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Table of Contents

    Topic review

    Creatine Supplementation and Lean Tissue

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    Submitted by: Scott Forbes

    Definition

    Creatine supplementation in conjunction with resistance training (RT) augments gains in lean tissue mass and strength in aging adults; however, there is a large amount of heterogeneity between individual studies that may be related to creatine ingestion strategies. 

    1. Introduction

    Approximately 10% of the adult population ≥60 years of age has sarcopenia [1], which has a profound negative effect on functional independence and overall quality of life [2]. Several lines of research suggest that sarcopenia is caused by age-related changes in muscle protein kinetics, neuromuscular function and physiology, skeletal muscle morphology, inflammation, and mitochondrial dysregulation [3][4][5]. In addition to these cellular and mechanistic changes, insufficient physical activity and nutritional intake also contribute to sarcopenia [2][6]. Interestingly, dietary intake of creatine, a key component for muscular bioenergetics, decreases with age [7].

    The combination of creatine supplementation and resistance training has the potential to serve as an effective countermeasure to the age-related loss in lean tissue mass and strength, possibly by influencing anaerobic energy metabolism, calcium and glycogen regulation, muscle protein kinetics, inflammation and oxidative stress [2][8][9]. However, results from individual studies (n = 20) are mixed, with 10 studies showing beneficial effects on measures of lean tissue mass and/or strength (leg press, chest press) while 10 studies found no greater benefit from creatine vs. placebo (Table 1). Finally, 4 of the 20 studies had participants ingest creatine only on resistance training days. Therefore, these studies were likely unpowered to detect small differences in lean tissue mass and strength (leg press, chest press).

