[en] Alaskan sled dogs develop a particular metabolic strategy during multiday submaximal exercise, allowing them to switch from intra-muscular to extra-muscular energy substrates thus postponing fatigue. Specifically, a progressively increasing stimulus for hepatic glycogenolysis and gluconeogenesis provides glucose for both fueling exercise and replenishing the depleted muscle glycogen. Moreover, recent studies have shown that with continuation of exercise sled dogs increase their insulin-sensitivity and their capacity to transport and oxidize glucose and carbohydrates rather than oxidizing fatty acids. Carnitine and acylcarnitines (AC) play an essential role as metabolic regulators in both fat and glucose metabolism; they serve as biomarkers in different species in both physiologic and pathologic conditions. We assessed the effect of multiday exercise in conditioned sled dogs on plasma short (SC), medium (MC) and long (LC) chain AC by tandem mass spectrometry (MS/MS). Our results show chain-specific modification of AC profiles during the exercise challenge: LCACs maintained a steady increase throughout exercise, some SCACs increased during the last phase of exercise and acetylcarnitine (C2) initially increased before decreasing during the later phase of exercise. We speculated that SCACs kinetics could reflect an increased protein catabolism and C2 pattern could reflect its hepatic uptake for energy-generating purposes to sustain gluconeogenesis. LCACs may be exported by muscle to avoid their accumulation to preserve glucose oxidation and insulin-sensitivity or they could be distributed by liver as energy substrates. These findings, although representing a "snapshot" of blood as a crossing point between different organs, shed further light on sled dogs metabolism that is liver-centric and more carbohydrate-dependent than fat-dependent and during prolonged submaximal exercise.
Research center :
Equine pole, Fundamental and Applied Research for Animals & Health (FARAH), Faculty of Veterinary Medicine, ULiege
Disciplines :
Veterinary medicine & animal health Anatomy (cytology, histology, embryology...) & physiology
Author, co-author :
Tosi, Irène ; Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) > Phys. neuro-muscul., de l'effort - Méd. sport. des animaux
Art, Tatiana ; Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) > Phys. neuro-muscul., de l'effort - Méd. sport. des animaux
BOEMER, François ; Université de Liège - ULiège > Biochemical Genetics Laboratory, CHU Sart-Tilman
Votion, Dominique ; Université de Liège - ULiège > Equine pole, Fundamental and Applied Research for Animals & Health (FARAH), Faculty of Veterinary Medicine
Davis, Michael S.; Oklahoma State University, Stillwater, Oklahoma, United States of America > Department of Physiological Sciences
Language :
English
Title :
Acylcarnitine profile in Alaskan sled dogs during submaximal multiday exercise points out metabolic flexibility and liver role in energy metabolism.
Publication date :
2021
Journal title :
PLoS ONE
eISSN :
1932-6203
Publisher :
Public Library of Science, United States - California
Davis MS, Hinchcliff KW, Williamson KK, McKenzie EC, Royer CM. Effect of multiday exercise on serum hormones and metabolic substrate concentrations in racing sled dogs. Comp Exerc Physiol. 2020; 16(3): 197–205.
Banse HE, Sides RH, Ruby BC, Bayly WM. Effects of endurance training on VO2max and submaximal blood lactate concentrations of untrained sled dogs. Equine Comp Exerc Physiol. 2007; 4(2): 89–94.
