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    Topic review

    Creatine in Health and Disease

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    Contributors: Jeffrey Stout , Richard Kreider
    Submitted by: Jeffrey Stout

    Definition

    Creatine has been mostly studied as an ergogenic aid for exercise, training, and sport, several health and potential therapeutic benefits have been reported. This is because creatine plays a critical role in cellular metabolism, particularly during metabolically stressed states, and limitations in the ability to transport and/or store creatine can impair metabolism. 

    1. Introduction

    Creatine supplementation is one of the most studied and effective ergogenic aids for athletes [1]. The multifaceted mechanisms by which creatine exerts its beneficial effect include increasing anaerobic energy capacity, decreasing protein breakdown, leading to increased muscle mass and physical performance [1]. While these well-recognized creatine effects benefit the athlete, creatine may also serve as a potential clinical and therapeutic supplementary treatment to conventional medical interventions [2][3][4][5][6][7][8][9][10]. In this regard, over recent years, researchers have been investigating the potential therapeutic role of creatine supplementation on health-related conditions such as diabetes [11], sarcopenia [4][6][12][13], osteoporosis [2][14], cancer [10][15][16][17][18], rehabilitation [4][19][20][21][22][23][24][25][26], cognition [3][27][28][29], and cardiovascular health [5][6][8][30][31][32], among others.

    2. Role of Creatine in Aging Populations

    Several studies have evaluated the effects of creatine supplementation in older populations in an attempt to prevent sarcopenia, maintain strength, and/or reduce the risk of chronic disease. The following discusses some of these potential applications.

    2.1. Muscle Mass, Strength, Bone and Body Composition

    Sarcopenia is an age-related muscle condition characterized by a reduction in muscle quantity, muscle strength, and functional capacity. Although multifactorial, sarcopenia may be caused by changes in muscle protein kinetics (synthesis and breakdown), neuromuscular function, inflammation, physical activity, and nutrition [12][14]. We also generally lose strength, muscle mass, bone mass, balance while increasing body fat as we age, whether clinically diagnosed with sarcopenia or not [3][33][34]. A number of nutritional and exercise interventions have been suggested to counteract sarcopenia in older individuals, including creatine supplementation during resistance training [12][14]. For example, Brose and colleagues [35] were among the first to report that creatine supplementation (5 g/day for 14 weeks) during heavy resistance training promoted greater gains in muscle mass and isometric muscle strength in older adults (>65 years). Chrusch and coworkers [36] reported that older participants (60–84 years) who supplemented their diet with creatine (0.3 g/kg/day for 5 days and 0.07 g/kg/day for 79 days) during supervised resistance training (3 days/week for 12 weeks) experienced greater gains in lean tissue mass, lower-body maximal strength, and endurance, and isokinetic knee flexion/extension power compared to controls. Candow and colleagues [37] reported that creatine (0.1 g/kg/day) and protein (0.3 g/kg/day) supplementation increased muscle mass and strength while decreasing protein degradation and bone resorption markers in older men. Chilibeck and associates [38] found that creatine supplementation (0.1 g/kg/day) during 12 months of resistance training increased strength and bone density in postmenopausal women. Gualano and coworkers [39] reported that creatine supplementation (20 g/day for 5 days; 5 g/day for 161 days) during resistance training improved appendicular lean mass and muscle function in older vulnerable women and that creatine supplementation alone resulted in similar gains in muscle mass compared to those engaged in resistance training alone. Aguiar and coworkers [40] also found that creatine supplementation (5 g/day for 12 weeks) combined with resistance training improved muscle endurance, ability to perform functional tasks, maximal strength, and muscle mass in older women.

