Abstract
The serine/threonine kinase AMP-activated protein kinase (AMPK) is a drug target for the treatment of obesity and type 2 diabetes (T2D). Metformin, a widely prescribed anti-hyperglycemic agent, and β-guanidinopropionic acid (β-GPA), a dietary supplement and creatine analog, have been shown to increase activity of AMPK. Macroautophagy is an intracellular degradation pathway for aggregated proteins and dysfunctional organelles, which can be mediated by AMPK. The present study sought to elucidate how metformin and β-GPA affect cell morphology, AMPK activity, autophagy and mitochondrial morphology and function in developing C2C12 myotubes. β-GPA reduced myotube diameter and increased length throughout differentiation, while metformin increased myotube diameter only at the 48 h time point. β-GPA treatment enhanced AMPK signaling and expression of autophagy-related proteins. β-GPA treatment also increased the density of autophagosomes, autolysosomes, and lysosomes. Metformin also increased activation of AMPK after 48 h, but in contrast to β-GPA, led to a dramatic reduction in the density of autophagosomes and lysosomes. Both metformin and β-GPA reduced the mitochondrial oxygen consumption rate, and differentially altered mitochondrial morphology. Obesity and T2D have been shown to increase mitochondrial dysfunction and reduce autophagic flux in skeletal muscle cells. Therefore, β-GPA may help to alleviate the effects of metabolic disease by increasing autophagic flux in skeletal muscle cells. In contrast, the reduction of autophagy by metformin may lead to dysregulation of mitochondrial maintenance, as well as muscle development.
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References
Baumgarner BL, Nagle AM, Quinn MR, Farmer AE, Kinsey ST (2015) Dietary supplementation of beta-guanidinopropionic acid (Beta Gpa) reduces whole-body and skeletal muscle growth in young Cd-1 mice. Mol Cell Biochem 403:1–2. https://doi.org/10.1007/s11010-015-2357-7
Benard G, Bellance N, James D, Parrone P, Fernandez H, Letellier T, Rossignol R (2007) Mitochondrial bioenergetics and structural network organization. J Cell Sci 120:838–848. https://doi.org/10.1242/jcs.03381
Bereiterhahn J, Voth M (1994) Dynamics of mitochondria in living cells - shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech 27(3):198–219. https://doi.org/10.1002/jemt.1070270303
Bergeron R, Ren JM, Cadman KS, Moore IK, Perret P, Pypaert M, Young LH, Semenkovich CF, Shulman GI (2001) Chronic activation of AMP kinase results in Nrf-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab 281(6):E1340–E1346
Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125(7):1241–1252. https://doi.org/10.1016/j.cell.2006.06.010
Chan DC (2012) Fusion and fission: interlinked processes critical for mitochondrial health. Annu Rev Genet 46:265–287
Cusi K, DeFronzo RA (1998) Metformin: a review of its metabolic effects. Diabetes Rev 6(2):89–131
Drake JC, Wilson RJ, Yan Z (2016) Molecular mechanisms for mitochondrial adaptation to exercise training in skeletal muscle. FASEB J 30(1):13–22. https://doi.org/10.1096/fj.15-276337
Egan DF, Kim J, Shaw RJ, Guan KL (2011) The autophagy initiating kinase Ulk1 Is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy 7(6):645–646. https://doi.org/10.4161/auto.7.6.15123
El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275(1):223–228. https://doi.org/10.1074/jbc.275.1.223
Fitch CD, Jellinek M, Fitts RH, Baldwin KM, Holloszy JO (1975) Phosphorylated beta-guanidinopropionate as a substitute for phosphocreatine in rat muscle. Am J Physiol 228(4):1123–1125
