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New insights into the trophic and cytoprotective effects of creatine in in vitro and in vivo models of cell maturation

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Abstract

A growing body of scientific reports indicates that the role of creatine (Cr) in cellular biochemistry and physiology goes beyond its contribution to cell energy. Indeed Cr has been shown to exert multiple effects promoting a wide range of physiological responses in vitro as well as in vivo. Included in these, Cr promotes in vitro neuron and muscle cell differentiation, viability and survival under normal or adverse conditions; anabolic, protective and pro-differentiative effects have also been observed in vivo. For example Cr has been shown to accelerate in vitro differentiation of cultured C2C12 myoblasts into myotubes, where it also induces a slight but significant hypertrophic effect as compared to unsupplemented cultures; Cr also prevents the anti-differentiation effects caused by oxidative stress in the same cells. In trained adults, Cr increases the mRNA expression of relevant myogemic factors, protein synthesis, muscle strength and size, in cooperation with physical exercise. As to neurons and central nervous system, Cr favors the electrophysiological maturation of chick neuroblasts in vitro and protects them from oxidative stress-caused killing; similarly, Cr promotes the survival and differentiation of GABA-ergic neurons in fetal spinal cord cultures in vitro; in vivo, maternal Cr supplementation promotes the morpho-functional development of hippocampal neurons in rat offsprings. This article, which presents also some new experimental data, focuses on the trophic, pro-survival and pro-differentiation effects of Cr and examines the ensuing preventive and therapeutic potential in pathological muscle and brain conditions.

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Abbreviations

AMPK:

AMP-activated protein kinase

AGAT:

Arginine:glycine amidinotransferase

BBB:

Blood–brain barrier

CNS:

Central nervous system

Cr:

Creatine

PCr:

Phospho-creatine

CK:

Creatine kinase

CrT:

Creatine transporter

GSH:

Glutathione

GAMT:

Guanidinoacetate methyltransferase

LTP:

Long-term potentiation

ROS:

Reactive oxygen species

SM:

Skeletal muscle

References

  • Adcock KH, Nedelcu J, Loenneker T, Martin E, Wallimann T, Wagner BP (2002) Neuroprotection of creatine supplementation in neonatal rats with transient cerebral hypoxia-ischemia. Dev Neurosci 24(5):382–388

    Article  CAS  PubMed  Google Scholar 

  • Alfieri RR, Bonelli MA, Cavazzoni A, Brigotti M, Fumarola C, Sestili P, Mozzoni P, De Palma G, Mutti A, Carnicelli D, Vacondio F, Silva C, Borghetti AF, Wheeler KP, Petronini PG (2006) Creatine as a compatible osmolyte in muscle cells exposed to hypertonic stress. J Physiol 576(Pt 2):391–401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allahyar R, Iqbal F (2014) Creatine monohydrate supplemented diets affect serum inflammatory cytokine levels (IL-6 and IL-18) in female albino mice following neonatal hypoxic ischemic encephalopathy. Pak J Zool 46(5):1311–1315

    CAS  Google Scholar 

  • Allahyar R, Akbar A, Iqbal F (2015) Creatine monohydrate supplementation for 10 weeks mediates neuroprotection and improves learning/memory following neonatal hypoxia ischemia encephalopathy in female albino mice. Brain Res 1595:92–100

    Article  CAS  Google Scholar 

  • Allen PJ (2012) Creatine metabolism and psychiatric disorders: does creatine supplementation have therapeutic value? Neurosci Biobehav Rev 36(5):1442–1462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allen PJ, DeBold JF, Rios M, Kanarek RB (2015) Chronic high-dose creatine has opposing effects on depression-related gene expression and behavior in intact and sex hormone-treated gonadectomized male and female rats. Pharmacol Biochem Behav 130:22–33

    Article  CAS  PubMed  Google Scholar 

  • Almeida LS, Salomons GS, Hogenboom F, Jakobs C, Schoffelmeer AN (2006) Exocytotic release of creatine in rat brain. Synapse 60(2):118–123

    Article  CAS  PubMed  Google Scholar 

  • Alves CR, Ferreira JC, de Siqueira-Filho MA, Carvalho CR, Lancha AH Jr, Gualano B (2012) Creatine-induced glucose uptake in type 2 diabetes: a role for AMPK-alpha? Amino Acids 43(4):1803–1807

    Article  CAS  PubMed  Google Scholar 

  • Andres R, Ducray A, Huber A, Pérez-Bouza A, Krebs S, Schlattner U, Seiler R, Wallimann T, Widmer HR (2005) Effects of creatine treatment on survival and differentiation of GABA-ergic neurons in cultured striatal tissue. J Neurochem 95(1):33–45

    Article  CAS  PubMed  Google Scholar 

  • Andres RH, Ducray AD, Schlattner U, Wallimann T, Widmer HR (2008) Functions and effects of creatine in the central nervous system. Brain Res Bull 76(4):329–343

    Article  CAS  PubMed  Google Scholar 

  • Ardite E, Barbera JA, Roca J, Fernandez-Checa JC (2004) Glutathione depletion impairs myogenic differentiation of murine skeletal muscle C2C12 cells through sustained NF-kappaB activation. Am J Pathol 165(3):719–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barbieri E, Sestili P (2012) Reactive oxygen species in skeletal muscle signaling. J Signal Transduct 2012:982794