    Additionally, McMorris et al. [41] reported that creatine supplementation (20 g/day for 7 days) after sleep deprivation improved balance measures. Bernat and colleagues [42] reported that creatine supplementation (0.1 g/kg/day) during 8 weeks of high-velocity resistance training in untrained healthy aging men promoted significantly greater gains in leg press and total lower-body strength, muscle thickness, and some measures of peak torque and physical performance. Moreover, a meta-analysis revealed that older individuals participating in resistance training experienced greater gains in muscle mass, strength, and functional capacity when supplementing their diet with creatine [43]. A similar meta-analysis conducted by Candow and colleagues [9] found that older individuals who took creatine during resistance training experienced significantly greater gains in muscle mass and upper body. While not all studies report statistically significant effects, the preponderance of available research supports contentions that creatine supplementation, when combined with resistance exercise, can help maintain or increase muscle mass, strength, and balance in older individuals and therefore serve as an effective countermeasure to attenuate sarcopenia. The role of creatine supplementation during resistance training in sarcopenic populations will be discussed in more detail in this paper series on aging, sarcopenia, and bone health.

    In addition, people often experience adult-onset obesity as they age, prompting them to diet to promote weight loss. Unfortunately, this often leads to loss of muscle mass and strength, which would be counterproductive in older individuals. Creatine supplementation while following an energy-restricted diet may be an effective strategy to maintain muscle mass, promote fat loss, and help manage adult-onset obesity. In support of this contention, Forbes and colleagues [44] recently conducted a meta-analysis on the effects of creatine on body composition and found that creatine supplementation may not only help maintain muscle mass but also promote fat mass loss. This strategy could be helpful in preventing or managing adult-onset obesity. Thus, although more research is needed, it can be reasonably concluded based on available literature that creatine supplementation, particularly when combined with resistance training, can promote gains in strength and help maintain or increase muscle mass and bone density in older individuals. Further, creatine supplementation during energy-restriction-induced weight loss interventions may be an effective way to preserve muscle mass, promote fat loss, and thereby help manage adult-onset obesity.

    2.2. Cognitive Function

    Creatine supplementation has been reported to increase brain PCr content by 5–15% and thereby enhance brain bioenergetics [21][45][33][34][46]. Consequently, research has examined whether creatine supplementation affects cognition, memory, and/or executive function in older individuals as well as patients with mild cognitive impairment [47][48][41][49][50]. Several studies have found that creatine supplementation attenuates mental fatigue [27][28][51] and/or can improve cognition, executive function, and/or memory [28][47][51][48][49][52]. For example, Watanabe and associates [53] found that creatine supplementation (8 g/day for 5 days) increased oxygen utilization in the brain and reduced mental fatigue in participants performing repetitive mathematical calculations. Rae et al. [49] found that working memory and processing speed increased with creatine supplementation (5 g/day for 6 weeks). McMorris and colleagues [41] reported that sleep-deprived participants better maintained random movement generation, time to react to choices, mood state, and balance when supplemented with creatine (20 g/day for 7 days). These researchers also reported that random number generation, forward spatial recall, and long-term memory tasks were significantly improved in elderly participants when supplemented with creatine. Ling et al. [50] also reported that cognition on some tasks was improved with creatine ethyl ester supplementation (5 g/day for 15 days). More recently, VAN Cutsem and coworkers [27] reported that creatine supplementation (20 g/day for 7 days) prior to performing a simulated soccer match improved muscular endurance and prolonged cognitive performance. While more research is needed and not all studies show benefit [51][54], it can be reasonably concluded based on current scientific evidence that creatine supplementation may increase brain creatine content and/or support cognitive function, particularly as one ages.

    2.3. Glucose Management and Diabetes

    Creatine uptake into tissue is influenced by glucose and insulin [55][56][57]. Creatine supplementation has also been reported to prevent declines in the GLUT-4 transporter during immobilization while increasing GLUT-4 by 40% during rehabilitation after atrophy [58]. Moreover, co-ingestion of creatine with carbohydrate [59][60] or creatine with carbohydrate and protein [61] has been reported to increase creatine uptake and/or muscle glycogen levels [59][61][62]. Consequently, research has evaluated whether creatine supplementation may influence glucose management [10][11][58][63][55][64]. For example, Gualano et al. [63] evaluated the effects of creatine supplementation (5 g/day for 12 weeks) during training in participants with type 2 diabetes. The researchers found that creatine supplementation improved glucose tolerance to ingesting a standard meal, increased GLUT-4 translocation, and promoted a significant reduction in HbA1c levels. Moreover, the AMPK-alpha protein content tended to be higher after Cr supplementation and was significantly related to the changes in GLUT-4 translocation and Hb1Ac levels, suggesting that AMPK signaling may be implicated in the effects of supplementation on glucose uptake in type 2 diabetes [64]. Thus, there is evidence to suggest that creatine supplementation enhances glucose uptake and insulin sensitivity and, therefore, can help individuals manage glucose and HbA1c levels, particularly when initiating an exercise program [10][11][65]. Based on this literature, it can be reasonably concluded that creatine supplementation may support healthy glucose management.

