Background Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood. Methods and Findings The current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 ± 1.0 y), overweight (body mass index, 27.8 ± 0.7 kg/m2) individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX), 12.5% CR + 12.5% increased energy expenditure (EE). In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, ？135 ± 42 kcal/d, p = 0.002 and CREX, ？117 ± 52 kcal/d, p = 0.008). Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05). In parallel, mitochondrial DNA content increased by 35% ± 5% in the CR group (p = 0.005) and 21% ± 4% in the CREX group (p < 0.004), with no change in the control group (2% ± 2%). However, the activity of key mitochondrial enzymes of the TCA (tricarboxylic acid) cycle (citrate synthase), beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase), and electron transport chain (cytochrome C oxidase II) was unchanged. DNA damage was reduced from baseline in the CR (？0.56 ± 0.11 arbitrary units, p = 0.003) and CREX (？0.45 ± 0.12 arbitrary units, p = 0.011), but not in the controls. In primary cultures of human myotubes, a nitric oxide donor (mimicking eNOS signaling) induced mitochondrial biogenesis but failed to induce SIRT1 protein expression, suggesting that additional factors may regulate SIRT1 content during CR. Conclusions The observed increase in muscle mitochondrial DNA in association with a decrease in whole body oxygen consumption and DNA damage suggests that caloric restriction improves mitochondrial function in young non-obese adults.
References
[1]
Weindruch R, Naylor PH, Goldstein AL, Walford RL (1988) Influences of aging and dietary restriction on serum thymosin alpha 1 levels in mice. J Gerontol 43: B40–42.
Bevilacqua L, Ramsey JJ, Hagopian K, Weindruch R, Harper ME (2004) Effects of short- and medium-term calorie restriction on muscle mitochondrial proton leak and reactive oxygen species production. Am J Physiol Endocrinol Metab 286: E852–861.
[5]
Bevilacqua L, Ramsey JJ, Hagopian K, Weindruch R, Harper ME (2005) 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 289: E429–438.
[6]
Lambert AJ, Wang B, Yardley J, Edwards J, Merry BJ (2004) The effect of aging and caloric restriction on mitochondrial protein density and oxygen consumption. Exp Gerontol 39: 289–295.
[7]
Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, et al. (2005) Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310: 314–317.
[8]
Lopez-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, et al. (2006) Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci U S A 103: 1768–1773.
[9]
St-Pierre J, Lin J, Krauss S, Tarr PT, Yang R, et al. (2003) Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1α and 1β (PGC-1α and PGC-1β) in muscle cells. J Biol Chem 278: 26597–26603.
[10]
Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, et al. (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98: 115–124.
[11]
Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, et al. (2005) Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434: 113–118.
[12]
Lin SJ, Defossez PA, Guarente L (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in . Science 289: 2126–2128.
[13]
Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I (2005) Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell 16: 4623–4635.
[14]
Nemoto S, Fergusson MM, Finkel T (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J Biol Chem 280: 16456–16460.
[15]
Villeneuve PJ, Morrison HI, Craig CL, Schaubel DE (1998) Physical activity, physical fitness, and risk of dying. Epidemiology 9: 626–631.
[16]
Menshikova EV, Ritov VB, Toledo FG, Ferrell RE, Goodpaster BH, et al. (2005) Effects of weight loss and physical activity on skeletal muscle mitochondrial function in obesity. Am J Physiol Endocrinol Metab 288: E818–825.
[17]
Russell AP, Hesselink MK, Lo SK, Schrauwen P (2005) Regulation of metabolic transcriptional co-activators and transcription factors with acute exercise. Faseb J 19: 986–988.
[18]
Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson-Meyer DE, et al. (2006) Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: A randomized controlled trial. JAMA 295: 1539–1548.
[19]
Bergstrom J (1975) Percutaneous needle biopsy of skeletal muscle in physiological and clinical research. Scand J Clin Lab Invest 35: 609–616.
[20]
Civitarese AE, Jenkinson CP, Richardson D, Bajaj M, Cusi K, et al. (2004) Adiponectin receptors gene expression and insulin sensitivity in non-diabetic Mexican Americans with or without a family history of type 2 diabetes. Diabetologia 47: 816–820.