Poole DC, Erickson HH. Highly athletic terrestrial mammals: horses and dogs. Compr Physiol. 2011; 1: 1–37. https://doi.org/10.1002/cphy.c091001 PMID: 23737162
Gunn HM. Differences in the histochemical properties of skeletal muscles of different breeds of horses and dogs. J Anat. 1978; 127(3): 615–634. PMID: 154495
Guy PS, Snow DH. Skeletal muscle fibre composition in the dog and its relationship to athletic ability. Res Vet Sci. 1981; 31(2): 244–248. PMID: 6459629
McKenzie E, Holbrook T, Williamson K, Royer C, Valberg S, Hinchcliff K, et al. Recovery of muscle glycogen concentrations in sled dogs during prolonged exercise. Med Sci Sports Exerc. 2005; 37(8): 1307–1312. https://doi.org/10.1249/01.mss.0000175086.41080.01 PMID: 16118576
Hinchcliff KW, Reinhart GA, Burr JR, Schreier CJ, Swenson RA. Metabolizable energy intake and sustained energy expenditure of Alaskan sled dogs during heavy exertion in the cold. Am J Vet Res. 1997; 58(12): 1457–1462. PMID: 9401699
Reynolds AJ, Fuhrer L, Dunlap HL, Finke M, Kallfelz FA. Effect of diet and training on muscle glycogen storage and utilization in sled dogs. J Appl Physiol. 1995; 79(5): 1601–1607. https://doi.org/10.1152/jappl.1995.79.5.1601 PMID: 8594020
Reynolds AJ, Reinhart GA, Carey DP, Simmerman DA, Frank DA, Kallfelz FA. Effect of protein intake during training on biochemical and performance variables in sled dogs. Am J Vet Res. 1999; 60(7): 789–795. PMID: 10407468
McKenzie EC, Hinchcliff KW, Valberg SJ, Williamson KK, Payton ME, et al. Assessment of alterations in triglyceride and glycogen concentrations in muscle tissue of Alaskan sled dogs during repetitive prolonged exercise. Am J Vet Res 2008; 69: 1097–1103. https://doi.org/10.2460/ajvr.69.8.1097 PMID: 18672977
McKenzie EC, Jose-Cunilleras E, Hinchcliff KW, Holbrook TC, Royer C, Payton ME, et al. Serum chemistry alterations in Alaskan sled dogs during five successive days of prolonged endurance exercise. Am Vet Med Assoc. 2007; 230: 1486–1492. https://doi.org/10.2460/javma.230.10.1486 PMID: 17504039
Miller BF, Drake JC, Peelor 3rd FF, Biela LM, Geor R, Hinchcliff K, et al. Participation in a 1,000-mile race increases the oxidation of carbohydrate in Alaskan sled dogs. J Appl Physiol. 2015; 118: 1502–1509. https://doi.org/10.1152/japplphysiol.00588.2014 PMID: 25150223
Miller B, Hamilton K, Boushel R, Williamson K, Laner V, Gnaiger E, et al. Mitochondrial respiration in highly aerobic canines in the non-raced state and after a 1600-km sled dog race. PLoS ONE. 2017; 12 (4): e0174874. https://doi.org/10.1371/journal.pone.0174874 PMID: 28445477
Davis MS, Bonen A, Snook LA, Jain SS, Bartels K, Geor R, et al. Conditioning increases the gain of contraction-induced sarcolemmal substrate transport in ultra-endurance racing sled dogs. PLoS ONE. 2014; 9(7): e103087. https://doi.org/10.1371/journal.pone.0103087 PMID: 25075856
Rui L. Energy metabolism in the liver. Compr Physiol. 2014; 4(1):177–197. https://doi.org/10.1002/cphy.c130024 PMID: 24692138
Vaz FM, Wanders RJA. Carnitine biosynthesis in mammals. Biochem J. 2002; 361: 417–429. https://doi.org/10.1042/0264-6021:3610417 PMID: 11802770
Evangeliou A, Vlassopoulos D. Carnitine metabolism and deficit when supplementation is necessary? Curr Pharm Biotechnol. 2003; 4(3): 211–219. https://doi.org/10.2174/1389201033489829 PMID: 12769764
Schönfeld P, Wojtczak L. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective. J Lipid Res. 2016; 57: 943–954. https://doi.org/10.1194/jlr.R067629 PMID: 27080715
Van Hove JLK, Zhang W, Kahler SG, Roe CR, Chen YT, Terada N. Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency: diagnosis by acylcarnitine analysis in blood. Am. J. Hum. Genet. 1993; 52: 958–966. PMID: 8488845
Brass EP. Supplemental carnitine and exercise. Am J Clin Nutr 2000; 72(suppl):618S–623S. https://doi.org/10.1093/ajcn/72.2.618S PMID: 10919968
Frohlich J, Seccombe DW, Hahn P, Dodek P, Hynie I. Effect of fasting on free and esterified carnitine levels in human serum and urine: correlation with serum levels of free fatty acids and beta-hydroxybutyrate. Metabolism. 1978; 27(5): 555–561. https://doi.org/10.1016/0026-0495(78)90022-7 PMID: 642827
