Beuster G., Kuhlow D., Guthke R., Platzer M., Kahn C.R., Ristow M.: Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal. Cell Metab 2012, 15, 451–465.

Journal of Veterinary Research

formerly Bulletin of the Veterinary Institute in Pulawy

Journal Information

IMPACT FACTOR J Vet Res 2017: 0.811

CiteScore 2017: 0.68

SCImago Journal Rank (SJR) 2017: 0.29
Source Normalized Impact per Paper (SNIP) 2017: 0.484


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 238 238 126
PDF Downloads 101 101 35