    2.4. Heart Disease

    Coronary artery disease limits blood supply to the heart, thereby increasing susceptibility to ischemic events, arrhythmias, and/or heart failure. Creatine and PCr play an important role in maintaining myocardial bioenergetics during ischemic events [21]. For this reason, there has been interest in assessing the role of creatine or PCr administration in reducing arrhythmias, ischemia-related damage, and/or heart function in individuals with chronic heart failure [66][67][68][69][70][71][72][73][74][75][76]. For example, Anyukhovsky et al. [74] reported that intravenous administration of PCr and phosphocreatinine (300 mg/kg) in canines prevented the accumulation of lysophosphoglycerides in the ischemic zone of the heart, which is associated with an increased prevalence of arrhythmias. The researchers concluded that this might explain the antiarrhythmic action of PCr and phosphocreatinine in acute myocardial ischemia. Sharov and coworkers [73] reported that exogenous PCr administration protected against ischemia in the heart. Likewise, Balestrino and coworkers [21] evaluated the effects of adding PCr to cardioplegic solutions on energy availability during myocardial ischemia. The researchers found that PCr administration improved energy availability to the heart, reduced the incidence of arrhythmias, and improved myocardial function. As noted below, there is also evidence that creatine supplementation may maintain energy availability during brain ischemia and reduce stroke-related damage. Moreover, several studies have reported some benefit of oral creatine supplementation in heart failure patients participating in rehabilitation programs [77][78][79][80]. While not all studies report benefit from oral creatine supplementation [23][81] and more research is needed, current evidence suggests that phosphocreatine administration and possibly creatine supplementation support heart metabolism and health, particularly during ischemic challenges.