Hiatt WR, Regensteiner JG, Wolfel EE, Ruff L, Brass EP. Carnitine and acylcarnitine metabolism during exercise in humans. Dependence on skeletal muscle metabolic state. J Clin Invest. 1989; 84(4): 1167–1173. https://doi.org/10.1172/JCI114281 PMID: 2794054
Mihalik SJ, Goodpaster BH, Kelley DE, Chace DH, Vockley J, Toledo FGS, et al. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity (Silver Spring). 2010; 18(9): 1695–1700. https://doi.org/10.1038/oby.2009.510 PMID: 20111019
Kalim S, Clish CB, Wenger J, Elmariah S, Yeh RW, Deferio JJ, et al. A Plasma long-chain acylcarnitine predicts cardiovascular mortality in incident dialysis patients. Am Heart Assoc. 2013; 2:e000542. https://doi.org/10.1161/JAHA.113.000542 PMID: 24308938
Ramos-Roman MA, Sweetman L, Valdez MJ, Parks EJ. Postprandial changes in plasma acylcarnitine concentrations as markers of fatty acid flux in overweight and obesity. Metabolis. 2012; 61(2): 202–212. https://doi.org/10.1016/j.metabol.2011.06.008 PMID: 21820684
Aguer C, McCoin CS, Knotts TA, Thrush AB, Ono-Moore K, McPherson R, et al. Acylcarnitines: potential implications for skeletal muscle insulin resistance. FASEB J. 2015; 29: 336–345. https://doi.org/10.1096/fj.14-255901 PMID: 25342132
Xu G, Hansen JS, Zhao XJ, Chen S, Hoene M, Wang XL, et al. Liver and muscle contribute differently to the plasma acylcarnitine pool during fasting and exercise in humans. J Clin Endocrinol Metab. 2016; 101: 5044–5052. https://doi.org/10.1210/jc.2016-1859 PMID: 27648961
Chace DH, Kalas TA, Naylor EW. Use of tandem mass spectrometry for multianalyte screening of dried blood specimens from newborns. Clin Chem. 2003; 49(11): 1797–817. https://doi.org/10.1373/clinchem.2003.022178 PMID: 14578311
Lennon DL, Stratman FW, Shrago E, Nagle FJ, Madden M, Hanson P, et al. Effects of acute moderate-intensity exercise on carnitine metabolism in men and women. J Appl Physiol Respir Environ Exerc Physiol. 1983; 55(2): 489–495. https://doi.org/10.1152/jappl.1983.55.2.489 PMID: 6618942
Brass EP, Hiatt WR. Carnitine metabolism during exercise. Life Sc. 1994; 54(19):1383–1393.
Arenas J, Ricoy JR, Encinas AR, Pola P, D’Iddio S, Zeviani M, et al. Carnitine in muscle, serum, and urine of nonprofessional athletes: Effects of physical exercise, training, and L-Carnitine administration. Muscle Nerve. 1991; 14: 598–604. https://doi.org/10.1002/mus.880140703 PMID: 1922166
Foster CVL, Roger CH. Formation of acetylcarnitine in muscle of horse during high intensity exercise. Eur J Appl Physiol. 1987; 56: 639–642. https://doi.org/10.1007/BF00424803 PMID: 3678216
Peters LWE, Smiet E, de Sain-van der Velden MGM, van der Kolk JH. Acylcarnitine ester utilization by the hindlimb of warmblood horses at rest and following low intensity exercise and carnitine supplementation. Vet Quart, 2015; 35(2): 76–81. https://doi.org/10.1080/01652176.2015.1027039 PMID: 25831401
Westermann CM, Dorland B, de Sain-van der Velden MG, Wijnberg ID, van Breda E, de Graaf-Roelfsema E, et al. Plasma acylcarnitine and fatty acid profiles during exercise and training in standardbreds. Am J Vet Res. 2008; 69: 1469–1475. https://doi.org/10.2460/ajvr.69.11.1469 PMID: 18980429
van der Kolk JH, Thomas S, Mach N, Ramseyer A, Burger D, Gerber V, et al. Acylcarnitine profile in endurance horses with and without metabolic dysfunction. Vet J. 2020; 255: 105419. https://doi.org/10.1016/j.tvjl.2019.105419 PMID: 31982078
Sahlin K. Muscle carnitine metabolism during incremental dynamic exercise in humans. Acta Physiol Scand. 1990; 138(3): 259–262. https://doi.org/10.1111/j.1748-1716.1990.tb08845.x PMID: 2327259
Constantin-Teodosiu D, Carlin JI, Cederblad G, Harris RC, Hultman E. Acetyl group accumulation and pyruvate dehydrogenase activity in human muscle during incremental exercise. Acta Physiol Scand. 1991; 143(4): 367–372. https://doi.org/10.1111/j.1748-1716.1991.tb09247.x PMID: 1815472