Fitch CD, Jellinek M, Mueller EJ (1974) Experimental depletion of creatine and phosphocreatine from skeletal-muscle. J Biol Chem 249(4):1060–1063
Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F, Viollet B (2010) Metformin inhibits hepatic gluconeogenesis in mice independently of the Lkb1/AMPK pathway via a decrease in hepatic energy state. J Clin Investig 120(7):2355–2369. https://doi.org/10.1172/JCI40671
Fryer LGD, Parbu-Patel A, Carling D (2002) The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 277:25226–25232. https://doi.org/10.1074/jbc.M202489200
Galuska D, Nolte LA, Zierath JR, Wallberghenriksson H (1994) Effect of metformin on insulin-stimulated glucose-transport in isolated skeletal-muscle obtained from patients with Niddm. Diabetologia 37:826–832. https://doi.org/10.1007/BF00404340
Ganley IG, Lam DH, Wang JR, Ding XJ, Chen S, Jiang XJ (2009) Ulk1 center Dot Atg13 center dot Fip200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 284(18):12297–12305. https://doi.org/10.1074/jbc.M900573200
Gingras AC, Raught B, Sonenberg N (2001) Regulation of translation initiation by Frap/mTOR. Genes Dev 15(7):807–826. https://doi.org/10.1101/gad.887201
Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13(5):589–207. https://doi.org/10.1038/ncb2220
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. https://doi.org/10.1016/j.molcel.2008.03.003
Hanke N, Meissner JD, Scheibe RJ, Endeward V, Gros G, Kubis HP (2008) Metabolic transformation of rabbit skeletal muscle cells in primary culture in response to low glucose. Biochim Biophys Acta 1783(5):813–825. https://doi.org/10.1016/j.bbamcr.2007.12.012
Hardie DG (2003) Minireview: the Amp-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 144(12):5179–5183. https://doi.org/10.1210/en.2003-0982
Hardie DG (2005) New roles for the Lkb1 - AMPK pathway. Curr Opin Cell Biol 17(2):167–173. https://doi.org/10.1016/j.ceb.2005.01.006
Hardie DG (2007) Amp-activated/Snf1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8(10):774–785. https://doi.org/10.1038/nrm2249
Hardie DG, Salt IP, Hawley SA, Davies SP (1999) AMP-activated protein kinase: an ultrasensitive system for monitoring cellular energy charge. Biochem J 338:717–722. https://doi.org/10.1042/0264-6021:3380717
Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG (1996) Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem 271(44):27879–27887
Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18(16):1926–1945. https://doi.org/10.1101/gad.1212704
Holmes BF, Kurth-Kraczek EJ, Winder WW (1999) Chronic activation of 5 '-Amp-activated protein kinase increases Glut-4, hexokinase, and glycogen in muscle. J Appl Physiol 87(5):1990–1995
Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S, Natsume T, Takehana K, Yamada N, Guan JL, Oshiro N, Mizushima N (2009) Nutrient-dependent Mtorc1 association with the Ulk1-Atg13-Fip200 complex required for autophagy. Mol Biol Cell 20(7):1981–1991. https://doi.org/10.1091/mbc.E08-12-1248
Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, Shulman GI (2000) Mechanism by which metformin reduces glucose production in type. Diabetes 49(12):2063–2069. https://doi.org/10.2337/diabetes.49.12.2063
Hutber CA, Hardie DG, Winder WW (1997) Electrical stimulation inactivates muscle acetyl-coa carboxylase and increases AMP-activated protein kinase. Am J Physiol Endocrinol Metab 272(2):E262–E266
Iglesias MA, Ye JM, Frangioudakis G, Saha AK, Tomas E, Ruderman NB, Cooney GJ, Kraegen EW (2002) AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats. Diabetes 51(10):2886–2894. https://doi.org/10.2337/diabetes.51.10.2886
