Abstract
The reduction of muscle mass in the elderly is widely studied as one of the most important landmark of human aging. This process, which occurs for the decay of the correct energetic and protein metabolism, has important functional consequences on individual functionality but also on metabolic adaptation and immunological response to environmental challenges. Uncoupling Protein 3 (UCP3) gene is expressed in skeletal muscle where it regulates fatty acid metabolism, redox state, and ROS formation. Considering the importance of these processes in aging, we studied two variants of the UCP3 gene in a large, aged (age range 65–105) population of southern Italy verifying if these variants were correlated to hand grip strength, the most reliable measure of muscle decay. We found that a previously described functional polymorphism, rs1800849, located in the promoter region of the UCP3 gene, has a significant impact on hand grip strength. In fact, the carriers of rs1800849 T allele showed higher hand grip than the remaining of the population. Since this allele has been reported to promote a higher expression of the gene, we conclude that a more efficient uncoupling process has a beneficial effect on the aging muscle by slowing down its age related decay.
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Arking DE, Fallin DM, Fried LP, Li T, Beamer BA, Xue QL, Chakravarti A, Walston J (2006) Variation in the ciliary neurotrophic factor gene and muscle strength in older Caucasian women. J Am Geriatr Soc 54(5):823–826
Balagopal P, Proctor D, Nair KS (1997) Sarcopenia and hormonal changes. Endocrine 7(1):57–60
Boss O, Samec S, Paoloni-Giacobino A, Rossier C, Dulloo A, Seydoux J, Muzzin P, Giacobino JP (1997) Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett 408(1):39–42
Carlson BM (1995) Factors influencing the repair and adaptation of muscles in aged individuals: satellite cells and innervation. J Gerontol A Biol Sci Med Sci 50 Spec No:96–100
Carmeli E, Reznick AZ, Coleman R, Carmeli V (2000) Muscle strength and mass of lower extremities in relation to functional abilities in elderly adults. Gerontology 46(5):249–257
Cesari M, Pahor M, Bartali B, Cherubini A, Penninx BW, Williams GR, Atkinson H, Martin A, Guralnik JM, Ferrucci L (2004) Antioxidants and physical performance in elderly persons: the invecchiare in chianti (InCHIANTI) study. Am J Clin Nutr 79(2):289–294
Chung SS, Weindruch R, Schwarze SR, McKenzie DI, Aiken JM (1994) Multiple age-associated mitochondrial DNA deletions in skeletal muscle of mice. Aging 6(3):193–200
Cortopassi GA, Arnheim N (1990) Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res 18(23):6927–6933
Cortopassi GA, Shibata D, Soong NW, Arnheim N (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci 89(16):7370–7374
Dardevet D, Sornet C, Balage M, Grizard J (2000) Stimulation of in vitro rat muscle protein synthesis by leucine decreases with age. J Nutr 130(11):2630–2635
Dato S, Krabbe KS, Thinggaard M, Pedersen BK, Christensen K, Bruunsgaard H, Christiansen L (2010) Commonly studied polymorphisms in inflammatory cytokine genes show only minor effects on mortality and related risk factors in nonagenarians. J Gerontol A Biol Sci Med Sci 65(3):225–235
De Mars G, Windelinckx A, Beunen G, Delecluse C, Lefevre J, Thomis MA (2007) Polymorphisms in the CNTF and CNTF receptor genes are associated with muscle strength in men and women. J Appl Physiol 102(5):1824–1831
Doherty TJ (2003) Invited review: aging and sarcopenia. J Appl Physiol 95(4):1717–1727
Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA, Harper JA, Roebuck SJ, Morrison A, Pickering S, Clapham JC, Brand MD (2002) Superoxide activates mitochondrial uncoupling proteins. Nature 415(6867):96–99
Excoffier L, Laval G, Schneider S (2005) Arlequin (version 3.0): an integrated software package for population genetics data analysis. Evol Bioinform Online 1:47–50