    The entry is from 10.3390/nu13020447

    References

    1. Kreider, R.B.; Kalman, D.S.; Antonio, J.; Ziegenfuss, T.N.; Wildman, R.; Collins, R.; Candow, D.G.; Kleiner, S.M.; Almada, A.L.; Lopez, H.L. International Society of Sports Nutrition position stand: Safety and efficacy of creatine supplementation in exercise, sport, and medicine. J. Int. Soc. Sports Nutr. 2017, 14, 18.
    2. Stares, A.; Bains, M. The Additive Effects of Creatine Supplementation and Exercise Training in an Aging Population: A Systematic Review of Randomized Controlled Trials. J. Geriatr. Phys. Ther. 2020, 43, 99–112.
    3. Dolan, E.; Gualano, B.; Rawson, E.S. Beyond muscle: The effects of creatine supplementation on brain creatine, cognitive processing, and traumatic brain injury. Eur. J. Sport Sci. 2019, 19, 1–14.
    4. Dolan, E.; Artioli, G.G.; Pereira, R.M.R.; Gualano, B. Muscular Atrophy and Sarcopenia in the Elderly: Is There a Role for Creatine Supplementation? Biomolecules 2019, 9, 642.
    5. Wallimann, T.; Riek, U.; Moddel, M. Intradialytic creatine supplementation: A scientific rationale for improving the health and quality of life of dialysis patients. Med. Hypotheses 2017, 99, 1–14.
    6. Riesberg, L.A.; Weed, S.A.; McDonald, T.L.; Eckerson, J.M.; Drescher, K.M. Beyond muscles: The untapped potential of creatine. Int. Immunopharmacol. 2016, 37, 31–42.
    7. Ellery, S.J.; Walker, D.W.; Dickinson, H. Creatine for women: A review of the relationship between creatine and the reproductive cycle and female-specific benefits of creatine therapy. Amino Acids 2016, 48, 1807–1817.
    8. Smith, R.N.; Agharkar, A.S.; Gonzales, E.B. A review of creatine supplementation in age-related diseases: More than a supplement for athletes. F1000Research 2014, 3, 222.
    9. Candow, D.G.; Chilibeck, P.D.; Forbes, S.C. Creatine supplementation and aging musculoskeletal health. Endocrine 2014, 45, 354–361.
    10. Gualano, B.; Roschel, H.; Lancha, A.H., Jr.; Brightbill, C.E.; Rawson, E.S. In sickness and in health: The widespread application of creatine supplementation. Amino Acids 2012, 43, 519–529.
    11. Pinto, C.L.; Botelho, P.B.; Pimentel, G.D.; Campos-Ferraz, P.L.; Mota, J.F. Creatine supplementation and glycemic control: A systematic review. Amino Acids 2016, 48, 2103–2129.
    12. Candow, D.G.; Forbes, S.C.; Chilibeck, P.D.; Cornish, S.M.; Antonio, J.; Kreider, R.B. Variables Influencing the Effectiveness of Creatine Supplementation as a Therapeutic Intervention for Sarcopenia. Front. Nutr. 2019, 6, 124.
    13. Chilibeck, P.D.; Kaviani, M.; Candow, D.G.; Zello, G.A. Effect of creatine supplementation during resistance training on lean tissue mass and muscular strength in older adults: A meta-analysis. Open Access J. Sports Med. 2017, 8, 213–226.
    14. Candow, D.G.; Forbes, S.C.; Chilibeck, P.D.; Cornish, S.M.; Antonio, J.; Kreider, R.B. Effectiveness of Creatine Supplementation on Aging Muscle and Bone: Focus on Falls Prevention and Inflammation. J. Clin. Med. 2019, 8, 488.
    15. Fairman, C.M.; Kendall, K.L.; Newton, R.U.; Hart, N.H.; Taaffe, D.R.; Chee, R.; Tang, C.I.; Galvao, D.A. Examining the effects of creatine supplementation in augmenting adaptations to resistance training in patients with prostate cancer undergoing androgen deprivation therapy: A randomised, double-blind, placebo-controlled trial. BMJ Open 2019, 9, e030080.
    16. Fairman, C.M.; Kendall, K.L.; Hart, N.H.; Taaffe, D.R.; Galvao, D.A.; Newton, R.U. The potential therapeutic effects of creatine supplementation on body composition and muscle function in cancer. Crit. Rev. Oncol Hematol 2019, 133, 46–57.