Izzo A, Nitti M, Mollo N, Paladino S, Procaccini C, Faicchia D, Cali G, Genesio R, Bonfiglio F, Cicatiello R, Polishchuk E, Polishchuk R, Pinton P, Matarese G, Conti A, Nitsch L (2017) Metformin restores the mitochondrial network and reverses mitochondrial dysfunction in down syndrome cells. Hum Mol Genet 26(6):1056–1069. https://doi.org/10.1093/hmg/ddx016
Jager S, Handschin C, Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of Pgc-1 alpha. Proc Natl Acad Sci USA 104(29):12017–12022. https://doi.org/10.1073/pnas.0705070104
Jheng HF, Tsal PJ, Guo SM, Rua LH, Chang CS, Su IJ, Chang CR, Tsai YS (2012) Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle. Mol Cell Biol 32(2):309–319. https://doi.org/10.1128/MCB.05603-11
Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, Kundu M, Kim DH (2009) Ulk-Atg13-Fip200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20(7):1992–2003. https://doi.org/10.1091/mbc.E08-12-1249
Kabeya Y, Mizushima N, Uero T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T (2000) Lc3, a mammalian homologue of yeast apg8p, is localized in autophagosome membranes after processing. EMBO J 19(21):5720–5728. https://doi.org/10.1093/emboj/19.21.5720
Kelley DE, He J, Menshikova EV, Ritov VB (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51(10):2944–2950. https://doi.org/10.2337/diabetes.51.10.2944
Kim J, Klionsky DJ (2000) Autophagy, cytoplasm-to-vacuole targeting pathway, and pexophagy in yeast and mammalian cells. Annu Rev Biochem 69:303–342. https://doi.org/10.1146/annurev.biochem.69.1.303
Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–171. https://doi.org/10.1038/ncb2152
Kim KH, Lee MS (2014) Autophagy-a key player in cellular and body metabolism. Nat Rev Endocrinol 10(6):322–337. https://doi.org/10.1038/nrendo.2014.35
Kosacka J, Kern M, Klöting N, Paeschke S, Rudich A, Haim Y et al (2015) Autophagy in adipose tissue of patients with obesity and type 2 diabetes. Mol Cell Endocrinol 409:21–32
Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW (1999) 5 ' AMP-activated protein kinase activation causes Glut4 translocation in skeletal muscle. Diabetes 48(8):1667–1671. https://doi.org/10.2337/diabetes.48.8.1667
Laker RC, Xu P, Ryall KA, Sujkowski A, Kenwood BM, Chain KH, Zhang M, Royal MA, Hoehn KL, Driscoll M, Adler PN, Wessells RJ, Saucerman JJ, Yan Z (2014) A novel mitotimer reporter gene for mitochondrial content, structure, stress, and damage in vivo. J Biol Chem 289(17):12005–12015. https://doi.org/10.1074/jbc.M113.530527
Laplante M, Sabatini DM (2009) An emerging role of mTOR in lipid biosynthesis. Curr Biol 19(22):R1046–R1052. https://doi.org/10.1016/j.cub.2009.09.058
Larsen S, Rabol R, Hansen CN, Madsbad S, Helge JW, Dela F (2012) Metformin-treated patients with type 2 diabetes have normal mitochondrial complex I respiration. Diabetologia 55(2):443–449. https://doi.org/10.1007/s00125-011-2340-0
Lemasters JJ (2005) Perspective - selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res 8(1):3–5. https://doi.org/10.1089/rej.2005.8.3
Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6(4):463–477. https://doi.org/10.1016/S1534-5807(04)00099-1
Lira VA, Okutsu M, Zhang M, Greene NP, Laker RC, Breen DS, Hoehn KL, Yan Z (2013) Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. FASEB J 27(10):4184–4193. https://doi.org/10.1096/fj.13-228486
Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, Metzger D, Reggiani C, Schiaffino S, Sandri M (2009) Autophagy is required to maintain muscle mass. Cell Metab 10(6):507–515. https://doi.org/10.1016/j.cmet.2009.10.008
Masini M, Bugliani M, Lupi R, del Guerra S, Boggi U, Filipponi F, Marselli L, Masiello P, Marchetti P (2009) Autophagy in human type 2 diabetes pancreatic beta cells. Diabetologia 52(6):1083–1086. https://doi.org/10.1007/s00125-009-1347-2