Fiatarone MA, O’Neill EF, Ryan ND, Clements KM, Solares GR, Nelson ME, Roberts SB, Kehayias JJ, Lipsitz LA, Evans WJ (1994) Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med 330(25):1769–1775
Frederiksen H, Gaist D, Petersen HC, Hjelmborg J, McGue M, Vaupel JW, Christensen K (2002) Hand grip strength: a phenotype suitable for identifying genetic variants affecting mid- and late-life physical functioning. Genet Epidemiol 23(2):110–122
Giampaoli S, Ferrucci L, Cecchi F, Lo Noce C, Poce A, Dima F, Santaquilani A, Vescio MF, Menotti A (1999) Hand-grip strength predicts incident disability in non-disabled older men. Age Ageing 28(3):283–288
Gong DW, He Y, Karas M, Reitman M (1997) Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta3-adrenergic agonists, and leptin. J Biol Chem 272(39):24129–24132
Janssen I, Heymsfield SB, Ross R (2002) Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc 50(5):889–896
Janssen I, Shepard DS, Katzmarzyk PT, Roubenoff R (2004) The healthcare costs of sarcopenia in the United States. J Am Geriatr Soc 52(1):80–85
Jozsi AC, Campbell WW, Joseph L, Davey SL, Evans WJ (1999) Changes in power with resistance training in older and younger men and women. J Gerontol A Biol Sci Med Sci 54(11):M591–M596
Larkin S, Mull E, Miao W, Pittner R, Albrandt K, Moore C, Young A, Denaro M, Beaumont K (1997) Regulation of the third member of the uncoupling protein family, UCP3, by cold and thyroid hormone. Biochem Biophys Res Commun 240(1):222–227
Larsson L (1995) Motor units: remodeling in aged animals. J Gerontol A Biol Sci Med Sci 50 Spec No: 91–95
Lee CM, Chung SS, Kaczkowski JM, Weindruch R, Aiken JM (1993) Multiple mitochondrial DNA deletions associated with age in skeletal muscle of rhesus monkeys. J Gerontol 48(6):B201–B205
Lexell J (1995) Human aging, muscle mass, and fiber type composition. J Gerontol A Biol Sci Med Sci 50 Spec No:11–16
Lexell J (1997) Evidence for nervous system degeneration with advancing age. J Nutr 127(5 Suppl):1011S–1013S
Lexell J, Taylor CC, Sjostrom M (1988) What is the cause of the ageing atrophy? total number, size and proportion of different fiber types studied in whole vastus lateralis muscle from 15 to 83 year old men. J Neurol Sci 84(2–3):275–294
Linnane AW, Baumer A, Maxwell RJ, Preston H, Zhang CF, Marzuki S (1990) Mitochondrial gene mutation: the ageing process and degenerative diseases. Biochem Int 22(6):1067–1076
McKenzie D, Bua E, McKiernan S, Cao Z, Aiken JM (2002) Mitochondrial DNA deletion mutations: a causal role in sarcopenia. Eur J Biochem 269(8):2010–2015
Meissner C, Bruse P, Oehmichen M (2006) Tissue-specific deletion patterns of the mitochondrial genome with advancing age. Exp Gerontol 41(5):518–524
Melov S, Hertz GZ, Stormo GD, Johnson TE (1994) Detection of deletions in the mitochondrial genome of Caenorhabditis elegans. Nucleic Acids Res 22(6):1075–1078
Meng SJ, Yu LJ (2010) Oxidative stress, molecular inflammation and sarcopenia. Int J Mol Sci 11(4):1509–1526
Metter EJ, Talbot LA, Schrager M, Conwit R (2002) Skeletal muscle strength as a predictor of all-cause mortality in healthy men. J Gerontol A Biol Sci Med Sci 57(10):B359–B365
Mookerjee SA, Divakaruni AS, Jastroch M, Brand MD (2010) Mitochondrial uncoupling and lifespan. Mech Ageing Dev 131(7–8):463–472
Morley JE, Baumgartner RN, Roubenoff R, Mayer J, Nair KS (2001) Sarcopenia. J Lab Clin Med 137(4):231–243
Nabben M, Hoeks J, Briede JJ, Glatz JF, Moonen-Kornips E, Hesselink MK, Schrauwen P (2008) The effect of UCP3 overexpression on mitochondrial ROS production in skeletal muscle of young versus aged mice. FEBS Lett 582(30):4147–4152
Nelson ME, Fiatarone MA, Morganti CM, Trice I, Greenberg RA, Evans WJ (1994) Effects of high-intensity strength training on multiple risk factors for osteoporotic fractures. JAMA 272(24):1909–1914