    Article  PubMed  CAS  Google Scholar 

  • Barbieri E, Battistelli M, Casadei L, Vallorani L, Piccoli G, Guescini M, Gioacchini AM, Polidori E, Zeppa S, Ceccaroli P, Stocchi L, Stocchi V, Falcieri E (2011) Morphofunctional and biochemical approaches for studying mitochondrial changes during myoblasts differentiation. J Aging Res 2011:845379

    Article  PubMed  PubMed Central  Google Scholar 

  • Barbieri E, Calcabrini C, Guescini M, Vallorani L, Luchetti F, Canonico B, Ciacci C, Casadei L, Gioacchini AM, Battistelli M, Falcieri E, Stocchi V, Sandri M, Sestili P (2013a) Creatine supplementation enhances the mitochondrial function in oxidatively injured myoblasts. Eur J Transl Myol Basic Appl Myol 23:130–131

    Google Scholar 

  • Barbieri E, Sestili P, Vallorani L, Guescini M, Calcabrini C, Gioacchini AM, Annibalini G, Lucertini F, Piccoli G, Stocchi V (2013b) Mitohormesis in muscle cells: a morphological, molecular, and proteomic approach. Muscles Ligaments Tendons J 3(4):254–266

    PubMed  Google Scholar 

  • Beal MF (2011) Neuroprotective effects of creatine. Amino Acids 40(5):1305–1313

    Article  CAS  PubMed  Google Scholar 

  • Bender A, Beckers J, Schneider I, Holter SM, Haack T, Ruthsatz T, Vogt-Weisenhorn DM, Becker L, Genius J, Rujescu D, Irmler M, Mijalski T, Mader M, Quintanilla-Martinez L, Fuchs H, Gailus-Durner V, de Angelis MH, Wurst W, Schmidt J, Klopstock T (2008) Creatine improves health and survival of mice. Neurobiol Aging 29(9):1404–1411

    Article  CAS  PubMed  Google Scholar 

  • Berneburg M, Gremmel T, Kurten V, Schroeder P, Hertel I, von Mikecz A, Wild S, Chen M, Declercq L, Matsui M, Ruzicka T, Krutmann J (2005) Creatine supplementation normalizes mutagenesis of mitochondrial DNA as well as functional consequences. J Invest Dermatol 125(2):213–220

    CAS  PubMed  Google Scholar 

  • Berti SL, Nasi GM, Garcia C, Castro FL, Nunes ML, Rojas DB, Moraes TB, Dutra-Filho CS, Wannmacher CM (2012) Pyruvate and creatine prevent oxidative stress and behavioral alterations caused by phenylalanine administration into hippocampus of rats. Metab Brain Dis 27(1):79–89

    Article  CAS  PubMed  Google Scholar 

  • Bortoluzzi VT, de Franceschi ID, Rieger E, Wannmacher CM (2014) Co-administration of creatine plus pyruvate prevents the effects of phenylalanine administration to female rats during pregnancy and lactation on enzymes activity of energy metabolism in cerebral cortex and hippocampus of the offspring. Neurochem Res 39(8):1594–1602

    Article  CAS  PubMed  Google Scholar 

  • Bothwell JH, Styles P, Bhakoo KK (2002) Swelling-activated taurine and creatine effluxes from rat cortical astrocytes are pharmacologically distinct. J Membr Biol 185(2):157–164

    Article  CAS  PubMed  Google Scholar 

  • Braissant O, Henry H, Villard AM, Speer O, Wallimann T, Bachmann C (2005) Creatine synthesis and transport during rat embryogenesis: spatiotemporal expression of AGAT, GAMT and CT1. BMC Dev Biol 5:9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Braissant O, Bachmann C, Henry H (2007) Expression and function of AGAT, GAMT and CT1 in the mammalian brain. Subcell Biochem 46:67–81

    Article  PubMed  Google Scholar 

  • Braissant O, Henry H, Beard E, Uldry J (2011) Creatine deficiency syndromes and the importance of creatine synthesis in the brain. Amino Acids 40(5):1315–1324

    Article  CAS  PubMed  Google Scholar 

  • Buck M, Chojkier M (1996) Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants. EMBO J 15(8):1753–1765

    CAS  PubMed  PubMed Central  Google Scholar 

  • Burke DG, Candow DG, Chilibeck PD, MacNeil LG, Roy BD, Tarnopolsky MA, Ziegenfuss T (2008) Effect of creatine supplementation and resistance-exercise training on muscle insulin-like growth factor in young adults. Int J Sport Nutr Exerc Metab 18(4):389–398

    CAS  PubMed  Google Scholar 

  • Candow DG (2011) Sarcopenia: current theories and the potential beneficial effect of creatine application strategies. Biogerontology 12(4):273–281

    Article  CAS  PubMed  Google Scholar 

  • Candow DG, Chilibeck PD, Forbes SC (2014) Creatine supplementation and aging musculoskeletal health. Endocrine 45(3):354–361

    Article  CAS  PubMed  Google Scholar 

  • Cannata DJ, Ireland Z, Dickinson H, Snow RJ, Russell AP, West JM, Walker DW (2010) Maternal creatine supplementation from mid-pregnancy protects the diaphragm of the newborn spiny mouse from intrapartum hypoxia-induced damage. Pediatr Res 68(5):393–398