    17. Di Biase, S.; Ma, X.; Wang, X.; Yu, J.; Wang, Y.C.; Smith, D.J.; Zhou, Y.; Li, Z.; Kim, Y.J.; Clarke, N.; et al. Creatine uptake regulates CD8 T cell antitumor immunity. J. Exp. Med. 2019, 216, 2869–2882.
    18. Campos-Ferraz, P.L.; Gualano, B.; das Neves, W.; Andrade, I.T.; Hangai, I.; Pereira, R.T.; Bezerra, R.N.; Deminice, R.; Seelaender, M.; Lancha, A.H. Exploratory studies of the potential anti-cancer effects of creatine. Amino Acids 2016, 48, 1993–2001.
    19. Dover, S.; Stephens, S.; Schneiderman, J.E.; Pullenayegum, E.; Wells, G.D.; Levy, D.M.; Marcuz, J.A.; Whitney, K.; Schulze, A.; Tein, I.; et al. The effect of creatine supplementation on muscle function in childhood myositis: A randomized, double-blind, placebo-controlled feasibility study. J. Rheumatol. 2020.
    20. Balestrino, M.; Adriano, E. Creatine as a Candidate to Prevent Statin Myopathy. Biomolecules 2019, 9, 496.
    21. Balestrino, M.; Sarocchi, M.; Adriano, E.; Spallarossa, P. Potential of creatine or phosphocreatine supplementation in cerebrovascular disease and in ischemic heart disease. Amino Acids 2016, 48, 1955–1967.
    22. Neves, M., Jr.; Gualano, B.; Roschel, H.; Fuller, R.; Benatti, F.B.; Pinto, A.L.; Lima, F.R.; Pereira, R.M.; Lancha, A.H., Jr.; Bonfa, E. Beneficial effect of creatine supplementation in knee osteoarthritis. Med. Sci. Sports Exerc. 2011, 43, 1538–1543.
    23. Cornelissen, V.A.; Defoor, J.G.; Stevens, A.; Schepers, D.; Hespel, P.; Decramer, M.; Mortelmans, L.; Dobbels, F.; Vanhaecke, J.; Fagard, R.H.; et al. Effect of creatine supplementation as a potential adjuvant therapy to exercise training in cardiac patients: A randomized controlled trial. Clin. Rehabil. 2010, 24, 988–999.
    24. Al-Ghimlas, F.; Todd, D.C. Creatine supplementation for patients with COPD receiving pulmonary rehabilitation: A systematic review and meta-analysis. Respirology 2010, 15, 785–795.
    25. Hespel, P.; Derave, W. Ergogenic effects of creatine in sports and rehabilitation. Subcell Biochem. 2007, 46, 245–259.
    26. Hespel, P.; Op’t Eijnde, B.; Van Leemputte, M.; Urso, B.; Greenhaff, P.L.; Labarque, V.; Dymarkowski, S.; Van Hecke, P.; Richter, E.A. Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans. J. Physiol. 2001, 536, 625–633.
    27. Van Cutsem, J.; Roelands, B.; Pluym, B.; Tassignon, B.; Verschueren, J.O.; De Pauw, K.; Meeusen, R. Can Creatine Combat the Mental Fatigue-associated Decrease in Visuomotor Skills? Med. Sci. Sports Exerc. 2020, 52, 120–130.
    28. Avgerinos, K.I.; Spyrou, N.; Bougioukas, K.I.; Kapogiannis, D. Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials. Exp. Gerontol. 2018, 108, 166–173.
    29. Toniolo, R.A.; Fernandes, F.B.F.; Silva, M.; Dias, R.D.S.; Lafer, B. Cognitive effects of creatine monohydrate adjunctive therapy in patients with bipolar depression: Results from a randomized, double-blind, placebo-controlled trial. J. Affect. Disord. 2017, 224, 69–75.
    30. Van Bavel, D.; de Moraes, R.; Tibirica, E. Effects of dietary supplementation with creatine on homocysteinemia and systemic microvascular endothelial function in individuals adhering to vegan diets. Fundam. Clin. Pharmacol. 2019, 33, 428–440.
    31. Zervou, S.; Whittington, H.J.; Russell, A.J.; Lygate, C.A. Augmentation of Creatine in the Heart. Mini Rev. Med. Chem. 2016, 16, 19–28.
    32. Clarke, H.; Kim, D.H.; Meza, C.A.; Ormsbee, M.J.; Hickner, R.C. The Evolving Applications of Creatine Supplementation: Could Creatine Improve Vascular Health? Nutrients 2020, 12, 2834.
    33. Rawson, E.S.; Venezia, A.C. Use of creatine in the elderly and evidence for effects on cognitive function in young and old. Amino Acids 2011, 40, 1349–1362.