    Table 1. Study characteristics, dosing strategy, and outcomes of research examining the influence of creatine in older adults with a resistance training program.
    First Author, Year Population Supplement Protocol Resistance Training Duration Outcomes
    Loading Protocol Maintenance Dose
    Lower-Dose/Absolute Studies (≤5 g/day)
    Alves et al. [10] N = 47; healthy women, Mean age = 66.8 years (range: 60–80 years) CR 20 g/day for 5 days CR (5 g/day) or PLA RT = 2 days/wk 24 wks ↔ 1RM strength compared to RT + PLA
    Aguiar et al. [11] N = 18; healthy women; Mean age = 65 years None CR (5 g/day) or PLA RT = 3 days/wk 12 wks CR ↑ gains in fat-free mass (+3.2%), muscle mass (+2.8%), 1RM bench press, knee extension, and biceps curl compared to PLA
    Bemben et al. and Eliot et al. [12][13] N = 42; healthy men; age = 48–72 years None CR (5 g/day) RT = 3 days/wk 14 wks ↔ lean tissue mass, 1RM strength
    Bermon et al. [14] N = 32 (16 men, 16 women); healthy; age = 67–80 years CR 20 g/day for 5 days CR (3 g/day) or PLA RT = 3 days/wk 7.4 wks (52 days) ↔ lower limb muscular volume, 1-, 12-repetitions maxima, and the isometric intermittent endurance
    Brose et al. [15] N = 28 (15 men, 13 women); healthy; age: men = 68.7, women = 70.8 years None CR (5 g/day) or PLA RT = 3 days/wk 14 wks CR ↑ gains in lean tissue mass and isometric knee extension strength; ↔ type 1, 2a, 2x muscle fiber area
    Deacon et al. [16] N = 80 (50 men, 30 women); COPD; age = 68.2 years CR 22 g/day for 5 days CR (3.76 g/day) or PLA RT = 3 days/wk 7 wks ↔ lean tissue mass or muscle strength
    Eijnde et al. [17] N = 46; healthy men; age = 55–75 years None CR (5 g/day) or PLA Cardiorespiratory + RT = 2–3 days/wk 26 wks ↔ lean tissue mass or isometric maximal strength
    Gualano et al. [18] N = 25 (9 men, 16 women); type 2 diabetes; age = 57 years None CR (5 g/day) or PLA RT = 3 days/wk 12 wks ↔ lean tissue mass
    Gualano et al. [19] N = 30; “vulnerable” women; Mean age = 65.4 years CR 20 g/day for 5 days CR (5 g/day) or PLA RT = 2 days/wk 24 wks CR + RT ↑ gains in 1RM bench press and appendicular lean mass compared to PLA + RT
    Hass et al. [20] N = 20 (17 men, 3 women with idiopathetic Parkinson’s disease); Mean age = 62 years CR 20 g/day for 5 days CR (5 g/day) or PLA RT = 2 days/wk 12 wks CR ↑ chest press strength, chair rise performance; ↔ Leg extension 1RM, muscular endurance
    Neves et al. [21] N = 24 (postmenopausal women with knee osteoarthritis); Age = 55–65 years CR 20 g/day for 1 week CR 5 (g/day) or PLA RT=3 days/wk 12 wks CR ↑ gains in limb lean mass. ↔ 1RM leg press
    Pinto et al. [22] N = 27 (men and women); healthy; age = 60–80 years None CR (5 g/day) or PLA RT = 3 days/wk 12 wks CR ↑ gains in lean tissue mass. ↔ 10 RM bench press or leg press strength
    Higher-Dose/Relative Studies (>5 g/day)
    Bernat et al. [23] N = 24 healthy men; age = 59 ± 6 years None CR (0.1 g/kg/day; ~9.5 g/day) or PLA High-velocity RT = 2 days/wk 8 wks ↔ muscle thickness, physical performance, upper body muscle strength. CR ↑ leg press strength, total lower body strength
    Candow et al. [24] N = 35; healthy men; age = 59–77 years None CR (0.1 g/kg/day; ~8.6 g/day) or PLA RT = 3 days/wk 10 wks CR ↑ muscle thickness compared to PLA. CR ↑ 1RM bench press ↔ 1RM leg press
    Candow et al. [25] N = 39 (17 men, 22 women); healthy; age = 50–71 years None CR (0.1 g/kg; ~7.7 g/day) before RT, CR (0.1 g/kg; ~8.8 g/day) after RT, or PLA RT = 3 days/wk 32 wks CR after RT ↑ lean tissue mass, 1RM leg press, 1RM chest press compared to PLA
    Candow et al. [26] N = 38; healthy men; age = 49–67 years None CR (On training days: 0.05 g/kg before and 0.05 g/kg after exercise; total ~9.3 g/day) + 0.1 g/kg/day on non-training days (2 equal doses) RT = 3 days/wk 12 months ↔ lean tissue mass, muscle thickness, or muscle strength
    Chilibeck et al. [27] N = 33; healthy women; Mean age = 57 years None CR (0.1 g/kg/day; ~6.9 g/day) or PLA RT = 3 days/wk 52 wks ↔ lean tissue mass and muscle thickness gains between groups. ↑ relative bench press strength compared to PLA.
    Chrusch et al. [28] N = 30; healthy men; age = 60–84 years CR 0.3 g/kg/d for 5 days CR 0.07 g/kg/day; ~6.2 g/day or PLA RT = 3 days/wk 12 wks CR ↑ gains in lean tissue mass. CR ↑ 1RM leg press, 1RM knee extension, leg press endurance, and knee extension endurance. ↔ 1RM bench press or bench press endurance.
    Cooke et al. [29] N = 20; healthy men; age = 55–70 years CR 20 g/day for 7 days CR 0.1 g/kg/day or ~8.8 g/day on training days RT = 3 days/wk 12 wks ↔ lean tissue mass, 1RM bench press, 1RM leg press
    Johannsmeyer et al. [30] N = 31 (17 men, 14 women); healthy; age = 58 years None CR 0.1 g/kg/day; ~7.8 g/day or PLA RT = 3 days/wk 12 wks CR ↑ gains in lean tissue mass and 1RM strength in men only

    Collectively, results showed that creatine and resistance training increased measures of lean tissue mass by ~1.2 kg and strength (leg press, chest press) more than placebo and resistance training. However, no sub-analyses were performed to determine whether the dosage of creatine used or the frequency of ingestion (i.e., only on resistance training days) influenced measures of lean tissue mass and/or strength. Therefore, the purpose of this review was to (1) perform updated meta-analyses comparing creatine vs. placebo (independent of dosage and frequency of ingestion) during a resistance training program on measures of lean tissue mass and strength, (2) perform meta-analyses examining the effects of different creatine dosing strategies (lower: 5 g/day), with and without a creatine-loading phase (20 g/day for 5–7 days, and (3) perform meta-analyses determining whether creatine supplementation only on resistance training days influences measures of lean tissue mass and strength.

