High intensity interval training improves liver and adipose tissue insulin sensitivity

Molecular Metabolism

Volumn 4, Issue 12, 2015, Pages 903-915

  Marcinko, Katarina ^a   Sikkema, Sarah R ^a   Samaan, M Constantine ^a   Kemp, Bruce E ^b   Fullerton, Morgan D ^a   Steinberg, Gregory R ^a  

^a MCMASTER UNIVERSITY   (Canada)

^b UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

AMPK; Exercise; HIIT; NAFLD; Obesity induced insulin resistance; Type 2 diabetes

Indexed keywords

ACETYL COENZYME A CARBOXYLASE; ACETYL COENZYME A CARBOXYLASE 1; ACETYL COENZYME A CARBOXYLASE 2; ALANINE; CARBOHYDRATE; GLUCOSE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; LIPID; SERINE; UNCLASSIFIED DRUG;

ADIPOSE TISSUE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CARBOHYDRATE METABOLISM; CONTROLLED STUDY; ENDURANCE TRAINING; ENZYME PHOSPHORYLATION; EXERCISE INTENSITY; EXERCISE TOLERANCE; FOOD INTAKE; GENE MUTATION; GENE TARGETING; GLUCOSE BLOOD LEVEL; HIGH INTENSITY INTERVAL TRAINING; HISTOPATHOLOGY; INFLAMMATION; INSULIN SENSITIVITY; LIPID DIET; LIPID LIVER LEVEL; LIVER; MALE; MOUSE; NONHUMAN; OBESITY; OXIDATION; PRIORITY JOURNAL; REAL TIME POLYMERASE CHAIN REACTION; THERAPY EFFECT; TREATMENT DURATION; WEIGHT REDUCTION; WESTERN BLOTTING; WILD TYPE;

EID: 84951138850     PISSN: None     EISSN: 22128778     Source Type: Journal    
DOI: 10.1016/j.molmet.2015.09.006     Document Type: Article

References (76)