    CAS  PubMed  Google Scholar 

  • Caretti A, Bianciardi P, Marini M, Abruzzo PM, Bolotta A, Terruzzi C, Lucchina F, Samaja M (2013) Supplementation of creatine and ribose prevents apoptosis and right ventricle hypertrophy in hypoxic hearts. Curr Pharm Des 19(39):6873–6879

    Article  CAS  PubMed  Google Scholar 

  • Ceddia RB, Sweeney G (2004) Creatine supplementation increases glucose oxidation and AMPK phosphorylation and reduces lactate production in L6 rat skeletal muscle cells. J Physiol 555(Pt 2):409–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charge SB, Rudnicki MA (2004) Cellular and molecular regulation of muscle regeneration. Physiol Rev 84(1):209–238

    Article  CAS  PubMed  Google Scholar 

  • Christie DL (2007) Functional insights into the creatine transporter. Subcell Biochem 46:99–118

    Article  PubMed  Google Scholar 

  • Collins CA, Olsen I, Zammit PS, Heslop L, Petrie A, Partridge TA, Morgan JE (2005) Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell 122(2):289–301

    Article  CAS  PubMed  Google Scholar 

  • Coughlan KA, Valentine RJ, Ruderman NB, Saha AK (2014) AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab Syndr Obes 7:241–253

    PubMed  PubMed Central  Google Scholar 

  • Cunha MP, Martin-de-Saavedra MD, Romero A, Parada E, Egea J, Del Barrio L, Rodrigues AL, Lopez MG (2013) Protective effect of creatine against 6-hydroxydopamine-induced cell death in human neuroblastoma SH-SY5Y cells: involvement of intracellular signaling pathways. Neuroscience 238:185–194

    Article  CAS  PubMed  Google Scholar 

  • Darabi S, Tiraihi T, Delshad A, Sadeghizadeh M (2013) A new multistep induction protocol for the transdifferentiation of bone marrow stromal stem cells into GABAergic neuron-like cells. Iran Biomed J 17(1):8–14

    CAS  PubMed  PubMed Central  Google Scholar 

  • Deldicque L, Louis M, Theisen D, Nielens H, Dehoux M, Thissen JP, Rennie MJ, Francaux M (2005) Increased IGF mRNA in human skeletal muscle after creatine supplementation. Med Sci Sports Exerc 37(5):731–736

    Article  CAS  PubMed  Google Scholar 

  • Deldicque L, Theisen D, Bertrand L, Hespel P, Hue L, Francaux M (2007) Creatine enhances differentiation of myogenic C2C12 cells by activating both p38 and Akt/PKB pathways. Am J Physiol Cell Physiol 293(4):C1263–C1271

    Article  CAS  PubMed  Google Scholar 

  • Deminice R, Jordao A (2012) Creatine supplementation reduces oxidative stress biomarkers after acute exercise in rats. Amino Acids 43(2):709–715

    Article  CAS  PubMed  Google Scholar 

  • Di Santo S, Mina A, Ducray A, Widmer HR, Senn P (2014) Creatine supports propagation and promotes neuronal differentiation of inner ear progenitor cells. Neuroreport 25(7):446–451

    PubMed  Google Scholar 

  • Dickinson H, Ellery S, Ireland Z, LaRosa D, Snow R, Walker DW (2014) Creatine supplementation during pregnancy: summary of experimental studies suggesting a treatment to improve fetal and neonatal morbidity and reduce mortality in high-risk human pregnancy. BMC Pregnancy Childbirth 14:150

    Article  PubMed  PubMed Central  Google Scholar 

  • Ding S, Schultz PG (2005) Small molecules and future regenerative medicine. Curr Top Med Chem 5(4):383–395

    Article  CAS  PubMed  Google Scholar 

  • Dolder M, Walzel B, Speer O, Schlattner U, Wallimann T (2003) Inhibition of the mitochondrial permeability transition by creatine kinase substrates. Requirement for microcompartmentation. J Biol Chem 278(20):17760–17766

    Article  CAS  PubMed  Google Scholar 

  • Duan B, Liu DS, Huang Y, Zeng WZ, Wang X, Yu H, Zhu MX, Chen ZY, Xu TL (2012) PI3-kinase/Akt pathway-regulated membrane insertion of acid-sensing ion channel 1a underlies BDNF-induced pain hypersensitivity. J Neurosci 32(18):6351–6363

    Article  CAS  PubMed  Google Scholar 

  • Ducray A, Kipfer S, Huber AW, Andres RH, Seiler RW, Schlattner U, Wallimann T, Widmer HR (2006) Creatine and neurotrophin-4/5 promote survival of nitric oxide synthase-expressing interneurons in striatal cultures. Neurosci Lett 395(1):57–62

    Article  CAS  PubMed  Google Scholar 

  • Ducray AD, Qualls R, Schlattner U, Andres RH, Dreher E, Seiler RW, Wallimann T, Widmer HR (2007a) Creatine promotes the GABAergic phenotype in human fetal spinal cord cultures. Brain Res 1137(1):50–57

    Article  CAS  PubMed  Google Scholar 

  • Ducray AD, Schlappi JA, Qualls R, Andres RH, Seiler RW, Schlattner U, Wallimann T, Widmer HR (2007b) Creatine treatment promotes differentiation of GABA-ergic neuronal precursors in cultured fetal rat spinal cord. J Neurosci Res 85(9):1863–1875