Melser S, Chatelain EH, Lavie J, Mahfouf W, Jose C, Obre E, Goorden S, Priault M, Elgersma Y, Rezvani HR, Rossignol R, Benard G (2013) Rheb regulates mitophagy induced by mitochondrial energetic status. Cell Metab 17(5):719–730. https://doi.org/10.1016/j.cmet.2013.03.014
Merrill GF, Kurth EJ, Hardie DG, Winder WW (1997) Aica riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol Endocrinol Metab 273(6):E1107–E1112
Morino K, Petersen KF, Shulman GI (2006) Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55:S9–S15. https://doi.org/10.2337/db06-S002
Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou GC, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ (2002) Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51(7):2074–2081. https://doi.org/10.2337/diabetes.51.7.2074
Nichenko AS, Southern WM, Atuan M, Luan J, Peissig KB, Foltz SJ, Beedle AM, Warren GL, Call JA (2016) Mitochondrial maintenance via autophagy contributes to functional skeletal muscle regeneration and remodeling. Am J Physiol Cell Physiol 311:C190–C200. https://doi.org/10.1152/ajpcell.00066.2016
Oakhill JS, Steel R, Chen ZP, Scott JW, Ling N, Tam S, Kemp BE (2011) Ampk Is a direct adenylate charge-regulated protein kinase. Science 332:1433–1435. https://doi.org/10.1126/science.1200094
Ohira Y, Kawano F, Roy RR, Edgerton VR (2003) Metabolic modulation of muscle fiber properties unrelated to mechanical stimuli. Jpn J Physiol 53(6):389–400. https://doi.org/10.2170/jjphysiol.53.389
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. https://doi.org/10.1271/bbb.100901
Ohira Y, Saito K, Wakatsuki T, Yasui W, Suetsugu T, Nakamura K, Tanaka H, Asakura T (1994) Responses of beta-adrenoceptor in rat soleus to phosphorus compound levels and/or unloading. Am J Physiol 266(5):C1257–C1262
Ota S, Horigome K, Ishii T, Nakai M, Hayashi K, Kawamura T, Kishino A, Taiji M, Kimura T (2009) Metformin suppresses glucose-6-phosphatase expression by a complex I inhibition and AMPK activation-independent mechanism. Biochem Biophys Res Commun 388(2):311–316. https://doi.org/10.1016/j.bbrc.2009.07.164
Pandke KE, Mullen KL, Snook LA, Bonen A, Dyck DJ (2008) Decreasing Intramuscular phosphagen content simultaneously increases plasma membrane Fat/Cd36 and Glut4 transporter abundance. Am J Physiol Regul Integr Comp Physiol 295(3):R806–R813. https://doi.org/10.1152/ajpregu.90540.2008
Pavlidou T, Rosina M, Fuoco C, Gerini G, Gargioli C, Castagnoli L, Cesareni G (2017) Regulation of myoblast differentiation by metabolic perturbations induced by metformin. PLoS ONE 12(8):e0182475. https://doi.org/10.1371/journal.pone.0182475
Ren JM, Ohira Y, Holloszy JO, Hamalainen N, Traub I, Pette D (1995) Effects of beta-guanidinopropionic acid-feeding on the patterns of myosin isoforms in rat fast-twitch muscle. Pflug Arch Eur J Physiol 430(3):389–393. https://doi.org/10.1007/BF00373914
Rena G, Hardie DG, Pearson ER (2017) The mechanisms of action of metformin. Diabetologia 60(9):1577–1585. https://doi.org/10.1007/s00125-017-4342-z
Reznick RM, Shulman GI (2006) The role of AMP-activated protein kinase in mitochondrial biogenesis. J Physiol Lond 574(1):33–39. https://doi.org/10.1113/jphysiol.2006.109512
Reznick RM, Zong HH, Li J, Morino K, Moore IK, Yu HJ, Liu ZX, Dong JY, Mustard KJ, Hawley SA, Befroy D, Pypaert M, Hardie DG, Young LH, Shulman GI (2007) Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab 5(2):151–156. https://doi.org/10.1016/j.cmet.2007.01.008
Ross TT, Overton JD, Houmard KF, Kinsey ST (2017) Beta-GPA treatment leads to elevated basal metabolic rate and enhanced hypoxic exercise tolerance in mice. Physiol Rep 5(5):13192. https://doi.org/10.14814/phy2.13192