1. Tuomilehto J., Lindström J., Eriksson J.G., Valle T.T., Hämäläinen H., Ilanne-Parikka P., et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. The New England Journal of Medicine 2001, 344(18):1343-1350. 10.1056/NEJM200105033441801.
2. Knowler W.C., Barrett-Connor E., Fowler S.E., Hamman R.F., Lachin J.M., Walker E.A., et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The New England Journal of Medicine 2002, 346(6):393-403. 10.1056/NEJMoa012512.
3. Pan X.R., Li G.W., Hu Y.H., Wang J.X., Yang W.Y., An Z.X., et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and diabetes study. Diabetes Care 1997, 20(4):537-544. 10.2337/diacare.20.4.537.
4. Godin G., Desharnais R., Valois P., Lepage L., Jobin J., Bradet R. Differences in perceived barriers to exercise between high and low intenders: observations among different populations. American Journal of Health Promotion 1994, 8(4):279-285. 10.4278/0890-1171-8.4.279.
5. Marquis-Gravela G., Hayamia D., Juneaua M., Nigama A., Guilbeaulta V., Latoura E., et al. Intensive lifestyle intervention including high-intensity interval training program improves insulin resistance and fasting plasma glucose in obese patients. Preventive Medicine Reports 2015, 2:314-318. 10.1016/j.pmedr.2015.04.015.
6. Cocks M., Shepherd S., Tipton K., Wagenmakers A., Shaw C. High-intensity interval training improves microvascular and macrovascular function and insulin sensitivity. British Journal of Sports Medicine 2010, 44(i9). 10.1136/bjsm.2010.078972.27.
7. Shaban N., Kenno K.A., Milne K.J. The effects of a 2 week modified high intensity interval training program on the homeostatic model of insulin resistance (HOMA-IR) in adults with type 2 diabetes. The Journal of Sports Medicine and Physical Fitness 2014, 54(2):203-209.
8. Little J.P., Gillen J.B., Percival M.E., Safdar A., Tarnopolsky M.a, Punthakee Z., et al. Low-volume high-intensity interval training reduces hyperglycemia and increases muscle mitochondrial capacity in patients with type 2 diabetes. Journal of Applied Physiology (Bethesda, Md.[U+202F]: 1985) 2011, 111(6):1554-1560. 10.1152/japplphysiol.00921.2011.
9. Cocks M., Shaw C., Shepherd S., Fisher J., Ranasinghe A., Barker T., et al. Sprint interval and moderate-intensity continuous training have equal benefits on aerobic capacity, insulin sensitivity, muscle capillarisation and endothelial eNOS/NAD(P)Hoxidase. Journal of Physiology 2015, 10.1113/jphysiol.2014.285254.
10. Lumeng C.N., Delproposto J.B., Westcott D.J., Saltiel A.R. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 2008, 57(12):3239-3246. 10.2337/db08-0872.
11. Lumeng C.N., DeYoung S.M., Bodzin J.L., Saltiel A.R. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 2007, 56(1):16-23. 10.2337/db06-1076.
12. Fabbrini E., Sullivan S., Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 2010, 51(2):679-689. 10.1002/hep.23280.
13. Pagadala M.R., McCullough A.J. Non-alcoholic fatty liver disease and obesity: not all about body mass index. The American Journal of Gastroenterology 2012, 107(12):1859-1861. 10.1038/ajg.2012.320.
14. Heilbronn L.K., Campbell L.V. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Current Pharmaceutical Design 2008, 14(12):1225-1230. 10.2174/138161208784246153.
15. Lee J. Adipose tissue macrophages in the development of obesity-induced inflammation, insulin resistance and type 2 diabetes. Archives of Pharmacal Research 2013, 208-222. 10.1007/s12272-013-0023-8.
16. Zelber-Sagi S., Nitzan-Kaluski D., Goldsmith R., Webb M., Zvibel I., Goldiner I., et al. Role of leisure-time physical activity in nonalcoholic fatty liver disease: a population-based study. Hepatology (Baltimore, Md.) 2008, 48(6):1791-1798. 10.1002/hep.22525.
17. Johnson N.A., Sachinwalla T., Walton D.W., Smith K., Armstrong A., Thompson M.W., et al. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology 2009, 50(4):1105-1112. 10.1002/hep.23129.
18. Jordy A.B., Kraakman M.J., Gardner T., Estevez E., Kammoun H.L., Weir J.M., et al. Analysis of the liver lipidome reveals insights into the protective effect of exercise on high-fat diet-induced hepatosteatosis in mice. American Journal of Physiology. Endocrinology and Metabolism 2015, 308(9):E778-E791. 10.1152/ajpendo.00547.2014.
19. Cintra D.E., Ropelle E.R., Vitto M.F., Luciano T.F., Souza D.R., Engelmann J., et al. Reversion of hepatic steatosis by exercise training in obese mice: the role of sterol regulatory element-binding protein-1c. Life Sciences 2012, 91(11-12):395-401. 10.1016/j.lfs.2012.08.002.