    Article  CAS  PubMed  Google Scholar 

  • Ellery SJ, Ireland Z, Kett MM, Snow R, Walker DW, Dickinson H (2013) Creatine pretreatment prevents birth asphyxia-induced injury of the newborn spiny mouse kidney. Pediatr Res 73(2):201–208

    Article  CAS  PubMed  Google Scholar 

  • Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, Kaddurah-Daouk R, Hersch SM, Beal MF (2000) Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci 20(12):4389–4397

    CAS  PubMed  Google Scholar 

  • Fimognari C, Sestili P, Lenzi M, Cantelli-Forti G, Hrelia P (2009) Protective effect of creatine against RNA damage. Mutat Res 670(1–2):59–67

    Article  CAS  PubMed  Google Scholar 

  • Forcales SV, Puri PL (2005) Signaling to the chromatin during skeletal myogenesis: novel targets for pharmacological modulation of gene expression. Semin Cell Dev Biol 16(4–5):596–611

    Article  CAS  PubMed  Google Scholar 

  • Fu X, Zhao JX, Zhu MJ, Foretz M, Viollet B, Dodson MV, Du M (2013) AMP-activated protein kinase alpha1 but not alpha2 catalytic subunit potentiates myogenin expression and myogenesis. Mol Cell Biol 33(22):4517–4525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerber I, ap Gwynn I, Alini M, Wallimann T (2005) Stimulatory effects of creatine on metabolic activity, differentiation and mineralization of primary osteoblast-like cells in monolayer and micromass cell cultures. Eur Cell Mater 10:8–22

    CAS  PubMed  Google Scholar 

  • Gualano B, Roschel H, Lancha-Jr AH, Brightbill CE, Rawson ES (2012) In sickness and in health: the widespread application of creatine supplementation. Amino Acids 43(2):519–529

    Article  CAS  PubMed  Google Scholar 

  • Guidi C, Potenza L, Sestili P, Martinelli C, Guescini M, Stocchi L, Zeppa S, Polidori E, Annibalini G, Stocchi V (2008) Differential effect of creatine on oxidatively-injured mitochondrial and nuclear DNA. Biochim Biophys Acta 1780(1):16–26

    Article  CAS  PubMed  Google Scholar 

  • Guimaraes-Ferreira L, Pinheiro CH, Gerlinger-Romero F, Vitzel KF, Nachbar RT, Curi R, Nunes MT (2012) Short-term creatine supplementation decreases reactive oxygen species content with no changes in expression and activity of antioxidant enzymes in skeletal muscle. Eur J Appl Physiol 112(11):3905–3911

    Article  CAS  PubMed  Google Scholar 

  • Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30(2):214–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamai N, Nakamura M, Asano A (1997) Inhibition of mitochondrial protein synthesis impaired C2C12 myoblast differentiation. Cell Struct Funct 22(4):421–431

    Article  CAS  PubMed  Google Scholar 

  • Handschin C, Spiegelman BM (2006) Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev 27(7):728–735

    Article  CAS  PubMed  Google Scholar 

  • Hansen JM, Klass M, Harris C, Csete M (2007) A reducing redox environment promotes C2C12 myogenesis: implications for regeneration in aged muscle. Cell Biol Int 31(6):546–553

    Article  CAS  PubMed  Google Scholar 

  • Herzberg NH, Zwart R, Wolterman RA, Ruiter JP, Wanders RJ, Bolhuis PA, van den Bogert C (1993) Differentiation and proliferation of respiration-deficient human myoblasts. Biochim Biophys Acta 1181(1):63–67

    Article  CAS  PubMed  Google Scholar 

  • Hespel P, Op’t Eijnde B, Van Leemputte M, Urso B, Greenhaff PL, Labarque V, Dymarkowski S, Van Hecke P, Richter EA (2001) Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans. J Physiol 536(Pt 2):625–633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holterman CE, Rudnicki MA (2005) Molecular regulation of satellite cell function. Semin Cell Dev Biol 16(4–5):575–584

    Article  CAS  PubMed  Google Scholar 

  • Holtzman D, Togliatti A, Khait I, Jensen F (1998) Creatine increases survival and suppresses seizures in the hypoxic immature rat. Pediatr Res 44(3):410–414

    Article  CAS  PubMed  Google Scholar 

  • Hosamani R, Ramesh SR, Muralidhara (2010) Attenuation of rotenone-induced mitochondrial oxidative damage and neurotoxicty in Drosophila melanogaster supplemented with creatine. Neurochem Res 35(9):1402–1412

    Article  CAS  PubMed  Google Scholar 

  • Ingwall JS (1976) Creatine and the control of muscle-specific protein synthesis in cardiac and skeletal muscle. Circ Res 38(5 Suppl 1):I115–I123

    CAS  PubMed  Google Scholar 

  • Ingwall JS, Morales MF, Stockdale FE (1972) Creatine and the control of myosin synthesis in differentiating skeletal muscle. Proc Natl Acad Sci USA 69(8):2250–2253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ipsiroglu OS, Stromberger C, Ilas J, Hoger H, Muhl A, Stockler-Ipsiroglu S (2001) Changes of tissue creatine concentrations upon oral supplementation of creatine-monohydrate in various animal species. Life Sci 69(15):1805–1815