Newman AB, Kupelian V, Visser M, Simonsick EM, Goodpaster BH, Kritchevsky SB, Tylavsky FA, Rubin SM, Harris TB (2006) Strength, but not muscle mass, is associated with mortality in the health, aging and body composition study cohort. J Gerontol A Biol Sci Med Sci 61(1):72–77
Rantanen T, Guralnik JM, Foley D, Masaki K, Leveille S, Curb JD, White L (1999) Midlife hand grip strength as a predictor of old age disability. JAMA 281(6):558–560
Rantanen T, Volpato S, Ferrucci L, Heikkinen E, Fried LP, Guralnik JM (2003) Handgrip strength and cause-specific and total mortality in older disabled women: exploring the mechanism. J Am Geriatr Soc 51(5):636–641
Ronkainen PH, Pollanen E, Tormakangas T, Tiainen K, Koskenvuo M, Kaprio J, Rantanen T, Sipila S, Kovanen V (2008) Catechol-o-methyltransferase gene polymorphism is associated with skeletal muscle properties in older women alone and together with physical activity. PLoS One 3(3):e1819
Roth SM, Schrager MA, Ferrell RE, Riechman SE, Metter EJ, Lynch NA, Lindle RS, Hurley BF (2001) CNTF genotype is associated with muscular strength and quality in humans across the adult age span. J Appl Physiol 90(4):1205–1210
Roubenoff R (2000a) Sarcopenia and its implications for the elderly. Eur J Clin Nutr 54(Suppl 3):S40–S47
Roubenoff R (2000b) Sarcopenia: a major modifiable cause of frailty in the elderly. J Nutr Health Aging 4(3):140–142
Roubenoff R (2003) Catabolism of aging: is it an inflammatory process? Curr Opin Clin Nutr Metab Care 6(3):295–299
Roubenoff R, Hughes VA (2000) Sarcopenia: current concepts. J Gerontol A Biol Sci Med Sci 55(12):M716–M724
Roubenoff R, Parise H, Payette HA, Abad LW, D’Agostino R, Jacques PF, Wilson PW, Dinarello CA, Harris TB (2003) Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham heart study. Am J Med 115(6):429–435
Schrager M, Bandinelli S, Maggi S, Ferrucci L (2003) Sarcopenia: twenty open questions for a research agenda. Basic Appl Myol 13(4):203–208
Schrauwen P, Xia J, Walder K, Snitker S, Ravussin E (1999) A novel polymorphism in the proximal UCP3 promoter region: effect on skeletal muscle UCP3 mRNA expression and obesity in male non-diabetic Pima Indians. Int J Obes Relat Metab Disord 23(12):1242–1245
Visser M (2009) Towards a definition of sarcopenia—results from epidemiologic studies. J Nutr Health Aging 13(8):713–716
Walsh S, Liu D, Metter EJ, Ferrucci L, Roth SM (2008) ACTN3 genotype is associated with muscle phenotypes in women across the adult age span. J Appl Physiol 105(5):1486–1491
Walsh S, Kelsey BK, Angelopoulos TJ, Clarkson PM, Gordon PM, Moyna NM, Visich PS, Zoeller RF, Seip RL, Bilbie S, Thompson PD, Hoffman EP, Price TB, Devaney JM, Pescatello LS (2009) CNTF 1357 G > a polymorphism and the muscle strength response to resistance training. J Appl Physiol 107(4):1235–1240
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(2):322–332
Weigle DS, Selfridge LE, Schwartz MW, Seeley RJ, Cummings DE, Havel PJ, Kuijper JL, BeltrandelRio H (1998) Elevated free fatty acids induce uncoupling protein 3 expression in muscle: a potential explanation for the effect of fasting. Diabetes 47(2):298–302
Weir BS (1996) Genetic data analysis II : methods for discrete population genetic data. Sinauer Associates, Sunderland
Yu XX, Barger JL, Boyer BB, Brand MD, Pan G, Adams SH (2000) Impact of endotoxin on UCP homolog mRNA abundance, thermoregulation, and mitochondrial proton leak kinetics. Am J Physiol Endocrinol Metab 279(2):E433–E446
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The work was supported by Fondi di Ateneo of the University of Calabria. AM was supported financially by a fellowship (assegno di ricerca) of the University of Calabria.
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Crocco, P., Montesanto, A., Passarino, G. et al. A common polymorphism in the UCP3 promoter influences hand grip strength in elderly people. Biogerontology 12, 265–271 (2011). https://doi.org/10.1007/s10522-011-9321-z
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DOI: https://doi.org/10.1007/s10522-011-9321-z