20. Cho J., Lee I., Kim D., Koh Y., Kong J., Lee S., et al. Effect of aerobic exercise training on non-alcoholic fatty liver disease induced by a high fat diet in C57BL/6 mice. Journal of Exercise Nutrition & Biochemistry 2014, 18(4):339-346. 10.5717/jenb.2014.18.4.339.
21. Marques C.M.M., Motta V.F., Torres T.S., Aguila M.B., Mandarim-de-Lacerda C.A. Beneficial effects of exercise training (treadmill) on insulin resistance and nonalcoholic fatty liver disease in high-fat fed C57BL/6 mice. Brazilian Journal of Medical and Biological Research 2010, 43(5):467-475.
22. Berglund E.D., Lustig D.G., Baheza R.A., Hasenour C.M., Lee-Young R.S., Donahue E.P., et al. Hepatic glucagon action is essential for exercise-induced reversal of mouse fatty liver. Diabetes 2011, 60(11):2720-2729. 10.2337/db11-0455.
23. Haram P.M., Kemi O.J., Lee S.J., Bendheim M., Al-Share Q.Y., Waldum H.L., et al. Aerobic interval training vs. continuous moderate exercise in the metabolic syndrome of rats artificially selected for low aerobic capacity. Cardiovascular Research 2009, 81(4):723-732. 10.1093/cvr/cvn332.
24. Bradley R.L., Jeon J.Y., Liu F.-F., Maratos-Flier E. Voluntary exercise improves insulin sensitivity and adipose tissue inflammation in diet-induced obese mice. American Journal of Physiology. Endocrinology and Metabolism 2008, 295(3):E586-E594. 10.1152/ajpendo.00309.2007.
25. Vieira V.J., Valentine R.J., Wilund K.R., Antao N., Baynard T., Woods J.A. Effects of exercise and low-fat diet on adipose tissue inflammation and metabolic complications in obese mice. American Journal of Physiology. Endocrinology and Metabolism 2009, 296(5):E1164-E1171. 10.1152/ajpendo.00054.2009.
26. Kawanishi N., Yano H., Yokogawa Y., Suzuki K. Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice. Exercise Immunology Review 2010, 16:105-118.
27. Gibala M.J., McGee S.L., Garnham A.P., Howlett K.F., Snow R.J., Hargreaves M. Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1alpha in human skeletal muscle. Journal of Applied Physiology (Bethesda, Md.[U+202F]: 1985) 2009, 106(3):929-934. 10.1152/japplphysiol.90880.2008.
28. Stephens T.J., Chen Z.-P., Canny B.J., Michell B.J., Kemp B.E., McConell G.K. Progressive increase in human skeletal muscle AMPKalpha2 activity and ACC phosphorylation during exercise. American Journal of Physiology. Endocrinology and Metabolism 2002, 282(3):E688-E694. 10.1152/ajpendo.00101.2001.
29. Park H., Kaushik V.K., Constant S., Prentki M., Przybytkowski E., Ruderman N., et al. Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise. Journal of Biological Chemistry 2002, 277(36):32571-32577. 10.1074/jbc.M201692200.
30. Wojtaszewski J.F., Nielsen P., Hansen B.F., Richter E.A., Kiens B. Isoform-specific and exercise intensity-dependent activation of 5'-AMP-activated protein kinase in human skeletal muscle. The Journal of Physiology 2000, 528(Pt 1):221-226. 10.1111/j.1469-7793.2000.t01-1-00221.x.
31. Camacho R.C., Donahue E.P., James F.D., Berglund E.D., Wasserman D.H. Energy state of the liver during short term and exhaustive exercise in C57BL/6J mice. American Journal of Physiology. Endocrinology Metabolism 2005, 290(3):E405-E408.
32. Watt M.J., Holmes A.G., Pinnamaneni S.K., Garnham A.P., Steinberg G.R., Kemp B.E., et al. Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue. American Journal of Physiology. Endocrinology and Metabolism 2006, 290(3):E500-E508. 10.1152/ajpendo.00361.2005.
33. Koh H.-J., Hirshman M.F., He H., Li Y., Manabe Y., Balschi J.A., et al. Adrenaline is a critical mediator of acute exercise-induced AMP-activated protein kinase activation in adipocytes. The Biochemical Journal 2007, 403(3):473-481. 10.1042/BJ20061479.
34. Galic S., Fullerton M.D., Schertzer J.D., Sikkema S., Marcinko K., Walkley C.R., et al. Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. Journal of Clinical Investigation 2011, 121(12):4903-4915. 10.1172/JCI58577.
35. Sag D., Carling D., Stout R.D., Suttles J. Adenosine 5'-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. Journal of Immunology (Baltimore, Md.[U+202F]: 1950) 2008, 181(12):8633-8641. Doi: 181/12/8633 [pii].
36. Steinberg G.R., Schertzer J.D. AMPK promotes macrophage fatty acid oxidative metabolism to mitigate inflammation: implications for diabetes and cardiovascular disease. Immunology and Cell Biology 2014, 92(4):340-345. 10.1038/icb.2014.11.