    Article  CAS  PubMed  Google Scholar 

  • Ireland Z, Dickinson H, Snow R, Walker DW (2008) Maternal creatine: does it reach the fetus and improve survival after an acute hypoxic episode in the spiny mouse (Acomys cahirinus)? Am J Obstet Gynecol 198(4):e431–e436

    Article  CAS  Google Scholar 

  • Ireland Z, Russell AP, Wallimann T, Walker DW, Snow R (2009) Developmental changes in the expression of creatine synthesizing enzymes and creatine transporter in a precocial rodent, the spiny mouse. BMC Dev Biol 9:39

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ireland Z, Castillo-Melendez M, Dickinson H, Snow R, Walker DW (2011) A maternal diet supplemented with creatine from mid-pregnancy protects the newborn spiny mouse brain from birth hypoxia. Neuroscience 194:372–379

    Article  CAS  PubMed  Google Scholar 

  • Jacquemin V, Butler-Browne GS, Furling D, Mouly V (2007) IL-13 mediates the recruitment of reserve cells for fusion during IGF-1-induced hypertrophy of human myotubes. J Cell Sci 120(Pt 4):670–681

    Article  CAS  PubMed  Google Scholar 

  • Jager S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA 104(29):12017–12022

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kley RA, Tarnopolsky MA, Vorgerd M (2011) Creatine for treating muscle disorders. Cochrane Database Syst Rev 6:CD004760

    Google Scholar 

  • Langen RC, Schols AM, Kelders MC, Van Der Velden JL, Wouters EF, Janssen-Heininger YM (2002) Tumor necrosis factor-alpha inhibits myogenesis through redox-dependent and -independent pathways. Am J Physiol Cell Physiol 283(3):C714–C721

    Article  CAS  PubMed  Google Scholar 

  • Lenz H, Schmidt M, Welge V, Schlattner U, Wallimann T, Elsasser HP, Wittern KP, Wenck H, Stab F, Blatt T (2005) The creatine kinase system in human skin: protective effects of creatine against oxidative and UV damage in vitro and in vivo. J Invest Dermatol 124(2):443–452

    Article  CAS  PubMed  Google Scholar 

  • Li XX, Tsoi B, Li YF, Kurihara H, He RR (2015) Cardiolipin and its different properties in mitophagy and apoptosis. J Histochem Cytochem 63(5):301–311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Wang LN (2014) Mitochondrial enhancement for neurodegenerative movement disorders: a systematic review of trials involving creatine, coenzyme Q10, idebenone and mitoquinone. CNS Drugs 28(1):63–68

    Article  PubMed  CAS  Google Scholar 

  • Louis M, Van Beneden R, Dehoux M, Thissen JP, Francaux M (2004) Creatine increases IGF-I and myogenic regulatory factor mRNA in C2C12 cells. FEBS Lett 557(1–3):243–247

    Article  CAS  PubMed  Google Scholar 

  • Lowe DA, Lund T, Alway SE (1998) Hypertrophy-stimulated myogenic regulatory factor mRNA increases are attenuated in fast muscle of aged quails. Am J Physiol 275(1 Pt 1):C155–C162

    CAS  PubMed  Google Scholar 

  • Lu Z, Xu X, Hu X, Fassett J, Zhu G, Tao Y, Li J, Huang Y, Zhang P, Zhao B, Chen Y (2010) PGC-1 alpha regulates expression of myocardial mitochondrial antioxidants and myocardial oxidative stress after chronic systolic overload. Antioxid Redox Signal 13(7):1011–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malcon C, Kaddurah-Daouk R, Beal MF (2000) Neuroprotective effects of creatine administration against NMDA and malonate toxicity. Brain Res 860(1):195–198

    Article  CAS  PubMed  Google Scholar 

  • Mazibuko SE, Muller CJ, Joubert E, de Beer D, Johnson R, Opoku AR, Louw J (2013) Amelioration of palmitate-induced insulin resistance in C(2)C(1)(2) muscle cells by rooibos (Aspalathus linearis). Phytomedicine 20(10):813–819

    Article  CAS  PubMed  Google Scholar 

  • Messina S, Bitto A, Aguennouz M, Minutoli L, Monici MC, Altavilla D, Squadrito F, Vita G (2006) Nuclear factor kappa-B blockade reduces skeletal muscle degeneration and enhances muscle function in Mdx mice. Exp Neurol 198(1):234–241

    Article  CAS  PubMed  Google Scholar 

  • Meyer LE, Machado LB, Santiago AP, da-Silva WS, De Felice FG, Holub O, Oliveira MF, Galina A (2006) Mitochondrial creatine kinase activity prevents reactive oxygen species generation: antioxidant role of mitochondrial kinase-dependent ADP re-cycling activity. J Biol Chem 281(49):37361–37371

    Article  CAS  PubMed  Google Scholar 

  • Mobley CB, Fox CD, Ferguson BS, Amin RH, Dalbo VJ, Baier S, Rathmacher JA, Wilson JM, Roberts MD (2014) L-leucine, beta-hydroxy-beta-methylbutyric acid (HMB) and creatine monohydrate prevent myostatin-induced Akirin-1/Mighty mRNA down-regulation and myotube atrophy. J Int Soc Sports Nutr 11:38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mohammad-Gharibani P, Tiraihi T, Mesbah-Namin SA, Arabkheradmand J, Kazemi H (2012) Induction of bone marrow stromal cells into GABAergic neuronal phenotype using creatine as inducer. Restor Neurol Neurosci 30(6):511–525

