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Created page with "{{DISPLAYTITLE:Lactate and Lactic Acid}} Lactate, also known as lactic acid, has a bad reputation. It's commonly viewed as a waste product that causes fatigue, burning muscles..."
{{DISPLAYTITLE:Lactate and Lactic Acid}}
Lactate, also known as lactic acid, has a bad reputation. It's commonly viewed as a waste product that causes fatigue, burning muscles, and [[Delayed Onset Muscle Soreness]] (DOMS). In reality, Lactate is an intermediary in the metabolism of carbohydrates, and is a fuel source that is preferred by working muscles over glucose. A crude analogy would be a steam train, where the coal (carbohydrate) is burnt to form steam (Lactate), and the steam is used to turn the wheels (muscles). This is a flawed analogy, as the creation of lactate from glucose provides direct energy for the muscles, and of course muscles have other fuel sources such as fat, but hopefully you get to the gist.
=Lactate Production=
At one time it was believed that Lactate was a waste product that indicated insufficient oxygen being supplied to the muscles, but this view has changed. Because Lactate is produced by metabolism in the absence of oxygen<ref name="HillLupton1923"/>, the natural conclusion was that the presence of Lactate indicates insufficient oxygen and therefore anaerobic metabolism<ref name="Wasserman-1984"/><ref name="Mizock-1992"/>. However, more recent studies have that Lactate production is related to exercise intensity, not insufficient oxygen supply<ref name="Connett-1986"/><ref name="Richardson-1998"/>. Lactate levels appear to depend on many factors, including the metabolism of glucose (to pyruvate), Lactate removal, fast twitch fiber recruitment, and energy demand (ADP/ATP ratio, which is in turn dependent on oxygen levels)<ref name="Gladden-2004"/>.
=Lactate and Fatigue=
Initial studies have indicated that that acidity may reduce force production in muscles<ref name="Hermansen-1981"/> or reduce the rate of glucose metabolism<ref name="Sahlin-1992"/>, leading to fatigue, and of course of Lactate is Lactic Acid in the blood. However, more recent studies have shown that the effects of acidity are not seen in more realistic situations<ref name="Westerblad-2002"/><ref name="Bangsbo-1996"/>. A study of isolated rat muscles showed Lactate can protect against fatigue<ref name="Nielsen-2001"/>. However, more research into the role of Lactate and fatigue are required<ref name="Gladden-2004"/>.
=Lactate as a Fuel=
The view of Lactate as a waste product has changed over time, and Lactate has been shown to be a mechanism for distributing carbohydrate (AKA the "Lactate Shuttle"<ref name="Brooks-2000"/>. During prolonged low-moderate intensity exercise, muscles that initially released Lactate into the blood can become net importers<ref name="Stainsby-1966"/><ref name="Gladden-1991"/>. At higher intensities, the working muscles extract and metabolize Lactate, even while being a net Lactate producer<ref name="Stanley-1986"/>. There is some evidence that muscles at rest will absorb and store Lactate<ref name="Kelley-2002"/>, while at exercise the majority of absorbed Lactate is metabolized by the working muscles<ref name="Kelley-2002"/><ref name="Mazzeo-1986"/>. Lactate is a preferred fuel source for working muscles, as extra Lactate injected will be metabolized in place of glucose<ref name="Miller-2002"/>. A low intensities, Lactate will be converted back to Glucose (AKA Gluconeogenesis)<ref name="Roef-2003"/>.
=Lactate Threshold=
In the spite of all of the myths around Lactate and lactic acid, the concept of [[Lactate Threshold]] is both valid and important. [[Lactate Threshold]] is a good predictor of athletic performance, especially in runners.
=Lactate and Wound Healing=
It's been known since the 1960 that lactate is an important part of wound healing, with collagen synthesis almost doubled when Lactate is increased to 15 mmol/l in cultures<ref name="GREEN-1964"/>. When you're used to looking at Lactate levels during exercise this seems ridiculously high, but values of 10-15 mmol/l are commonly seen in healing wounds<ref name="Hunt-1978"/>, and this does not appear to be due to low oxygen levels<ref name="Trabold-2003"/>. In fact, oxygen levels seem to have little impact on lactate levels<ref name="Constant-2000"/><ref name="Sheikh-2000"/>. It's possible that the beneficial effects of Lactate may be in stimulating vascular growth (angiogenesis)<ref name="Constant-2000"/> and/or increased oxygen supply to the wound through vasodilation<ref name="Mori-1998"/><ref name="Trabold-2003"/>.