Spriet LL1, MacLean DA, Dyck DJ, Hultman E, Cederblad G, Graham TE. Caffeine ingestion and muscle metabolism during prolonged exercise in humans. Am J Physiol. 1992; 262(6 Pt 1): E891–E898. https://doi.org/10.1152/ajpendo.1992.262.6.E891 PMID: 1616022
Carlin JI, Reddan WG, Sanjak M, Hodach R. Carnitine metabolism during prolonged exercise and recovery in humans. J Appl Physiol (1985). 1986; 61(4): 1275–1278. https://doi.org/10.1152/jappl.1986.61.4.1275 PMID: 3536833
Lehmann R, Zhao X, Weigert C, Simon P, Fehrenbach E, Fritsche J, et al. Medium chain acylcarnitines dominate the metabolite pattern in humans under moderate intensity exercise and support lipid oxidation. PLoS ONE. 2010; 5(7):e11519. https://doi.org/10.1371/journal.pone.0011519 PMID: 20634953
Soop M, Björkman O, Cederblad G, Hagenfeldt L, Wahren J. Influence of carnitine supplementation on muscle substrate and carnitine metabolism during exercise. J Appl Physiol (1985). 1988; 64(6): 2394–2399. https://doi.org/10.1152/jappl.1988.64.6.2394 PMID: 3042733
Soeters MR, Sauerwein HP, Duran M, Wanders RJ, Ackermans MT, Fliers E. Muscle acylcarnitines during short-term fasting in lean healthy men. Clin Sci. 2009; 116: 585–592. https://doi.org/10.1042/ CS20080433 PMID: 18945215
Schooneman MG, Achterkamp N, Argmannd CA, Soeters MR, Houten SM. Plasma acylcarnitines inadequately reflect tissue acylcarnitine metabolism. Biochim Biophys Acta. 2014; 1841: 987–994. https://doi.org/10.1016/j.bbalip.2014.04.001 PMID: 24747043
Schooneman MG, Ten Have GAM, van Vlies N, Houten SM, Deutz NEP, Soeters MR. Transorgan fluxes in a porcine model reveal a central role for liver in acylcarnitine metabolism. Am J Physiol Endocrinol Metab. 2015; 309: E256–E264. https://doi.org/10.1152/ajpendo.00503.2014 PMID: 26037250
Makrecka M, Kuka J, Volska K, Antone U, Sevostjanovs E, Cirule H, et al. Long-chain acylcarnitine content determines the pattern of energy metabolism in cardiac mitochondria. Mol Cell Biochem. 2014; 395: 1–10. https://doi.org/10.1007/s11010-014-2106-3 PMID: 24878991
Davis M, Willard M, Williamson K, Royer C, Payton M, Steiner JM. Temporal relationship between gastrointestinal protein loss, gastric ulceration or erosion, and strenuous exercise in racing Alaskan sled dogs. J Vet Intern Med. 2006; 20: 835–839. https://doi.org/10.1892/0891-6640(2006)20[835:trbgpl]2.0. co;2 PMID: 16955805
Chace DH, Pons R, Chiriboga CA, McMahon DJ, Tein I, Naylor EW, et al. Neonatal blood carnitine concentrations: normative data by electrospray tandem mass spectrometry. Pediatr Res. 2003; 53(5): 823–829. https://doi.org/10.1203/01.PDR.0000059220.39578.3D PMID: 12612202
Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metabolis. 2008; 7: 45–56. https://doi.org/10.1016/j.cmet.2007.10.013 PMID: 18177724
Costa CCG, Tavares De Almeida I, Jakobs C, Poll-The BT, Duran M. Dynamic changes of plasma acylcarnitine levels induced by fasting and sunflower oil challenge test in children. Pediatr Res. 1999; 46: 440–444. https://doi.org/10.1203/00006450-199910000-00013 PMID: 10509365
Wolf M, Chen S, Zhao X, Scheler M, Irmler M, Staiger H, et al. Production and release of acylcarnitines by primary myotubes reflect the differences in fasting fat oxidation of the donors. J Clin Endocrinol Metab. 2013; 98(6): E1137–E1142. https://doi.org/10.1210/jc.2012-3976 PMID: 23633211
Simcox J, Geoghegan G, Maschek JA, Bensard CL, Pasquali M, Miao R. Global analysis of plasma lipids identifies liver-derived acylcarnitines as a fuel source for brown fat thermogenesis. Cell Metab. 2017; 26(3): 509–522. https://doi.org/10.1016/j.cmet.2017.08.006 PMID: 28877455
Ramsay RR, Arduini A. The carnitine acyltransferases and their role in modulating Acyl-CoA pools. Arch Biochem Biophys. 1993; 302(2): 307–314. https://doi.org/10.1006/abbi.1993.1216 PMID: 8489235
Pratt-Phillips SE, Geor RJ, Buser M, Zirkle A, Moore A, Love SB et al. Effect of a single bout of exercise and chronic exercise training on insulin sensitivity in racing sled dogs. Comp Exerc Physiol. 2014; 10 (3): 167–172.