    2. Discussion

    The most important results from these meta-analyses were: (1) creatine supplementation (independent of creatine-loading, maintenance dosage and frequency of ingestion) during a resistance training program increased measures of lean tissue mass and strength compared to the placebo and resistance training in older adults, (2) the combination of creatine-loading followed by lower-dose creatine (≤5 g/day) was effective for increasing chest press strength, (3) the combination of creatine-loading and higher-dose creatine (>5 g/day) was effective for increasing leg press strength, (4) creatine supplementation only on resistance training days significantly increased measures of lean tissue mass and strength compared to the placebo. These results have application for the design of effective creatine supplementation strategies for older adults. For example, older adults wanting to improve whole-body lean tissue mass and strength may expect these benefits from creatine supplementation (i.e., ≥5 g) either daily or only on training days during a resistance training program.
    Increasing whole-body lean tissue mass and strength is fundamental for mitigating sarcopenia and associated conditions of osteoporosis and physical frailty (3). Older adults specifically looking to improve upper-body strength (perhaps to improve functionality, posture and/or the ability to perform upper-body activities of daily living such as carrying groceries) may need to load with creatine before proceeding to a lower daily dosage (≤5 g) during their resistance training program. To specifically increase lower-body strength (perhaps to improve balance, reduce the risk of falls and/or the ability to perform lower-body activities of daily living such as climbing stairs), older adults may need to load with creatine before proceeding to a higher daily dosage (>5 g) during their resistance training program. While some have hypothesized creatine may have harmful effects [31], a plethora of evidence shows no adverse events (compared to the placebo) with long-term supplementation [32][33][34].
    Previous meta-analyses have shown greater gains in measures of lean tissue mass (~1.2–1.3 kg) and strength from creatine supplementation and resistance training in older adults compared to the placebo [8][35][36]. Since the date of these publications, two additional studies [23][26] have been performed. When these studies were included in the current meta-analyses, creatine supplementation and resistance training still increased measures of lean tissue mass (~1.32 kg) and strength compared to the placebo. Collectively, results across meta-analyses suggest that the combination of creatine supplementation and resistance training has the potential to mitigate sarcopenia. Although none of the studies included in any of the meta-analyses were powdered to directly examine the effects of creatine vs. placebo in older adults diagnosed with sarcopenia, sub-analyses from three studies showed that the combination of creatine and resistance training eliminated the classification of sarcopenia in 11 older adults [19][22][25]. Creatine supplementation may augment lean tissue mass and strength through various mechanisms [2][37][9][35][34]. First, supplementation increases intramuscular PCr resulting in greater resynthesis of ATP during and following muscle contractions. Supplementation also increases muscle GLUT-4 content and translocation to the sarcolemma which may increase glucose uptake and subsequent glycogen resynthesis [38][39]. Creatine supplementation facilitates calcium re-uptake via creatine kinase into the sarcoplasmic reticulum, and this may increase myofibrillar cross-bride cycling, cell swelling, the expression of myogenic transcription factors (i.e., Mrf4, myogenin), satellite cell proliferation, and the expression of growth factors (i.e., insulin-like growth factor-1) [40][41]. Creatine supplementation enhances the activation of protein kinases downstream in the mammalian target of rapamycin (mTOR) pathway, and this may subsequently reduce measures of muscle protein catabolism (i.e., leucine oxidation, urinary 3-methylhistidine) [24][30]. Finally, creatine supplementation could reduce inflammation (i.e., cytokines) [42][43] and oxidative stress [44][45][46], and again, this may help reduce the loss of lean tissue mass with aging [37].