[21]
Bogacka I, Xie H, Bray GA, Smith SR (2005) Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 54: 1392–1399.
[22]
Hulver MW, Berggren JR, Carper MJ, Miyazaki M, Ntambi JM, et al. (2005) Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans. Cell Metab 2: 251–261.
[23]
Ukropcova B, McNeil M, Sereda O, de Jonge L, Xie H, et al. (2005) Dynamic changes in fat oxidation in human primary myocytes mirror metabolic characteristics of the donor. J Clin Invest 115: 1934–1941.
[24]
Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, et al. (2003) Mitochondrial biogenesis in mammals: The role of endogenous nitric oxide. Science 299: 896–899.
[25]
Toubro S, Sorensen TI, Ronn B, Christensen NJ, Astrup A (1996) Twenty-four-hour energy expenditure: The role of body composition, thyroid status, sympathetic activity, and family membership. J Clin Endocrinol Metab 81: 2670–2674.
[26]
Fontana L, Meyer TE, Klein S, Holloszy JO (2004) Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci U S A 101: 6659–6663.
[27]
Roth GS, Lane MA, Ingram DK, Mattison JA, Elahi D, et al. (2002) Biomarkers of caloric restriction may predict longevity in humans. Science 297: 811.
[28]
Larson-Meyer DE, Heilbronn LK, Redman LM, Newcomer BR, Frisard MI, et al. (2006) Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects. Diabetes Care 29: 1337–1344.
[29]
Zhu M, Miura J, Lu LX, Bernier M, DeCabo R, et al. (2004) Circulating adiponectin levels increase in rats on caloric restriction: The potential for insulin sensitization. Exp Gerontol 39: 1049–1059.
[30]
Wolfe BE, Jimerson DC, Orlova C, Mantzoros CS (2004) Effect of dieting on plasma leptin, soluble leptin receptor, adiponectin and resistin levels in healthy volunteers. Clin Endocrinol (Oxf) 61: 332–338.
[31]
Wang H, Hiatt WR, Barstow TJ, Brass EP (1999) Relationships between muscle mitochondrial DNA content, mitochondrial enzyme activity and oxidative capacity in man: Alterations with disease. Eur J Appl Physiol Occup Physiol 80: 22–27.
[32]
Civitarese AE, Ukropcova B, Carling S, Hulver M, Defronzo RA, et al. (2006) Role of adiponectin in human skeletal muscle bioenergetics. Cell Metab 4: 75–87.
[33]
Ramsey JJ, Harper ME, Weindruch R (2000) Restriction of energy intake, energy expenditure, and aging. Free Radic Biol Med 29: 946–968.
[34]
Blanc S, Schoeller D, Kemnitz J, Weindruch R, Colman R, et al. (2003) Energy expenditure of rhesus monkeys subjected to 11 years of dietary restriction. J Clin Endocrinol Metab 88: 16–23.
[35]
DeLany JP, Hansen BC, Bodkin NL, Hannah J, Bray GA (1999) Long-term calorie restriction reduces energy expenditure in aging monkeys. J Gerontol A Biol Sci Med Sci 54: B5–11. discussion.
[36]
Ballor DL (1991) Effect of dietary restriction and/or exercise on 23-h metabolic rate and body composition in female rats. J Appl Physiol 71: 801–806.
[37]
Dulloo AG, Girardier L (1993) 24 hour energy expenditure several months after weight loss in the underfed rat: Evidence for a chronic increase in whole-body metabolic efficiency. Int J Obes Relat Metab Disord 17: 115–123.
[38]
McCarter RJ, Palmer J (1992) Energy metabolism and aging: A lifelong study of Fischer 344 rats. Am J Physiol 263: E448–452.
[39]
Selman C, Phillips T, Staib JL, Duncan JS, Leeuwenburgh C, et al. (2005) Energy expenditure of calorically restricted rats is higher than predicted from their altered body composition. Mech Ageing Dev 126: 783–793.
[40]
Leibel RL, Rosenbaum M, Hirsch J (1995) Changes in energy expenditure resulting from altered body weight. N Engl J Med 332: 621–628.