=References=
<references>
<ref name="Mori-1998">K. Mori, Y. Nakaya, S. Sakamoto, Y. Hayabuchi, S. Matsuoka, Y. Kuroda, Lactate-induced vascular relaxation in porcine coronary arteries is mediated by Ca2+-activated K+ channels., J Mol Cell Cardiol, volume 30, issue 2, pages 349-56, Feb 1998, doi [http://dx.doi.org/10.1006/jmcc.1997.0598 10.1006/jmcc.1997.0598], PMID [http://www.ncbi.nlm.nih.gov/pubmed/9515011 9515011]</ref>
<ref name="Sheikh-2000">AY. Sheikh, JJ. Gibson, MD. Rollins, HW. Hopf, Z. Hussain, TK. Hunt, Effect of hyperoxia on vascular endothelial growth factor levels in a wound model., Arch Surg, volume 135, issue 11, pages 1293-7, Nov 2000, PMID [http://www.ncbi.nlm.nih.gov/pubmed/11074883 11074883]</ref>
<ref name="Constant-2000">JS. Constant, JJ. Feng, DD. Zabel, H. Yuan, DY. Suh, H. Scheuenstuhl, TK. Hunt, MZ. Hussain, Lactate elicits vascular endothelial growth factor from macrophages: a possible alternative to hypoxia., Wound Repair Regen, volume 8, issue 5, pages 353-60, PMID [http://www.ncbi.nlm.nih.gov/pubmed/11115148 11115148]</ref>
<ref name="Trabold-2003">O. Trabold, S. Wagner, C. Wicke, H. Scheuenstuhl, MZ. Hussain, N. Rosen, A. Seremetiev, HD. Becker, TK. Hunt, Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing., Wound Repair Regen, volume 11, issue 6, pages 504-9, PMID [http://www.ncbi.nlm.nih.gov/pubmed/14617293 14617293]</ref>
<ref name="Hunt-1978">TK. Hunt, WB. Conolly, SB. Aronson, P. Goldstein, Anaerobic metabolism and wound healing: an hypothesis for the initiation and cessation of collagen synthesis in wounds., Am J Surg, volume 135, issue 3, pages 328-32, Mar 1978, PMID [http://www.ncbi.nlm.nih.gov/pubmed/626315 626315]</ref>
<ref name="GREEN-1964">H. GREEN, B. GOLDBERG, COLLAGEN AND CELL PROTEIN SYNTHESIS BY AN ESTABLISHED MAMMALIAN FIBROBLAST LINE., Nature, volume 204, pages 347-9, Oct 1964, PMID [http://www.ncbi.nlm.nih.gov/pubmed/14228868 14228868]</ref>
<ref name="Roef-2003">MJ. Roef, K. de Meer, SC. Kalhan, H. Straver, R. Berger, DJ. Reijngoud, Gluconeogenesis in humans with induced hyperlactatemia during low-intensity exercise., Am J Physiol Endocrinol Metab, volume 284, issue 6, pages E1162-71, Jun 2003, doi [http://dx.doi.org/10.1152/ajpendo.00425.2002 10.1152/ajpendo.00425.2002], PMID [http://www.ncbi.nlm.nih.gov/pubmed/12604505 12604505]</ref>
<ref name="Miller-2002">BF. Miller, JA. Fattor, KA. Jacobs, MA. Horning, F. Navazio, MI. Lindinger, GA. Brooks, Lactate and glucose interactions during rest and exercise in men: effect of exogenous lactate infusion., J Physiol, volume 544, issue Pt 3, pages 963-75, Nov 2002, PMID [http://www.ncbi.nlm.nih.gov/pubmed/12411539 12411539]</ref>
<ref name="Mazzeo-1986">RS. Mazzeo, GA. Brooks, DA. Schoeller, TF. Budinger, Disposal of blood [1-13C]lactate in humans during rest and exercise., J Appl Physiol (1985), volume 60, issue 1, pages 232-41, Jan 1986, PMID [http://www.ncbi.nlm.nih.gov/pubmed/3080398 3080398]</ref>
<ref name="Kelley-2002">KM. Kelley, JJ. Hamann, C. Navarre, LB. Gladden, Lactate metabolism in resting and contracting canine skeletal muscle with elevated lactate concentration., J Appl Physiol (1985), volume 93, issue 3, pages 865-72, Sep 2002, doi [http://dx.doi.org/10.1152/japplphysiol.01119.2001 10.1152/japplphysiol.01119.2001], PMID [http://www.ncbi.nlm.nih.gov/pubmed/12183479 12183479]</ref>