Roussel D, Lhenry F, Ecochard L, Sempore B, Rouanet JL, Favier R (2000) Differential effects of endurance training and creatine depletion on regional mitochondrial adaptations in rat skeletal muscle. Biochem J 350:547–553. https://doi.org/10.1042/0264-6021:3500547
Rubinsztein DC, Codogno P, Levine B (2012) Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov 11(9):709–784. https://doi.org/10.1038/nrd3802
Rush JWE, Tullson PC, Terjung RL (1998) Molecular and kinetic alterations of muscle AMP deaminase during chronic creatine depletion. Am J Physiol Cell Physiol 274(2):C465–C471
Saladini S, Aventaggiato M, Barreca F, Morgante E, Sansone L, Russo MA, Tafani M (2019) Metformin impairs glutamine metabolism and autophagy in tumour cells. Cells 8:1–22. https://doi.org/10.3390/cells8010049
Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9(7):676–682. https://doi.org/10.1038/NMETH.2019
Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, DePinho RA, Montminy M, Cantley LC (2005) The kinase Lkb1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310(5754):1642–1646. https://doi.org/10.1126/science.1120781
Shi WY, Xiao D, Wang L, Dong LH, Yan ZX, Shen ZX, Chen SJ, Chen Y, Zhao WL (2012) Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis 3(3):e275. https://doi.org/10.1038/cddis.2012.13
Shields RP, Whitehair CK (1973) Muscle creatine - in-vivo depletion by feeding beta-guanidinopropionic acid. Can J Biochem 51:1046–1049. https://doi.org/10.1139/o73-136
Shoubridge EA, Challiss RAJ, Hayes DJ, Radda GK (1985) Biochemical adaptation in the skeletal-muscle of rats depleted of creatine with the substrate-analog beta-guanidinopropionic acid. Biochem J 232(1):125–131. https://doi.org/10.1042/bj2320125
Stephenne X, Foretz M, Taleux N, van der Zon GC, Sokal E, Hue L, Viollet B, Guigas B (2011) Metformin activates amp-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia 54(12):3101–3110. https://doi.org/10.1007/s00125-011-2311-5
Stumvoll M, Haring HU, Matthaei S (2007) Metformin. Endocr Res 32(1–2):39–57. https://doi.org/10.1080/07435800701743828
Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE (1995) Metabolic effects of metformin in non-insulin-dependent diabetes-mellitus. N Engl J Med 333:550–554. https://doi.org/10.1056/NEJM199508313330903
Suwa M, Nakano H, Kumagai S (2003) Effects of chronic aicar treatment on fiber composition, enzyme activity, Ucp3, and Pgc-1 in rat muscles. J Appl Physiol 95(3):960–968. https://doi.org/10.1152/japplphysiol.00349.2003
Tomic T, Botton T, Cerezo M, Robert G, Luciano F, Puissant A, Gounon P, Allegra M, Bertolotto C, Bereder JM, Tartare-Deckert S, Bahadoran P, Auberger P, Ballotti R, Rocchi S (2011) Metformin inhibits melanoma development through autophagy and apoptosis mechanisms. Cell Death Dis 2(9):e199. https://doi.org/10.1038/cddis.2011.86
Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S, Da Cruz S, Clerc P, Raschke I, Merkwirth C, Ehses S, Krause F, Chan DC, Alexander C, Bauer C, Youle R, Langer T, Martinou JC (2009) Slp-2 is required for stress-induced mitochondrial hyperfusion. EMBO J 28(11):1589–1600. https://doi.org/10.1038/emboj.2009.89
Toyama EQ, Herzig S, Courchet J, Lewis TL, Loson OC, Hellberg K, Young NP, Chen H, Polleux F, Chan DC, Shaw RJ (2016) Amp-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351(6270):275–281. https://doi.org/10.1126/science.aab4138
Viollet B, Guigas B, Garcia NS, Leclerc J, Foretz M, Andreelli F (2012) Cellular and Molecular mechanisms of metformin: an overview. Clin Sci 122:5–6. https://doi.org/10.1042/cs20110386