Davis MS, Geor RJ, Williamson KK. Effect of Endurance Conditioning on Insulin-mediated Glucose Clearance in Dogs. Med Sci Sports Exerc. 2018; 50(12): 2494–2499. https://doi.org/10.1249/MSS. 0000000000001718 PMID: 30001223
Rossi A, Ruoppolo M, Formisano P, Villani G, Albano L, Gallo G, et al. Insulin-resistance in glycogen storage disease type Ia: linking carbohydrates and mitochondria? J Inherit Metab Dis. 2018; 41(6): 985–995. https://doi.org/10.1007/s10545-018-0149-4 PMID: 29435782
Muoio DM, Kovers TR. Lipid-induced metabolic dysfunction in skeletal muscle. Novart FDN Symp. 2007; 286: 24–38. https://doi.org/10.1002/9780470985571.ch4 PMID: 18269172
Makrecka-Kuka M, Sevostjanovs E, Vilks K, Volska K, Antone U, Kuka J, et al. Plasma acylcarnitine concentrations reflect the acylcarnitine profile in cardiac tissues. Nature Scientific Report. 2017; 7: 17528. https://doi.org/10.1038/s41598-017-17797-x PMID: 29235526
Iwen KA, Backhaus J, Cassens M, Waltl M, Hedesan OC, Merkel M, et al. Cold-induced brown adipose tissue activity alters plasma fatty acids and improves glucose metabolism in men. J Clin Endocrinol Metab. 2017; 102(11): 4226–4234. https://doi.org/10.1210/jc.2017-01250 PMID: 28945846
Philips CJ, Coppinger RP, Schimel DS. Hyperthermia in running sled dogs. Physiology. 1981; 51(1): 135–142.
Rovira S, Munoz A, Benito M. Effect of exercise on physiological, blood and endocrine parameters in search and rescue-trained dogs. Vet Med-Czech. 2008; 53(6): 333–346.
Reddy JK, Hashimoto T. Peroxisomal beta-oxidation and peroxisome proliferator–activated receptor α: an adaptive metabolic system. Annu Rev Nutr. 2001; 21: 193–230. https://doi.org/10.1146/annurev.nutr.21.1.193 PMID: 11375435
Björkhem I. On the mechanism of regulation of ω oxidation of fatty acids. J Biol Chem. 1976; 251(17): 5259–5266. PMID: 956185
Sauer SW, Okun JG, Hoffmann GF, Koelker S, Morath MA. Impact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs on mitochondrial energy metabolism. Biochim Biophys Acta. 2008; 1777: 1276–1282. https://doi.org/10.1016/j.bbabio.2008.05.447 PMID: 18582432
Shaw WAS, Issekutz TB, Issekutz B. Gluconeogenesis from glycerol at rest and during exercise in normal, diabetic, and methylprednisolone-treated dogs. Metabolis. 1976; 25(3): 329–339.