    CAS  PubMed  Google Scholar 

  • Moon A, Heywood L, Rutherford S, Cobbold C (2013) Creatine supplementation: can it improve quality of life in the elderly without associated resistance training? Curr Aging Sci 6(3):251–257

    Article  CAS  PubMed  Google Scholar 

  • Moraes R, Van Bavel D, Moraes BS, Tibirica E (2014) Effects of dietary creatine supplementation on systemic microvascular density and reactivity in healthy young adults. Nutr J 13(1):115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Naia L, Ribeiro MJ, Rego AC (2011) Mitochondrial and metabolic-based protective strategies in Huntington’s disease: the case of creatine and coenzyme Q. Rev Neurosci 23(1):13–28

    PubMed  Google Scholar 

  • Nasrallah F, Feki M, Kaabachi N (2010) Creatine and creatine deficiency syndromes: biochemical and clinical aspects. Pediatr Neurol 42(3):163–171

    Article  PubMed  Google Scholar 

  • Nomura A, Zhang M, Sakamoto T, Ishii Y, Morishima Y, Mochizuki M, Kimura T, Uchida Y, Sekizawa K (2003) Anti-inflammatory activity of creatine supplementation in endothelial cells in vitro. Br J Pharmacol 139(4):715–720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohira Y, Matsuoka Y, Kawano F, Ogura A, Higo Y, Ohira T, Terada M, Oke Y, Nakai N (2011) Effects of creatine and its analog, beta-guanidinopropionic acid, on the differentiation of and nucleoli in myoblasts. Biosci Biotechnol Biochem 75(6):1085–1089

    Article  CAS  PubMed  Google Scholar 

  • Olsen S, Aagaard P, Kadi F, Tufekovic G, Verney J, Olesen JL, Suetta C, Kjaer M (2006) Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training. J Physiol 573(Pt 2):525–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Otten JV, Fitch CD, Wheatley JB, Fischer VW (1986) Thyrotoxic myopathy in mice: accentuation by a creatine transport inhibitor. Metabolism 35(6):481–484

    Article  CAS  PubMed  Google Scholar 

  • Owen L, Sunram-Lea SI (2011) Metabolic agents that enhance ATP can improve cognitive functioning: a review of the evidence for glucose, oxygen, pyruvate, creatine, and L-carnitine. Nutrients 3(8):735–755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Partridge TA, Grounds M, Sloper JC (1978) Evidence of fusion between host and donor myoblasts in skeletal muscle grafts. Nature 273(5660):306–308

    Article  CAS  PubMed  Google Scholar 

  • Passaquin AC, Renard M, Kay L, Challet C, Mokhtarian A, Wallimann T, Ruegg UT (2002) Creatine supplementation reduces skeletal muscle degeneration and enhances mitochondrial function in mdx mice. Neuromuscul Disord: NMD 12(2):174–182

    Article  PubMed  Google Scholar 

  • Pena-Altamira E, Crochemore C, Virgili M, Contestabile A (2005) Contestabile A (2005) Neurochemical correlates of differential neuroprotection by long-term dietary creatine supplementation. Brain Res 1058(1–2):183–188

    Article  CAS  PubMed  Google Scholar 

  • Perasso L, Spallarossa P, Gandolfo C, Ruggeri P, Balestrino M (2013) Therapeutic use of creatine in brain or heart ischemia: available data and future perspectives. Med Res Rev 33(2):336–363

    Article  CAS  PubMed  Google Scholar 

  • Pizza FX, Peterson JM, Baas JH, Koh TJ (2005) Neutrophils contribute to muscle injury and impair its resolution after lengthening contractions in mice. J Physiol 562(Pt 3):899–913

    Article  CAS  PubMed  Google Scholar 

  • Pold R, Jensen LS, Jessen N, Buhl ES, Schmitz O, Flyvbjerg A, Fujii N, Goodyear LJ, Gotfredsen CF, Brand CL, Lund S (2005) Long-term AICAR administration and exercise prevents diabetes in ZDF rats. Diabetes 54(4):928–934

    Article  CAS  PubMed  Google Scholar 

  • Pourrajab F, Babaei Zarch M, Baghi Yazdi M, Rahimi Zarchi A, Vakili Zarch A (2014) Application of stem cell/growth factor system, as a multimodal therapy approach in regenerative medicine to improve cell therapy yields. Int J Cardiol 173(1):12–19

    Article  PubMed  Google Scholar 

  • Prass K, Royl G, Lindauer U, Freyer D, Megow D, Dirnagl U, Stockler-Ipsiroglu G, Wallimann T, Priller J (2007) Improved reperfusion and neuroprotection by creatine in a mouse model of stroke. J Cereb Blood Flow Metab 27(3):452–459

    Article  CAS  PubMed  Google Scholar 

  • Rae CD, Broer S (2015) Creatine as a booster for human brain function. How might it work? Neurochem Int 89:249–259

    Article  CAS  PubMed  Google Scholar 

  • Rahimi R (2011) Creatine supplementation decreases oxidative DNA damage and lipid peroxidation induced by a single bout of resistance exercise. J Strength Cond Res 25(12):3448–3455