Wakatsuki T, Ohira Y, Nakamura K, Asakura T, Ohno H, Yamamoto M (1995) Changes of contractile properties of extensor digitorum longus in response to creatine-analogue administration and/or hindlimb suspension in rats. Jpn J Physiol 45(6):979–989. https://doi.org/10.2170/jjphysiol.45.979
Wallimann T, Dolder M, Schlattner U, Eder M, Hornemann T, O’Gorman E, Ruck A, Brdiczka D (1998) Some New aspects of creatine kinase (Ck): compartmentation, structure, function and regulation for cellular and mitochondrial bioenergetics and physiology. Biofactors 8(3–4):229–234. https://doi.org/10.1002/biof.5520080310
Wang QL, Zhang M, Torres G, Wu SN, Ouyang CH, Xie ZL, Zou MH (2017) Metformin suppresses diabetes-accelerated atherosclerosis via the inhibition of Drp1-mediated mitochondrial fission. Diabetes 66(1):193–205. https://doi.org/10.2337/db16-0915
Williams DB, Sutherland LN, Bomhof MR, Basaraba SAU, Thrush AB, Dyck DJ, Field CJ, Wright DC (2009) Muscle-specific differences in the response of mitochondrial proteins to beta-gpa feeding: an evaluation of potential mechanisms. Am J Physiol Endocrinol Metab 296(6):E1400–E1408. https://doi.org/10.1152/ajpendo.90913.2008
Williamson DL, Butler DC, Alway SE (2009) Ampk inhibits myoblast differentiation through a Pgc-1 alpha-dependent mechanism. Am J Physiol Endocrinol Metab 297(2):E304–E314. https://doi.org/10.1152/ajpendo.91007.2008
Winder WW, Hardie DG (1996) Inactivation of Acetyl-coa carboxylase and activation of amp-activated protein kinase in muscle during exercise. Am J Physiol Endocrinol Metab 270(2):E299–E304
Winder WW, Hardie DG (1999) Amp-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol Endocrinol Metab 277(1):E1–E10
Wullschleger S, Loewith R, Hall MN (2006) Tor signaling in growth and metabolism. Cell 124(3):471–484. https://doi.org/10.1016/j.cell.2006.01.016
Xie ZL, Lau K, Eby B, Lozano P, He CY, Pennington B, Li HL, Rathi S, Dong YZ, Tian R, Kem D, Zou MH (2011) Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic ove26 mice. Diabetes 60(6):1770–1778. https://doi.org/10.2337/db10-0351
Yan Z, Lira VA, Greene NP (2012) Exercise training-induced regulation of mitochondrial quality. Exerc Sport Sci Rev 40(3):159–164
Yang S, Long LH, Li D, Zhang JK, Jin S, Wang F, Chen JG (2015) Beta-guanidinopropionic acid extends the lifespan of drosophila melanogaster via an amp-activated protein kinase-dependent increase in autophagy. Aging Cell 14(6):1024–1033. https://doi.org/10.1111/acel.12371
Yu TZ, Robotham JL, Yoon Y (2006) Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci USA 103(8):2653–2658. https://doi.org/10.1073/pnas.0511154103
Zhang BB, Zhou GC, Li C (2009) Ampk: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab 9(5):407–416. https://doi.org/10.1016/j.cmet.2009.03.012
Zhou GC, Myers R, Li Y, Chen YL, Shen XL, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of Amp-Activated protein kinase in mechanism of metformin action. J Clin Investig 108(8):1167–1174. https://doi.org/10.1172/JCI13505
Zong HH, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI (2002) AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci USA 99(25):15983–15987. https://doi.org/10.1073/pnas.252625599
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Financial support was provided by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (R15-DK106688).
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Crocker, C.L., Baumgarner, B.L. & Kinsey, S.T. β-guanidinopropionic acid and metformin differentially impact autophagy, mitochondria and cellular morphology in developing C2C12 muscle cells. J Muscle Res Cell Motil 41, 221–237 (2020). https://doi.org/10.1007/s10974-019-09568-0
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DOI: https://doi.org/10.1007/s10974-019-09568-0