Wasserman DH, Lacy DB, Green DR, Williams PE, Cherrington AD. Dynamics of hepatic lactate and glucose balances during prolonged exercise and recovery in the dog. J Appl Physiol (1985). 1987; 63 (6): 2411–2417. https://doi.org/10.1152/jappl.1987.63.6.2411 PMID: 3325489
Davis MS. Glucocentric Metabolism in Ultra-Endurance Sled Dogs. Integr Comp Biol. 2021; 19: icab026. https://doi.org/10.1093/icb/icab026 PMID: 33871632
Wasserman DH, Spalding JA, Lacy DB, Colburn CA, Goldstein RE, Cherrington AD. Glucagon is a primary controller of hepatic glycogenolysis and gluconeogenesis during muscular work. Am J Physiol. 1989; 257(1 Pt 1): E108–17. https://doi.org/10.1152/ajpendo.1989.257.1.E108 PMID: 2665514
Wagenmakers AJM, Coakley JH, Edwards RHT. Metabolism of branched-chain amino acids and ammonia during exercise: clues from McArdle’s disease. Int J Sports Med 1990; 11: S101–S113. https://doi.org/10.1055/s-2007-1024861 PMID: 2193889
Henriksson J. Effect of exercise on amino acid concentrations in skeletal muscle and plasma. J. exp. Biol. 1991; 160: 149–165. PMID: 1960512
Miller BF, Ehrlicher SE, Drake JC, Peelor FF, Biela LM, Pratt-Phillips S. Assessment of protein synthesis in highly aerobic canine species at the onset and during exercise training. J Appl Physiol. 2015; 118: 811–817. https://doi.org/10.1152/japplphysiol.00982.2014 PMID: 25614602
Mendelson SD. 10-Nutritional supplements and metabolic syndrome. In: Mendelson SD, editor. Metabolic Syndrome and Psychiatric Illness. Academic Press; 2008. pp. 141–186.
Hack A, Busch V, Pascher B, Busch R, Bieger I, Gempel K, et al. Monitoring of ketogenic diet for carnitine metabolites by subcutaneous microdialysis. Pediatr Res. 2006; 60(1): 93–96. https://doi.org/10.1203/01.pdr.0000219479.95410.79 PMID: 16690958
Emhoff CAW, Messonnier LA, Horning MA, Fattor JA, Carlson TJ, Brooks GA. Gluconeogenesis and hepatic glycogenolysis during exercise at the lactate threshold. J Appl Physiol. 2013; 114:297–306. https://doi.org/10.1152/japplphysiol.01202.2012 PMID: 23239870
Keene BW, Panciera DP, Atkins CE, Regitz V, Schmidt MJ, Shug AL. Myocardial L-carnitine deficiency in a family of dogs with dilated cardiomyopathy. J Am Vet Med Assoc. 1991; 198(4): 647–650. PMID: 2019534
Sanderson SL. Taurine and carnitine in canine cardiomyopathy. Vet Clin North Am Small Anim Pract. 2006; 36(6): 1325–1343. https://doi.org/10.1016/j.cvsm.2006.08.010 PMID: 17085238
Neumann S, Welling H, Thuere S, Kaup FJ. Plasma L-carnitine concentration in healthy dogs and dogs with hepatopathy. Vet Clin Pathol. 2007; 36(2): 137–140. https://doi.org/10.1111/j.1939-165x.2007.tb00199.x PMID: 17523086
Reynolds AJ, Fuhrer L, Dunlap HL, Finke M, Kallfelz FA. Effect of diet and training on muscle glycogen storage and utilization in sled dogs. J Appl Physiol. 1985; 79(5), 1601–1607.
Ostrander EA, Wayne RK, Freedman AH, Davis BW. Demographic history, selection and functional diversity of the canine genome. Nat Rev Genet. 2017; 18(12): 705–720. https://doi.org/10.1038/nrg.2017.67 PMID: 28944780
Arendt M, Fall T, Lindblad-Toh K, Axelsson E. Amylase activity is associated with AMY2B copy numbers in dog: implications for dog domestication, diet and diabetes. Anim Genet. 2014; 45(5): 716 722. https://doi.org/10.1111/age.12179 PMID: 24975239
Arendt M, Cairns KM, Ballard JW, Savolainen P, Axelsson E. Diet adaptation in dog reflects spread of prehistoric agriculture. Heredity (Edinb). 2016; 117(5): 301–306. https://doi.org/10.1038/hdy.2016.48 PMID: 27406651
Reiter T, Jagoda E, Capellini TD. Dietary variation and evolution of gene copy number among dog breeds. PLoS One. 2016; 11(2):e0148899. https://doi.org/10.1371/journal.pone.0148899 PMID: 26863414