    34. Gualano, B.; Rawson, E.S.; Candow, D.G.; Chilibeck, P.D. Creatine supplementation in the aging population: Effects on skeletal muscle, bone and brain. Amino Acids 2016, 48, 1793–1805.
    35. Brose, A.; Parise, G.; Tarnopolsky, M.A. Creatine supplementation enhances isometric strength and body composition improvements following strength exercise training in older adults. J. Gerontol. A Biol. Sci. Med. Sci. 2003, 58, 11–19.
    36. Chrusch, M.J.; Chilibeck, P.D.; Chad, K.E.; Davison, K.S.; Burke, D.G. Creatine supplementation combined with resistance training in older men. Med. Sci. Sports Exerc. 2001, 33, 2111–2117.
    37. Candow, D.G.; Little, J.P.; Chilibeck, P.D.; Abeysekara, S.; Zello, G.A.; Kazachkov, M.; Cornish, S.M.; Yu, P.H. Low-dose creatine combined with protein during resistance training in older men. Med. Sci. Sports Exerc. 2008, 40, 1645–1652.
    38. Chilibeck, P.D.; Candow, D.G.; Landeryou, T.; Kaviani, M.; Paus-Jenssen, L. Effects of Creatine and Resistance Training on Bone Health in Postmenopausal Women. Med. Sci. Sports Exerc. 2015, 47, 1587–1595.
    39. Gualano, B.; Macedo, A.R.; Alves, C.R.; Roschel, H.; Benatti, F.B.; Takayama, L.; de Sa Pinto, A.L.; Lima, F.R.; Pereira, R.M. Creatine supplementation and resistance training in vulnerable older women: A randomized double-blind placebo-controlled clinical trial. Exp. Gerontol. 2014, 53, 7–15.
    40. Aguiar, A.F.; Januario, R.S.; Junior, R.P.; Gerage, A.M.; Pina, F.L.; do Nascimento, M.A.; Padovani, C.R.; Cyrino, E.S. Long-term creatine supplementation improves muscular performance during resistance training in older women. Eur. J. Appl. Physiol. 2013, 113, 987–996.
    41. McMorris, T.; Harris, R.C.; Swain, J.; Corbett, J.; Collard, K.; Dyson, R.J.; Dye, L.; Hodgson, C.; Draper, N. Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology 2006, 185, 93–103.
    42. Bernat, P.; Candow, D.G.; Gryzb, K.; Butchart, S.; Schoenfeld, B.J.; Bruno, P. Effects of high-velocity resistance training and creatine supplementation in untrained healthy aging males. Appl. Physiol. Nutr. Metab. 2019, 44, 1246–1253.
    43. Devries, M.C.; Phillips, S.M. Creatine supplementation during resistance training in older adults-a meta-analysis. Med. Sci. Sports Exerc. 2014, 46, 1194–1203.
    44. Forbes, S.C.; Candow, D.G.; Krentz, J.R.; oberts, M.D.; Young, K.C. Changes in Fat Mass Following Creatine Supplementation and Resistance Training in Adults ≥50 Years of Age: A Meta-Analysis. J. Funct. Morphol. Kinesio. 2019, 4, 62.
    45. Braissant, O.; Henry, H.; Beard, E.; Uldry, J. Creatine deficiency syndromes and the importance of creatine synthesis in the brain. Amino Acids 2011, 40, 1315–1324.
    46. Balestrino, M.; Adriano, E. Beyond sports: Efficacy and safety of creatine supplementation in pathological or paraphysiological conditions of brain and muscle. Med. Res. Rev. 2019, 39, 2427–2459.
    47. McMorris, T.; Mielcarz, G.; Harris, R.C.; Swain, J.P.; Howard, A. Creatine supplementation and cognitive performance in elderly individuals. Neuropsychol. Dev. Cogn. B Aging Neuropsychol. Cogn. 2007, 14, 517–528.
    48. McMorris, T.; Harris, R.C.; Howard, A.N.; Langridge, G.; Hall, B.; Corbett, J.; Dicks, M.; Hodgson, C. Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior. Physiol. Behav. 2007, 90, 21–28.
    49. Rae, C.; Digney, A.L.; McEwan, S.R.; Bates, T.C. Oral creatine monohydrate supplementation improves brain performance: A double-blind, placebo-controlled, cross-over trial. Proc. Biol. Sci. 2003, 270, 2147–2150.