37. Mounier R., Théret M., Arnold L., Cuvellier S., Bultot L., Göransson O., et al. AMPKα1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. Cell Metabolism 2013, 18(2):251-264. 10.1016/j.cmet.2013.06.017.
38. Fullerton M.D., Galic S., Marcinko K., Sikkema S., Pulinilkunnil T., Chen Z.-P., et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nature Medicine 2013, 19(12):1649-1654. 10.1038/nm.3372.
39. Steinberg G.R., Jorgensen S.B. The AMP-activated protein kinase: role in regulation of skeletal muscle metabolism and insulin sensitivity. Mini Reviews in Medical Chemistry 2007, 7(5):519-526. 10.2174/138955707780619662.
40. Crane J.D., Palanivel R., Mottillo E.P., Bujak A.L., Wang H., Ford R.J., et al. Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nature Medicine 2015, 21:166-172. 10.1038/nm.3766.
41. Watt M.J., Dzamko N., Thomas W.G., Rose-John S., Ernst M., Carling D., et al. CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nature Medicine 2006, 12(5):541-548. 10.1038/nm1383.
42. Steele R. Influences of glucose loading and of injected insulin on hepatic glucose output. Annals of the New York Academy of Sciences 1959, 82:420-430. 10.1111/j.1749-6632.1959.tb44923.x.
43. Bligh E.G., Dyer W.J. A rapid method of total lipid Extraction and purification. Canadian Journal of Biochemistry and Physiology 1959, 37(8):911-917. 10.1139/o59-099.
44. Preiss J., Loomis C.R., Bishop W.R., Stein R., Niedel J.E., Bell R.M. Quantitative measurement of sn-1,2-diacylglycerols present in platelets, hepatocytes, and ras- and sis-transformed normal rat kidney cells. Journal of Biological Chemistry 1986, 261(19):8597-8600.
45. Livak K.J., Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods (San Diego, Calif.) 2001, 25(4):402-408. 10.1006/meth.2001.1262.
46. Lund J., Hafstad A.D., Boardman N.T., Rossvoll L., Rolim N.P., Ahmed M.S., et al. Exercise training promotes cardioprotection through oxygen-sparing action in high fat-fed mice. American Journal of Physiology. Heart and Circulatory Physiology 2015, 308(8):H823-H829. 10.1152/ajpheart.00734.2014.
47. Apontes P., Liu Z., Su K., Benard O., Youn D.Y., Li X., et al. Mangiferin stimulates carbohydrate oxidation and protects against high fat diet induced metabolic disorders. Diabetes 2014, 63(11):3626-3636. 10.2337/db14-0006.
48. Corpeleijn E., Saris W.H.M., Blaak E.E. Metabolic flexibility in the development of insulin resistance and type 2 diabetes: effects of lifestyle: etiology and pathophysiology. Obesity Reviews 2009, 10(2):178-193. 10.1111/j.1467-789X.2008.00544.x.
49. Jorgensen S.B., O'Neill H.M., Sylow L., Honeyman J., Hewitt K.A., Palanivel R., et al. Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity. Diabetes 2013, 62(1):56-64. 10.2337/db12-0443.
50. Shulman G.I. Cellular mechanisms of insulin resistance in humans. The American Journal of Cardiology 1999, 84(1A):3J-10J. 10.1016/S0002-9149(99)00350-1.
51. Yu C., Chen Y., Cline G.W., Zhang D., Zong H., Wang Y., et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. Journal of Biological Chemistry 2002, 277(52):50230-50236. 10.1074/jbc.M200958200.
52. O'Neill H.M., Lally J.S., Galic S., Thomas M., Azizi P.D., Fullerton M.D., et al. AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice. Diabetologia 2014, 57(8):1693-1702. 10.1007/s00125-014-3273-1.
53. Nagasawa J., Sato Y., Ishiko T. Effect of training and detraining on in vivo insulin sensitivity. International Journal of Sports Medicine 1990, 11(2):107-110. 10.1055/s-2007-1024772.
54. Chi M.M., Hintz C.S., Coyle E.F., Martin W.H., Ivy J.L., Nemeth P.M., et al. Effects of detraining on enzymes of energy metabolism in individual human muscle fibers. The American Journal of Physiology 1983, 244(3):C276-C287.
55. Mazzucatto F., Higa T., Fonseca-Alaniz M., Evangelista F. Reversal of metabolic adaptations induced by physical training after two weeks of physical detraining. International Journal of Clinical and Experimental Medicine 2014, 7(8):2000-2008.
56. Nogueira L., Ramirez-Sanchez I., Perkins G.A., Murphy A., Taub P.R., Ceballos G., et al. (-)-Epicatechin enhances fatigue resistance and oxidative capacity in mouse muscle. The Journal of Physiology 2011, 589(Pt 18):4615-4631. 10.1113/jphysiol.2011.209924.
57. Peirce V., Vidal-Puig A. Regulation of glucose homoeostasis by brown adipose tissue. The Lancet Diabetes & Endocrinology 2013, 1(4):353-360. 10.1016/S2213-8587(13)70055-X.