    Incorporating a creatine-loading phase during the initial stages of a resistance training program was determined to be important for improving upper- and lower-body strength. It is well established that creatine-loading results in significant elevations in intramuscular creatine levels [47]. However, the magnitude of the effect on strength outcome measures may also depend on the maintenance dosage of creatine used for the remainder of the training program.
    Regarding upper-body strength, older adults who loaded with creatine and then proceeded to ingest lower-dose creatine daily experienced greater upper body strength gains compared to those on placebo. However, independent of a creatine-loading phase, lower-dose creatine supplementation was no more effective than placebo. When all studies were included in the analysis, higher-dose creatine supplementation daily, with and without a creatine-loading phase, had no greater effect on upper-body strength compared to the placebo. However, sensitivity analysis showed that when the Candow et al. [26] study was removed, results became significant in favor of creatine. In this study, older males supplemented with higher-dose creatine daily during supervised, whole-body resistance training for 52 weeks. Results showed that changes in upper-body strength were similar between creatine and placebo over time. Both creatine and placebo groups experienced large increases in strength over time (creatine: ~69 kg; placebo: ~76 kg) which likely masked any effect from creatine supplementation.
    Regarding lower-body strength, creatine-loading followed by higher-dose creatine daily had a favorable effect on strength whereas creatine-loading followed by lower-dose creatine daily had no greater effect compared to the placebo. The magnitude of responsiveness to creatine supplementation in older adults may depend on initial intramuscular creatine levels [9][48]. There is some evidence to suggest that phosphocreatine stores decrease with aging [9], especially in muscles of the lower limbs, possibly due to type-II muscle fiber atrophy, reduced participation in high-intensity activities and reduced meat consumption [35]. Furthermore, lower-body muscle groups are more negatively affected (i.e., greater strength deficit) by the aging process than upper-body muscle groups [49]. Therefore, to overcome possible age-related changes in muscle creatine content and lower-body muscle morphology, higher creatine dosages (as opposed to lower-creatine dosages) may be needed on a daily basis after a creatine-loading phase to improve lower-body strength in older adults.
    Most importantly, all the studies identified as using a high dose (i.e., >5 g/day) were based on a relative dosing strategy (based on body mass; g/kg/day), while all the low dose studies used an absolute dosing strategy (g/day). As such, future research is required to directly compare an absolute and relative strategy to determine which method is superior.
    Older adults who ingested creatine only on resistance training days experienced greater gains in measures of lean tissue mass and strength compared to the placebo. One study implemented a creatine-loading phase prior to lower-dose creatine daily [29] whereas the other studies implemented a higher-dose daily strategy [24][25]. A common theme across all studies was that creatine was consumed within 60 min’ post-exercise. While the mechanistic actions of creatine were not determined in these studies, previous research has shown that prior muscle contractions (i.e., resistance training sessions) stimulate greater creatine uptake into muscle [50] possibly through increased activation of creatine transport kinetics [51][52]. These results may be important, as compliance to a creatine supplementation program may be higher when creatine is only consumed on training days. However, it is unknown whether older adults experience the same muscle benefits when consuming creatine supplementation daily vs. only on training days during a resistance training program. In addition, a provision of creatine from a regular diet should be accounted for a total exposure to creatine in this population since creatine consumption varies in the elderly [53].
    Although the focus of this review was on combining creatine with resistance exercise, there appears to be some benefits of creatine without concomitant exercise in older adults [54][55]. Future research may be warranted to examine the dose of creatine to enhance muscle performance without exercise.