    50. Ling, J.; Kritikos, M.; Tiplady, B. Cognitive effects of creatine ethyl ester supplementation. Behav. Pharmacol. 2009, 20, 673–679.
    51. Benton, D.; Donohoe, R. The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores. Br. J. Nutr. 2011, 105, 1100–1105.
    52. Robinson, J.L.; McBreairty, L.E.; Ryan, R.A.; Randunu, R.; Walsh, C.J.; Martin, G.M.; Brunton, J.A.; Bertolo, R.F. Effects of supplemental creatine and guanidinoacetic acid on spatial memory and the brain of weaned Yucatan miniature pigs. PLoS ONE 2020, 15, e0226806.
    53. Watanabe, A.; Kato, N.; Kato, T. Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neurosci. Res. 2002, 42, 279–285.
    54. Rawson, E.S.; Lieberman, H.R.; Walsh, T.M.; Zuber, S.M.; Harhart, J.M.; Matthews, T.C. Creatine supplementation does not improve cognitive function in young adults. Physiol. Behav. 2008, 95, 130–134.
    55. Op’t Eijnde, B.; Jijakli, H.; Hespel, P.; Malaisse, W.J. Creatine supplementation increases soleus muscle creatine content and lowers the insulinogenic index in an animal model of inherited type 2 diabetes. Int. J. Mol. Med. 2006, 17, 1077–1084.
    56. Rooney, K.; Bryson, J.; Phuyal, J.; Denyer, G.; Caterson, I.; Thompson, C. Creatine supplementation alters insulin secretion and glucose homeostasis in vivo. Metabolism 2002, 51, 518–522.
    57. Newman, J.E.; Hargreaves, M.; Garnham, A.; Snow, R.J. Effect of creatine ingestion on glucose tolerance and insulin sensitivity in men. Med. Sci. Sports Exerc. 2003, 35, 69–74.
    58. Op’t Eijnde, B.; Urso, B.; Richter, E.A.; Greenhaff, P.L.; Hespel, P. Effect of oral creatine supplementation on human muscle GLUT4 protein content after immobilization. Diabetes 2001, 50, 18–23.
    59. Green, A.L.; Hultman, E.; Macdonald, I.A.; Sewell, D.A.; Greenhaff, P.L. Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans. Am. J. Physiol. 1996, 271, E821–E826.
    60. Greenwood, M.; Kreider, R.B.; Earnest, C.P.; Rasmussen, C.; Almada, A. Differences in creatine retention among three nutritional formulations of oral creatine supplements. J. Exerc. Physiol. Online 2003, 6, 37–43.
    61. Steenge, G.R.; Simpson, E.J.; Greenhaff, P.L. Protein- and carbohydrate-induced augmentation of whole body creatine retention in humans. J. Appl. Physiol. 2000, 89, 1165–1171.
    62. Nelson, A.G.; Arnall, D.A.; Kokkonen, J.; Day, R.; Evans, J. Muscle glycogen supercompensation is enhanced by prior creatine supplementation. Med. Sci. Sports Exerc. 2001, 33, 1096–1100.
    63. Gualano, B.; V, D.E.S.P.; Roschel, H.; Artioli, G.G.; Neves, M., Jr.; De Sa Pinto, A.L.; Da Silva, M.E.; Cunha, M.R.; Otaduy, M.C.; Leite Cda, C.; et al. Creatine in type 2 diabetes: A randomized, double-blind, placebo-controlled trial. Med. Sci. Sports Exerc. 2011, 43, 770–778.
    64. Alves, C.R.; Ferreira, J.C.; de Siqueira-Filho, M.A.; Carvalho, C.R.; Lancha, A.H., Jr.; Gualano, B. Creatine-induced glucose uptake in type 2 diabetes: A role for AMPK-alpha? Amino Acids 2012, 43, 1803–1807.
    65. Gualano, B.; Artioli, G.G.; Poortmans, J.R.; Lancha Junior, A.H. Exploring the therapeutic role of creatine supplementation. Amino Acids 2010, 38, 31–44.
    66. Hultman, J.; Ronquist, G.; Forsberg, J.O.; Hansson, H.E. Myocardial energy restoration of ischemic damage by administration of phosphoenolpyruvate during reperfusion. A study in a paracorporeal rat heart model. Eur. Surg. Res. 1983, 15, 200–207.
    67. Thelin, S.; Hultman, J.; Ronquist, G.; Hansson, H.E. Metabolic and functional effects of creatine phosphate in cardioplegic solution. Studies on rat hearts during and after normothermic ischemia. Scand. J. Thorac. Cardiovasc. Surg. 1987, 21, 39–45.