<ref name="Stanley-1986">WC. Stanley, EW. Gertz, JA. Wisneski, RA. Neese, DL. Morris, GA. Brooks, Lactate extraction during net lactate release in legs of humans during exercise., J Appl Physiol (1985), volume 60, issue 4, pages 1116-20, Apr 1986, PMID [http://www.ncbi.nlm.nih.gov/pubmed/3084443 3084443]</ref>
<ref name="Gladden-1991">LB. Gladden, Net lactate uptake during progressive steady-level contractions in canine skeletal muscle., J Appl Physiol (1985), volume 71, issue 2, pages 514-20, Aug 1991, PMID [http://www.ncbi.nlm.nih.gov/pubmed/1938723 1938723]</ref>
<ref name="Stainsby-1966">WN. Stainsby, HG. Welch, Lactate metabolism of contracting dog skeletal muscle in situ., Am J Physiol, volume 211, issue 1, pages 177-83, Jul 1966, PMID [http://www.ncbi.nlm.nih.gov/pubmed/5911036 5911036]</ref>
<ref name="Brooks-2000">GA. Brooks, Intra- and extra-cellular lactate shuttles., Med Sci Sports Exerc, volume 32, issue 4, pages 790-9, Apr 2000, PMID [http://www.ncbi.nlm.nih.gov/pubmed/10776898 10776898]</ref>
<ref name="Nielsen-2001">OB. Nielsen, F. de Paoli, K. Overgaard, Protective effects of lactic acid on force production in rat skeletal muscle., J Physiol, volume 536, issue Pt 1, pages 161-6, Oct 2001, PMID [http://www.ncbi.nlm.nih.gov/pubmed/11579166 11579166]</ref>
<ref name="Bangsbo-1996">J. Bangsbo, K. Madsen, B. Kiens, EA. Richter, Effect of muscle acidity on muscle metabolism and fatigue during intense exercise in man., J Physiol, volume 495 ( Pt 2), pages 587-96, Sep 1996, PMID [http://www.ncbi.nlm.nih.gov/pubmed/8887768 8887768]</ref>
<ref name="Westerblad-2002">H. Westerblad, DG. Allen, J. Lännergren, Muscle fatigue: lactic acid or inorganic phosphate the major cause?, News Physiol Sci, volume 17, pages 17-21, Feb 2002, PMID [http://www.ncbi.nlm.nih.gov/pubmed/11821531 11821531]</ref>
<ref name="Sahlin-1992">K. Sahlin, Metabolic factors in fatigue., Sports Med, volume 13, issue 2, pages 99-107, Feb 1992, PMID [http://www.ncbi.nlm.nih.gov/pubmed/1561513 1561513]</ref>
<ref name="Hermansen-1981">L. Hermansen, Effect of metabolic changes on force generation in skeletal muscle during maximal exercise., Ciba Found Symp, volume 82, pages 75-88, 1981, PMID [http://www.ncbi.nlm.nih.gov/pubmed/6913479 6913479]</ref>
<ref name="Gladden-2004">LB. Gladden, Lactate metabolism: a new paradigm for the third millennium., J Physiol, volume 558, issue Pt 1, pages 5-30, Jul 2004, doi [http://dx.doi.org/10.1113/jphysiol.2003.058701 10.1113/jphysiol.2003.058701], PMID [http://www.ncbi.nlm.nih.gov/pubmed/15131240 15131240]</ref>
<ref name="Richardson-1998">RS. Richardson, EA. Noyszewski, JS. Leigh, PD. Wagner, Lactate efflux from exercising human skeletal muscle: role of intracellular PO2., J Appl Physiol (1985), volume 85, issue 2, pages 627-34, Aug 1998, PMID [http://www.ncbi.nlm.nih.gov/pubmed/9688741 9688741]</ref>
<ref name="Wasserman-1984">K. Wasserman, The anaerobic threshold measurement to evaluate exercise performance., Am Rev Respir Dis, volume 129, issue 2 Pt 2, pages S35-40, Feb 1984, PMID [http://www.ncbi.nlm.nih.gov/pubmed/6421216 6421216]</ref>
<ref name="HillLupton1923">A. V. Hill, H. Lupton, Muscular Exercise, Lactic Acid, and the Supply and Utilization of Oxygen, QJM, volume os-16, issue 62, 1923, pages 135–171, ISSN [http://www.worldcat.org/issn/1460-2725 1460-2725], doi [http://dx.doi.org/10.1093/qjmed/os-16.62.135 10.1093/qjmed/os-16.62.135]</ref>
<ref name="Mizock-1992">BA. Mizock, JL. Falk, Lactic acidosis in critical illness., Crit Care Med, volume 20, issue 1, pages 80-93, Jan 1992, PMID [http://www.ncbi.nlm.nih.gov/pubmed/1309494 1309494]</ref>