58. Boström P., Wu J., Jedrychowski M.P., Korde A., Ye L., Lo J.C., et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012, 481(7382):463-468. 10.1038/nature10777.
59. Little J.P., Safdar A., Wilkin G.P., Tarnopolsky M.A., Gibala M.J. A practical model of low-volume high-intensity interval training induces mitochondrial biogenesis in human skeletal muscle: potential mechanisms. The Journal of Physiology 2010, 588(Pt 6):1011-1022. 10.1113/jphysiol.2009.181743.
60. Motta V.F., de Lacerda C.A. Beneficial effects of exercise training (Treadmill) on body mass and skeletal muscle capillaries/myocyte ratio in C57BL/6 mice fed high-fat diet. International Journal of Morphology 2012, 30(1):205-210.
61. Mitranun W., Deerochanawong C., Tanaka H., Suksom D. Continuous vs interval training on glycemic control and macro- and microvascular reactivity in type 2 diabetic patients. Scandinavian Journal of Medicine & Science in Sports 2014, 24:e69-76. 10.1111/sms.12112.
62. Nybo L., Sundstrup E., Jakobsen M.D., Mohr M., Hornstrup T., Simonsen L., et al. High-intensity training versus traditional exercise interventions for promoting health. Medicine and Science in Sports and Exercise 2010, 42(10):1951-1958. 10.1249/MSS.0b013e3181d99203.
63. Tjønna A.E., Lee S.J., Rognmo Ø., Stølen T.O., Bye A., Haram P.M., et al. Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome: a pilot study. Circulation 2008, 118(4):346-354. 10.1161/CIRCULATIONAHA.108.772822.
64. Rao X., Zhong J., Xu X., Jordan B., Maurya S., Braunstein Z., et al. Exercise protects against diet-induced insulin resistance through downregulation of protein kinase Cβ in mice. PLoS One 2013, 8(12). 10.1371/journal.pone.0081364.
65. Sarvas J., Otis J., Khaper N., Lees S. Voluntary physical activity prevents insulin resistance in a tissue specific manner. Physiological Reports 2015, 3(2):e12277. 10.14814/phy2.12277.
66. Rector R.S., Thyfault J.P., Morris R.T., Laye M.J., Borengasser S.J., Booth F.W., et al. Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in Otsuka Long-Evans Tokushima Fatty rats. American Journal of Physiology. Gastrointestinal and Liver Physiology 2008, 294(3):G619-G626. 10.1152/ajpgi.00428.2007.
67. Rector R.S., Thyfault J.P., Laye M.J., Morris R.T., Borengasser S.J., Uptergrove G.M., et al. Cessation of daily exercise dramatically alters precursors of hepatic steatosis in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. The Journal of Physiology 2008, 586(Pt 17):4241-4249. 10.1113/jphysiol.2008.156745.
68. Thyfault J.P., Rector R.S., Uptergrove G.M., Borengasser S.J., Morris E.M., Wei Y., et al. Rats selectively bred for low aerobic capacity have reduced hepatic mitochondrial oxidative capacity and susceptibility to hepatic steatosis and injury. The Journal of Physiology 2009, 587(Pt 8):1805-1816. 10.1113/jphysiol.2009.169060.
69. Ellingsgaard H., Hauselmann I., Schuler B., Habib A.M., Baggio L.L., Meier D.T., et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nature Medicine 2011, 1481-1489. 10.1038/nm.2513.
70. Weisberg S.P., McCann D., Desai M., Rosenbaum M., Leibel R.L., Ferrante A.W. Obesity is associated with macrophage accumulation in adipose tissue. Journal of Clinical Investigation 2003, 112(12):1796-1808. 10.1172/JCI200319246.
71. Pedersen B.K. The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control. Essays in Biochemistry 2006, 42:105-117.
72. Turner N., Kowalski G.M., Leslie S.J., Risis S., Yang C., Lee-Young R.S., et al. Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding. Diabetologia 2013, 56(7):1638-1648. 10.1007/s00125-013-2913-1.
73. Aparicio-Vergara M., Hommelberg P.P.H., Schreurs M., Gruben N., Stienstra R., Shiri-Sverdlov R., et al. Tumor necrosis factor receptor 1 gain-of-function mutation aggravates nonalcoholic fatty liver disease but does not cause insulin resistance in a murine model. Hepatology (Baltimore, Md.) 2013, 57(2):566-576. 10.1002/hep.26046.
74. Hallsworth K., Fattakhova G., Hollingsworth K.G., Thoma C., Moore S., Taylor R., et al. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut 2011, 60(9):1278-1283. 10.1136/gut.2011.242073.
75. Petersen K.F., Dufour S., Befroy D., Lehrke M., Hendler R.E., Shulman G.I. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 2005, 54(3):603-608. 10.2337/diabetes.54.3.603.
76. Romijn J.A., Gastaldelli A., Horowitz J.F., Endert E., Wolfe R.R. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. The American Journal of Physiology 1993, 265(3p1):380-391.