    68. Osbakken, M.; Ito, K.; Zhang, D.; Ponomarenko, I.; Ivanics, T.; Jahngen, E.G.; Cohn, M. Creatine and cyclocreatine effects on ischemic myocardium: 31P nuclear magnetic resonance evaluation of intact heart. Cardiology 1992, 80, 184–195.
    69. Thorelius, J.; Thelin, S.; Ronquist, G.; Halden, E.; Hansson, H.E. Biochemical and functional effects of creatine phosphate in cardioplegic solution during aortic valve surgery–A clinical study. Thorac. Cardiovasc. Surg. 1992, 40, 10–13.
    70. Boudina, S.; Laclau, M.N.; Tariosse, L.; Daret, D.; Gouverneur, G.; Bonoron-Adele, S.; Saks, V.A.; Dos Santos, P. Alteration of mitochondrial function in a model of chronic ischemia in vivo in rat heart. Am. J. Physiol. Heart Circ. Physiol. 2002, 282, H821–H831.
    71. Laclau, M.N.; Boudina, S.; Thambo, J.B.; Tariosse, L.; Gouverneur, G.; Bonoron-Adele, S.; Saks, V.A.; Garlid, K.D.; Dos Santos, P. Cardioprotection by ischemic preconditioning preserves mitochondrial function and functional coupling between adenine nucleotide translocase and creatine kinase. J. Mol. Cell Cardiol. 2001, 33, 947–956.
    72. Conorev, E.A.; Sharov, V.G.; Saks, V.A. Improvement in contractile recovery of isolated rat heart after cardioplegic ischaemic arrest with endogenous phosphocreatine: Involvement of antiperoxidative effect? Cardiovasc. Res. 1991, 25, 164–171.
    73. Sharov, V.G.; Saks, V.A.; Kupriyanov, V.V.; Lakomkin, V.L.; Kapelko, V.I.; Steinschneider, A.; Javadov, S.A. Protection of ischemic myocardium by exogenous phosphocreatine. I. Morphologic and phosphorus 31-nuclear magnetic resonance studies. J. Thorac. Cardiovasc. Surg. 1987, 94, 749–761.
    74. Anyukhovsky, E.P.; Javadov, S.A.; Preobrazhensky, A.N.; Beloshapko, G.G.; Rosenshtraukh, L.V.; Saks, V.A. Effect of phosphocreatine and related compounds on the phospholipid metabolism of ischemic heart. Biochem. Med. Metab. Biol. 1986, 35, 327–334.
    75. Sharov, V.G.; Afonskaya, N.I.; Ruda, M.Y.; Cherpachenko, N.M.; Pozin, E.; Markosyan, R.A.; Shepeleva, I.I.; Samarenko, M.B.; Saks, V.A. Protection of ischemic myocardium by exogenous phosphocreatine (neoton): Pharmacokinetics of phosphocreatine, reduction of infarct size, stabilization of sarcolemma of ischemic cardiomyocytes, and antithrombotic action. Biochem. Med. Metab. Biol. 1986, 35, 101–114.
    76. Perasso, L.; Spallarossa, P.; Gandolfo, C.; Ruggeri, P.; Balestrino, M. Therapeutic use of creatine in brain or heart ischemia: Available data and future perspectives. Med. Res. Rev. 2013, 33, 336–363.
    77. Gordon, A.; Hultman, E.; Kaijser, L.; Kristjansson, S.; Rolf, C.J.; Nyquist, O.; Sylven, C. Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance. Cardiovasc. Res. 1995, 30, 413–418.
    78. Andrews, R.; Greenhaff, P.; Curtis, S.; Perry, A.; Cowley, A.J. The effect of dietary creatine supplementation on skeletal muscle metabolism in congestive heart failure. Eur. Heart J. 1998, 19, 617–622.
    79. Kuethe, F.; Krack, A.; Richartz, B.M.; Figulla, H.R. Creatine supplementation improves muscle strength in patients with congestive heart failure. Pharmazie 2006, 61, 218–222.
    80. Fumagalli, S.; Fattirolli, F.; Guarducci, L.; Cellai, T.; Baldasseroni, S.; Tarantini, F.; Di Bari, M.; Masotti, G.; Marchionni, N. Coenzyme Q10 terclatrate and creatine in chronic heart failure: A randomized, placebo-controlled, double-blind study. Clin. Cardiol. 2011, 34, 211–217.
    81. Carvalho, A.P.; Rassi, S.; Fontana, K.E.; Kde, S.C.; Feitosa, R.H. Influence of creatine supplementation on the functional capacity of patients with heart failure. Arq. Bras. Cardiol. 2012, 99, 623–629.
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