    3. Conclusions

    Increasing whole-body lean tissue mass and strength is fundamental for mitigating sarcopenia and associated conditions of osteoporosis and physical frailty [2]. Similar to previous meta-analyses [8][35], our results showed that creatine supplementation and resistance training increases measures of lean tissue mass and strength in older adults vs. placebo. However, unique and important results from our sub-analyses indicate that a creatine-loading phase is important for older adults wanting to improve muscle strength. In addition to a creatine-loading phase, a lower daily dosage of creatine (≤5 g) appears sufficient to improve upper-body strength. However, a higher daily dosage of creatine (>5 g) after the loading phase is needed to increase lower-body strength. Regarding the effects of creatine ingestion frequency, creatine supplementation only on resistance training days significantly increased measures of lean tissue mass and strength compared to placebo.

    The entry is from 10.3390/nu13061912

    References

    1. Shafiee, G.; Keshtkar, A.; Soltani, A.; Ahadi, Z.; Larijani, B.; Heshmat, R. Prevalence of sarcopenia in the world: A systematic review and meta- analysis of general population studies. J. Diabetes Metab. Disord. 2017, 16, 21.
    2. Candow, D.G.; Forbes, S.C.; Kirk, B.; Duque, G. Current Evidence and Possible Future Applications of Creatine Supplementation for Older Adults. Nutrients 2021, 13, 745.
    3. Cruz-Jentoft, A.J.; Bahat, G.; Bauer, J.; Boirie, Y.; Bruyere, O.; Cederholm, T.; Cooper, C.; Landi, F.; Rolland, Y.; Sayer, A.A.; et al. Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and the Extended Group for EWGSOP2 Sarcopenia: Revised European consensus on definition and diagnosis. Age Ageing 2019, 48, 16–31.
    4. Mitchell, W.K.; Williams, J.; Atherton, P.; Larvin, M.; Lund, J.; Narici, M. Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. Front. Physiol. 2012, 3, 260.
    5. Tournadre, A.; Vial, G.; Capel, F.; Soubrier, M.; Boirie, Y. Sarcopenia. Jt. Bone Spine 2019, 86, 309–314.
    6. Kirk, B.; Prokopidis, K.; Duque, G. Nutrients to mitigate osteosarcopenia: The role of protein, vitamin D and calcium. Curr. Opin. Clin. Nutr. Metab. Care 2021, 24, 25–32.
    7. Brosnan, J.T.; Brosnan, M.E. Creatine: Endogenous metabolite, dietary, and therapeutic supplement. Annu. Rev. Nutr. 2007, 27, 241–261.
    8. Candow, D.G.; Chilibeck, P.D.; Forbes, S.C. Creatine supplementation and aging musculoskeletal health. Endocrine 2014, 45, 354–361.
    9. 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.
    10. Alves, C.R.; Merege Filho, C.A.; Benatti, F.B.; Brucki, S.; Pereira, R.M.; de Sa Pinto, A.L.; Lima, F.R.; Roschel, H.; Gualano, B. Creatine supplementation associated or not with strength training upon emotional and cognitive measures in older women: A randomized double-blind study. PLoS ONE 2013, 8, e76301.
    11. 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.
    12. Bemben, M.G.; Witten, M.S.; Carter, J.M.; Eliot, K.A.; Knehans, A.W.; Bemben, D.A. The effects of supplementation with creatine and protein on muscle strength following a traditional resistance training program in middle-aged and older men. J. Nutr. Health Aging 2010, 14, 155–159.
    13. Eliot, K.A.; Knehans, A.W.; Bemben, D.A.; Witten, M.S.; Carter, J.; Bemben, M.G. The effects of creatine and whey protein supplementation on body composition in men aged 48 to 72 years during resistance training. J. Nutr. Health Aging 2008, 12, 208–212.
    14. Bermon, S.; Venembre, P.; Sachet, C.; Valour, S.; Dolisi, C. Effects of creatine monohydrate ingestion in sedentary and weight-trained older adults. Acta Physiol. Scand. 1998, 164, 147–155.