    Article  PubMed  Google Scholar 

  • Rambo L, Ribeiro L, Della-Pace I, Stamm D, da Rosa GR, Prigol M, Pinton S, Nogueira C, Furian A, Oliveira M, Fighera M, Royes L (2013) Acute creatine administration improves mitochondrial membrane potential and protects against pentylenetetrazol-induced seizures. Amino Acids 44(3):857–868

    Article  CAS  PubMed  Google Scholar 

  • Ribas F, Villarroya J, Hondares E, Giralt M, Villarroya F (2014) FGF21 expression and release in muscle cells: involvement of MyoD and regulation by mitochondria-driven signalling. Biochem J 463(2):191–199

    Article  CAS  PubMed  Google Scholar 

  • Rochard P, Rodier A, Casas F, Cassar-Malek I, Marchal-Victorion S, Daury L, Wrutniak C, Cabello G (2000) Mitochondrial activity is involved in the regulation of myoblast differentiation through myogenin expression and activity of myogenic factors. J Biol Chem 275(4):2733–2744

    Article  CAS  PubMed  Google Scholar 

  • Sabourin LA, Rudnicki MA (2000) The molecular regulation of myogenesis. Clin Genet 57(1):16–25

    Article  CAS  PubMed  Google Scholar 

  • Safdar A, Yardley NJ, Snow R, Melov S, Tarnopolsky MA (2008) Global and targeted gene expression and protein content in skeletal muscle of young men following short-term creatine monohydrate supplementation. Physiol Genomics 32(2):219–228

    Article  CAS  PubMed  Google Scholar 

  • Saks V, Kaambre T, Guzun R, Anmann T, Sikk P, Schlattner U, Wallimann T, Aliev M, Vendelin M (2007) The creatine kinase phosphotransfer network: thermodynamic and kinetic considerations, the impact of the mitochondrial outer membrane and modelling approaches. Subcell Biochem 46:27–65

    Article  PubMed  Google Scholar 

  • Santiago AP, Chaves EA, Oliveira MF, Galina A (2008) Reactive oxygen species generation is modulated by mitochondrial kinases: correlation with mitochondrial antioxidant peroxidases in rat tissues. Biochimie 90(10):1566–1577

    Article  CAS  PubMed  Google Scholar 

  • Saraiva AL, Ferreira AP, Silva LF, Hoffmann MS, Dutra FD, Furian AF, Oliveira MS, Fighera MR, Royes LF (2012) Creatine reduces oxidative stress markers but does not protect against seizure susceptibility after severe traumatic brain injury. Brain Res Bull 87(2–3):180–186

    Article  CAS  PubMed  Google Scholar 

  • Sartini S, Sestili P, Colombo E, Martinelli C, Bartolini F, Ciuffoli S, Lattanzi D, Sisti D, Cuppini R (2012) Creatine affects in vitro electrophysiological maturation of neuroblasts and protects them from oxidative stress. J Neurosci Res 90(2):435–446

    Article  CAS  PubMed  Google Scholar 

  • Sartini S, Lattanzi D, Ambrogini P, Di Palma M, Galati C, Savelli D, Polidori E, Calcabrini C, Rocchi MB, Sestili P, Cuppini R (2015) Maternal creatine supplementation affects the morpho-functional development of hippocampal neurons in rat offspring. Neuroscience 312:120–129

    Article  PubMed  CAS  Google Scholar 

  • Schulze A (2013) Creatine deficiency syndromes. Handb Clin Neurol 113:1837–1843

    Article  PubMed  Google Scholar 

  • Sestili P, Martinelli C, Bravi G, Piccoli G, Curci R, Battistelli M, Falcieri E, Agostini D, Gioacchini AM, Stocchi V (2006) Creatine supplementation affords cytoprotection in oxidatively injured cultured mammalian cells via direct antioxidant activity. Free Radic Biol Med 40(5):837–849

    Article  CAS  PubMed  Google Scholar 

  • Sestili P, Barbieri E, Martinelli C, Battistelli M, Guescini M, Vallorani L, Casadei L, D’Emilio A, Falcieri E, Piccoli G, Agostini D, Annibalini G, Paolillo M, Gioacchini AM, Stocchi V (2009) Creatine supplementation prevents the inhibition of myogenic differentiation in oxidatively injured C2C12 murine myoblasts. Mol Nutr Food Res 53(9):1187–1204

    Article  CAS  PubMed  Google Scholar 

  • Sestili P, Martinelli C, Colombo E, Barbieri E, Potenza L, Sartini S, Fimognari C (2011) Creatine as an antioxidant. Amino Acids 40(5):1385–1396

    Article  CAS  PubMed  Google Scholar 

  • Sestili P, Barbieri E, Stocchi V (2015) Effects of creatine in skeletal muscle cells and in myoblasts differentiating under normal or oxidatively stressing conditions. Mini Rev Med Chem 16(1):4–11

    Article  CAS  Google Scholar 

  • Shamban AT (2009) Current and new treatments of photodamaged skin. Facial Plast Surg 25(5):337–346

    Article  CAS  PubMed  Google Scholar 

  • Singh S, Canseco DC, Manda SM, Shelton JM, Chirumamilla RR, Goetsch SC, Ye Q, Gerard RD, Schneider JW, Richardson JA, Rothermel BA, Mammen PP (2014) Cytoglobin modulates myogenic progenitor cell viability and muscle regeneration. Proc Natl Acad Sci USA 111(1):E129–E138