<ref name="Connett-1986">RJ. Connett, TE. Gayeski, CR. Honig, Lactate efflux is unrelated to intracellular PO2 in a working red muscle in situ., J Appl Physiol (1985), volume 61, issue 2, pages 402-8, Aug 1986, PMID [http://www.ncbi.nlm.nih.gov/pubmed/3745033 3745033]</ref>
</references>
Lactate, also known as lactic acid, has a bad reputation. It's commonly viewed as a waste product that causes fatigue, burning muscles, and [[Delayed Onset Muscle Soreness]] (DOMS). In reality, Lactate is an intermediary in the metabolism of carbohydrates, and is a fuel source that is preferred by working muscles over glucose. A crude analogy would be a steam train, where the coal (carbohydrate) is burnt to form steam (Lactate), and the steam is used to turn the wheels (muscles). This is a flawed analogy, as the creation of lactate from glucose provides direct energy for the muscles, and of course muscles have other fuel sources such as fat, but hopefully you get to the gist.
=Lactate Production=
At one time it was believed that Lactate was a waste product that indicated insufficient oxygen being supplied to the muscles, but this view has changed. Because Lactate is produced by metabolism in the absence of oxygen<ref name="HillLupton1923"/>, the natural conclusion was that the presence of Lactate indicates insufficient oxygen and therefore anaerobic metabolism<ref name="Wasserman-1984"/><ref name="Mizock-1992"/>. However, more recent studies have that Lactate production is related to exercise intensity, not insufficient oxygen supply<ref name="Connett-1986"/><ref name="Richardson-1998"/>. Lactate levels appear to depend on many factors, including the metabolism of glucose (to pyruvate), Lactate removal, fast twitch fiber recruitment, and energy demand (ADP/ATP ratio, which is in turn dependent on oxygen levels)<ref name="Gladden-2004"/>.
=Lactate and Fatigue=
Initial studies have indicated that that acidity may reduce force production in muscles<ref name="Hermansen-1981"/> or reduce the rate of glucose metabolism<ref name="Sahlin-1992"/>, leading to fatigue, and of course of Lactate is Lactic Acid in the blood. However, more recent studies have shown that the effects of acidity are not seen in more realistic situations<ref name="Westerblad-2002"/><ref name="Bangsbo-1996"/>. A study of isolated rat muscles showed Lactate can protect against fatigue<ref name="Nielsen-2001"/>. However, more research into the role of Lactate and fatigue are required<ref name="Gladden-2004"/>.
=Lactate as a Fuel=
The view of Lactate as a waste product has changed over time, and Lactate has been shown to be a mechanism for distributing carbohydrate (AKA the "Lactate Shuttle"<ref name="Brooks-2000"/>. During prolonged low-moderate intensity exercise, muscles that initially released Lactate into the blood can become net importers<ref name="Stainsby-1966"/><ref name="Gladden-1991"/>. At higher intensities, the working muscles extract and metabolize Lactate, even while being a net Lactate producer<ref name="Stanley-1986"/>. There is some evidence that muscles at rest will absorb and store Lactate<ref name="Kelley-2002"/>, while at exercise the majority of absorbed Lactate is metabolized by the working muscles<ref name="Kelley-2002"/><ref name="Mazzeo-1986"/>. Lactate is a preferred fuel source for working muscles, as extra Lactate injected will be metabolized in place of glucose<ref name="Miller-2002"/>. A low intensities, Lactate will be converted back to Glucose (AKA Gluconeogenesis)<ref name="Roef-2003"/>.