    15. 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.
    16. Deacon, S.J.; Vincent, E.E.; Greenhaff, P.L.; Fox, J.; Steiner, M.C.; Singh, S.J.; Morgan, M.D. Randomized controlled trial of dietary creatine as an adjunct therapy to physical training in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2008, 178, 233–239.
    17. Eijnde, B.O.; Van Leemputte, M.; Goris, M.; Labarque, V.; Taes, Y.; Verbessem, P.; Vanhees, L.; Ramaekers, M.; Vanden Eynde, B.; Van Schuylenbergh, R.; et al. Effects of creatine supplementation and exercise training on fitness in men 55–75 yr old. J. Appl. Physiol. 2003, 95, 818–828.
    18. Gualano, B.; DE Salles Painneli, V.; Roschel, H.; Artioli, G.G.; Neves, M.; 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.
    19. 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.
    20. Hass, C.J.; Collins, M.A.; Juncos, J.L. Resistance training with creatine monohydrate improves upper-body strength in patients with Parkinson disease: A randomized trial. Neurorehabil. Neural Repair 2007, 21, 107–115.
    21. Neves, M.; Gualano, B.; Roschel, H.; Fuller, R.; Benatti, F.B.; Pinto, A.L.; Lima, F.R.; Pereira, R.M.; Lancha, A.H.; Bonfa, E. Beneficial effect of creatine supplementation in knee osteoarthritis. Med. Sci. Sports Exerc. 2011, 43, 1538–1543.
    22. Pinto, C.L.; Botelho, P.B.; Carneiro, J.A.; Mota, J.F. Impact of creatine supplementation in combination with resistance training on lean mass in the elderly. J. Cachexia Sarcopenia Muscle 2016, 7, 413–421.
    23. 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.
    24. 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.
    25. Candow, D.G.; Vogt, E.; Johannsmeyer, S.; Forbes, S.C.; Farthing, J.P. Strategic creatine supplementation and resistance training in healthy older adults. Appl. Physiol. Nutr. Metab. 2015, 40, 689–694.
    26. Candow, D.G.; Chilibeck, P.D.; Gordon, J.; Vogt, E.; Landeryou, T.; Kaviani, M.; Paus-Jensen, L. Effect of 12 months of creatine supplementation and whole-body resistance training on measures of bone, muscle and strength in older males. Nutr. Health 2020.
    27. 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.
    28. 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.
    29. Cooke, M.B.; Brabham, B.; Buford, T.W.; Shelmadine, B.D.; McPheeters, M.; Hudson, G.M.; Stathis, C.; Greenwood, M.; Kreider, R.; Willoughby, D.S. Creatine supplementation post-exercise does not enhance training-induced adaptations in middle to older aged males. Eur. J. Appl. Physiol. 2014, 114, 1321–1332.
    30. Johannsmeyer, S.; Candow, D.G.; Brahms, C.M.; Michel, D.; Zello, G.A. Effect of creatine supplementation and drop-set resistance training in untrained aging adults. Exp. Gerontol. 2016, 83, 112–119.
    31. Yu, P.H.; Deng, Y. Potential cytotoxic effect of chronic administration of creatine, a nutrition supplement to augment athletic performance. Med. Hypotheses 2000, 54, 726–728.
    32. Antonio, J.; Candow, D.G.; Forbes, S.C.; Gualano, B.; Jagim, A.R.; Kreider, R.B.; Rawson, E.S.; Smith-Ryan, A.E.; VanDusseldorp, T.A.; Willoughby, D.S.; et al. Common questions and misconceptions about creatine supplementation: What does the scientific evidence really show? J. Int. Soc. Sports Nutr. 2021, 18, 13.
    33. Dalbo, V.J.; Roberts, M.D.; Stout, J.R.; Kerksick, C.M. Putting to rest the myth of creatine supplementation leading to muscle cramps and dehydration. Br. J. Sports Med. 2008, 42, 567–573.
    34. 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.
    35. 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.
    36. 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.
    37. 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.