Sohal RS, Agarwal S, Candas M, Forster MJ, Lal H (1994) Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech Ageing Dev 76: 215–224.
[43]
Zurlo F, Larson K, Bogardus C, Ravussin E (1990) Skeletal muscle metabolism is a major determinant of resting energy expenditure. J Clin Invest. pp. 1423–1427.
Baker DJ, Betik AC, Krause DJ, Hepple RT (2006) No decline in skeletal muscle oxidative capacity with aging in long-term calorically restricted rats: Effects are independent of mitochondrial DNA integrity. J Gerontol A Biol Sci Med Sci 61: 675–684.
[46]
Desai VG, Weindruch R, Hart RW, Feuers RJ (1996) Influences of age and dietary restriction on gastrocnemius electron transport system activities in mice. Arch Biochem Biophys 333: 145–151.
[47]
Hepple RT, Baker DJ, Kaczor JJ, Krause DJ (2005) Long-term caloric restriction abrogates the age-related decline in skeletal muscle aerobic function. Faseb J 19: 1320–1322.
[48]
Sreekumar R, Unnikrishnan J, Fu A, Nygren J, Short KR, et al. (2002) Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle. Am J Physiol Endocrinol Metab 283: E38–43.
[49]
Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, et al. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444: 337–342.
[50]
Kempen KP, Saris WH, Kuipers H, Glatz JF, Van Der Vusse GJ (1998) Skeletal muscle metabolic characteristics before and after energy restriction in human obesity: Fibre type, enzymatic beta-oxidative capacity and fatty acid-binding protein content. Eur J Clin Invest 28: 1030–1037.
[51]
Simoneau JA, Veerkamp JH, Turcotte LP, Kelley DE (1999) Markers of capacity to utilize fatty acids in human skeletal muscle: Relation To insulin resistance and obesity and effects of weight loss. FASEB J 13: 2051–2060.
[52]
Menshikova EV, Ritov VB, Fairfull L, Ferrell RE, Kelley DE, 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.
[53]
Cipolat S, Rudka T, Hartmann D, Costa V, Serneels L, et al. (2006) Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126: 163–175.
[54]
Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, et al. (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305: 390–392.
[55]
Krebs HA, Veech RL (1969) Equilibrium relations between pyridine nucleotides and adenine nucleotides and their roles in the regulation of metabolic processes. Adv Enzyme Regul 7: 397–413.
[56]
Sahlin K, Katz A, Henriksson J (1987) Redox state and lactate accumulation in human skeletal muscle during dynamic exercise. Biochem J 245: 551–556.
[57]
Koves TR, Li P, An J, Akimoto T, Slentz D, et al. (2005) Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J Biol Chem 280: 33588–33598.
[58]
Short KR, Vittone JL, Bigelow ML, Proctor DN, Rizza RA, et al. (2003) Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity. Diabetes 52: 1888–1896.
[59]
Hood DA (2001) Invited Review: Contractile activity-induced mitochondrial biogenesis in skeletal muscle. J Appl Physiol 90: 1137–1157.
[60]
Russell AP, Feilchenfeldt J, Schreiber S, Praz M, Crettenand A, et al. (2003) Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes 52: 2874–2881.
[61]
Nisoli E, Carruba MO (2006) Nitric oxide and mitochondrial biogenesis. J Cell Sci 119: 2855–2862.
[62]
Navarro A, Torrejon R, Bandez MJ, Lopez-Cepero JM, Boveris A (2005) Mitochondrial function and mitochondria-induced apoptosis in an overstimulated rat ovarian cycle. Am J Physiol Endocrinol Metab 289: E1101–1109.
[63]
Brown GC, Cooper CE (1994) Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Lett 356: 295–298.
[64]
Poderoso JJ, Carreras MC, Lisdero C, Riobo N, Schopfer F, et al. (1996) Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles. Arch Biochem Biophys 328: 85–92.
[65]
Valdez LB, Zaobornyj T, Boveris A (2006) Mitochondrial metabolic states and membrane potential modulate mtNOS activity. Biochim Biophys Acta 1757: 166–172.