    Article  CAS  PubMed  Google Scholar 

  • Smith RN, Agharkar AS, Gonzales EB (2014) A review of creatine supplementation in age-related diseases: more than a supplement for athletes. F1000Res 3:222

    PubMed  PubMed Central  Google Scholar 

  • Stevens PR, Gawryluk JW, Hui L, Chen X, Geiger JD (2014) Creatine protects against mitochondrial dysfunction associated with HIV-1 Tat-induced neuronal injury. Curr HIV Res 12(6):378–387

    Article  CAS  PubMed  Google Scholar 

  • Tang JM, Wang JN, Zhang L, Zheng F, Yang JY, Kong X, Guo LY, Chen L, Huang YZ, Wan Y, Chen SY (2011) VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovasc Res 91(3):402–411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tarnopolsky MA (2007) Clinical use of creatine in neuromuscular and neurometabolic disorders. Subcell Biochem 46:183–204

    Article  PubMed  Google Scholar 

  • Tarnopolsky MA (2011) Creatine as a therapeutic strategy for myopathies. Amino Acids 40(5):1397–1407

    Article  CAS  PubMed  Google Scholar 

  • Tidball JG (2005) Inflammatory processes in muscle injury and repair. Am J Physiol Regul Integr Comp Physiol 288(2):R345–R353

    Article  CAS  PubMed  Google Scholar 

  • Toscano A, Messina S, Campo GM, Di Leo R, Musumeci O, Rodolico C, Aguennouz M, Annesi G, Messina C, Vita G (2005) Oxidative stress in myotonic dystrophy type 1. Free Radic Res 39(7):771–776

    Article  CAS  PubMed  Google Scholar 

  • Vierck JL, Icenoggle DL, Bucci L, Dodson MV (2003) The effects of ergogenic compounds on myogenic satellite cells. Med Sci Sports Exerc 35(5):769–776

    Article  CAS  PubMed  Google Scholar 

  • Wallimann T (2015) The extended, dynamic mitochondrial reticulum in skeletal muscle and the creatine kinase (CK)/phosphocreatine (PCr) shuttle are working hand in hand for optimal energy provision. J Muscle Res Cell Motil 36(4):297–300

    Article  PubMed  Google Scholar 

  • Wallimann T, Tokarska-Schlattner M, Schlattner U (2011) The creatine kinase system and pleiotropic effects of creatine. Amino Acids 40(5):1271–1296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williamson DL, Butler DC, Alway SE (2009) AMPK inhibits myoblast differentiation through a PGC-1alpha-dependent mechanism. Am J Physiol Endocrinol Metab 297(2):E304–E314

    Article  CAS  PubMed  Google Scholar 

  • Willoughby DS, Rosene J (2001) Effects of oral creatine and resistance training on myosin heavy chain expression. Med Sci Sports Exerc 33(10):1674–1681

    Article  CAS  PubMed  Google Scholar 

  • Willoughby DS, Rosene JM (2003) Effects of oral creatine and resistance training on myogenic regulatory factor expression. Med Sci Sports Exerc 35(6):923–929

    Article  CAS  PubMed  Google Scholar 

  • Wyss M, Braissant O, Pischel I, Salomons GS, Schulze A, Stockler S, Wallimann T (2007) Creatine and creatine kinase in health and disease–a bright future ahead? Subcell Biochem 46:309–334

    Article  PubMed  Google Scholar 

  • Young JF, Larsen LB, Malmendal A, Nielsen NC, Straadt IK, Oksbjerg N, Bertram HC (2010) Creatine-induced activation of antioxidative defence in myotube cultures revealed by explorative NMR-based metabonomics and proteomics. J Int Soc Sports Nutr 7(1):7–9

    Article  CAS  Google Scholar 

  • Zaccagnini G, Martelli F, Magenta A, Cencioni C, Fasanaro P, Nicoletti C, Biglioli P, Pelicci PG, Capogrossi MC (2007) p66(ShcA) and oxidative stress modulate myogenic differentiation and skeletal muscle regeneration after hind limb ischemia. J Biol Chem 282(43):31453–31459

    Article  CAS  PubMed  Google Scholar 

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    Authors and Affiliations

    1. Department of Biomolecolar Sciences, Università degli Studi di Urbino Carlo Bo, Via Saffi 2, 61029, Urbino, Italy

      Piero Sestili, Patrizia Ambrogini, Elena Barbieri, Stefano Sartini, Cinzia Calcabrini, Anna Rita Diaz, Michele Guescini, Emanuela Polidori, Francesca Luchetti, Barbara Canonico, Davide Lattanzi, Riccardo Cuppini, Stefano Papa & Vilberto Stocchi

    2. IIM, Interuniversitary Institute of Myology, Padua, Italy

      Elena Barbieri

    3. Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921, Rimini, Italy

      Carmela Fimognari & Cinzia Calcabrini

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    1. Piero Sestili
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    Handling Editor: T. Wallimann and R. Harris.

    P. Ambrogini, E. Barbieri and S. Sartini have contributed equally to this work.

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    Sestili, P., Ambrogini, P., Barbieri, E. et al. New insights into the trophic and cytoprotective effects of creatine in in vitro and in vivo models of cell maturation. Amino Acids 48, 1897–1911 (2016). https://doi.org/10.1007/s00726-015-2161-4

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