    38. Ju, J.S.; Smith, J.L.; Oppelt, P.J.; Fisher, J.S. Creatine feeding increases GLUT4 expression in rat skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 2005, 288, 347.
    39. Roberts, P.A.; Fox, J.; Peirce, N.; Jones, S.W.; Casey, A.; Greenhaff, P.L. Creatine ingestion augments dietary carbohydrate mediated muscle glycogen supercompensation during the initial 24 h of recovery following prolonged exhaustive exercise in humans. Amino Acids 2016, 48, 1831–1842.
    40. Burke, D.G.; Candow, D.G.; Chilibeck, P.D.; MacNeil, L.G.; Roy, B.D.; Tarnopolsky, M.A.; Ziegenfuss, T. Effect of creatine supplementation and resistance-exercise training on muscle insulin-like growth factor in young adults. Int. J. Sport Nutr. Exerc. Metab. 2008, 18, 389–398.
    41. Safdar, A.; Yardley, N.J.; Snow, R.; Melov, S.; Tarnopolsky, M.A. Global and targeted gene expression and protein content in skeletal muscle of young men following short-term creatine monohydrate supplementation. Physiol. Genom. 2008, 32, 219–228.
    42. Bassit, R.A.; Curi, R.; Costa Rosa, L.F. Creatine supplementation reduces plasma levels of pro-inflammatory cytokines and PGE2 after a half-ironman competition. Amino Acids 2008, 35, 425–431.
    43. Santos, R.V.; Bassit, R.A.; Caperuto, E.C.; Costa Rosa, L.F. The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30km race. Life Sci. 2004, 75, 1917–1924.
    44. Saraiva, A.L.; Ferreira, A.P.; Silva, L.F.; Hoffmann, M.S.; Dutra, F.D.; Furian, A.F.; Oliveira, M.S.; Fighera, M.R.; Royes, L.F. Creatine reduces oxidative stress markers but does not protect against seizure susceptibility after severe traumatic brain injury. Brain Res. Bull. 2012, 87, 180–186.
    45. Rahimi, R. Creatine supplementation decreases oxidative DNA damage and lipid peroxidation induced by a single bout of resistance exercise. J. Strength Cond. Res. 2011, 25, 3448–3455.
    46. Deminice, R.; Rosa, F.T.; Franco, G.S.; Jordao, A.A.; de Freitas, E.C. Effects of creatine supplementation on oxidative stress and inflammatory markers after repeated-sprint exercise in humans. Nutrition 2013, 29, 1127–1132.
    47. Harris, R.C.; Soderlund, K.; Hultman, E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin. Sci. 1992, 83, 367–374.
    48. Syrotuik, D.G.; Bell, G.J. Acute creatine monohydrate supplementation: A descriptive physiological profile of responders vs. nonresponders. J. Strength Cond. Res. 2004, 18, 610–617.
    49. Candow, D.G.; Chilibeck, P.D. Differences in size, strength, and power of upper and lower body muscle groups in young and older men. J. Gerontol. A Biol. Sci. Med. Sci. 2005, 60, 148–156.
    50. Robinson, T.M.; Sewell, D.A.; Hultman, E.; Greenhaff, P.L. Role of submaximal exercise in promoting creatine and glycogen accumulation in human skeletal muscle. J. Appl. Physiol. 1999, 87, 598–604.
    51. Persky, A.M.; Brazeau, G.A.; Hochhaus, G. Pharmacokinetics of the dietary supplement creatine. Clin. Pharmacokinet. 2003, 42, 557–574.
    52. Forbes, S.C.; Candow, D.G. Timing of creatine supplementation and resistance training: A brief review. J. Exerc. Nutr. 2018, 1, 1.
    53. Ostojic, S.M.; Korovljev, D.; Stajer, V. Dietary creatine and cognitive function in U.S. adults aged 60 years and over. Aging Clin. Exp. Res. 2021.
    54. Forbes, S.C.; Candow, D.G.; Ferreira, L.H.B.; Souza-Junior, T.P. Effects of Creatine Supplementation on Properties of Muscle, Bone, and Brain Function in Older Adults: A Narrative Review. J. Diet. Suppl. 2021, 1–18.
    55. Moon, A.; Heywood, L.; Rutherford, S.; Cobbold, C. Creatine supplementation: Can it improve quality of life in the elderly without associated resistance training? Curr. Aging Sci. 2013, 6, 251–257.
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