=Lactate Threshold=
In the spite of all of the myths around Lactate and lactic acid, the concept of [[Lactate Threshold]] is both valid and important. [[Lactate Threshold]] is a good predictor of athletic performance, especially in runners.
=Lactate and Wound Healing=
It's been known since the 1960 that lactate is an important part of wound healing, with collagen synthesis almost doubled when Lactate is increased to 15 mmol/l in cultures<ref name="GREEN-1964"/>. When you're used to looking at Lactate levels during exercise this seems ridiculously high, but values of 10-15 mmol/l are commonly seen in healing wounds<ref name="Hunt-1978"/>, and this does not appear to be due to low oxygen levels<ref name="Trabold-2003"/>. In fact, oxygen levels seem to have little impact on lactate levels<ref name="Constant-2000"/><ref name="Sheikh-2000"/>. It's possible that the beneficial effects of Lactate may be in stimulating vascular growth (angiogenesis)<ref name="Constant-2000"/> and/or increased oxygen supply to the wound through vasodilation<ref name="Mori-1998"/><ref name="Trabold-2003"/>.
=References=
<references>
<ref name="Mori-1998">K. Mori, Y. Nakaya, S. Sakamoto, Y. Hayabuchi, S. Matsuoka, Y. Kuroda, Lactate-induced vascular relaxation in porcine coronary arteries is mediated by Ca2+-activated K+ channels., J Mol Cell Cardiol, volume 30, issue 2, pages 349-56, Feb 1998, doi [http://dx.doi.org/10.1006/jmcc.1997.0598 10.1006/jmcc.1997.0598], PMID [http://www.ncbi.nlm.nih.gov/pubmed/9515011 9515011]</ref>
<ref name="Sheikh-2000">AY. Sheikh, JJ. Gibson, MD. Rollins, HW. Hopf, Z. Hussain, TK. Hunt, Effect of hyperoxia on vascular endothelial growth factor levels in a wound model., Arch Surg, volume 135, issue 11, pages 1293-7, Nov 2000, PMID [http://www.ncbi.nlm.nih.gov/pubmed/11074883 11074883]</ref>
<ref name="Constant-2000">JS. Constant, JJ. Feng, DD. Zabel, H. Yuan, DY. Suh, H. Scheuenstuhl, TK. Hunt, MZ. Hussain, Lactate elicits vascular endothelial growth factor from macrophages: a possible alternative to hypoxia., Wound Repair Regen, volume 8, issue 5, pages 353-60, PMID [http://www.ncbi.nlm.nih.gov/pubmed/11115148 11115148]</ref>
<ref name="Trabold-2003">O. Trabold, S. Wagner, C. Wicke, H. Scheuenstuhl, MZ. Hussain, N. Rosen, A. Seremetiev, HD. Becker, TK. Hunt, Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing., Wound Repair Regen, volume 11, issue 6, pages 504-9, PMID [http://www.ncbi.nlm.nih.gov/pubmed/14617293 14617293]</ref>
<ref name="Hunt-1978">TK. Hunt, WB. Conolly, SB. Aronson, P. Goldstein, Anaerobic metabolism and wound healing: an hypothesis for the initiation and cessation of collagen synthesis in wounds., Am J Surg, volume 135, issue 3, pages 328-32, Mar 1978, PMID [http://www.ncbi.nlm.nih.gov/pubmed/626315 626315]</ref>
<ref name="GREEN-1964">H. GREEN, B. GOLDBERG, COLLAGEN AND CELL PROTEIN SYNTHESIS BY AN ESTABLISHED MAMMALIAN FIBROBLAST LINE., Nature, volume 204, pages 347-9, Oct 1964, PMID [http://www.ncbi.nlm.nih.gov/pubmed/14228868 14228868]</ref>
<ref name="Roef-2003">MJ. Roef, K. de Meer, SC. Kalhan, H. Straver, R. Berger, DJ. Reijngoud, Gluconeogenesis in humans with induced hyperlactatemia during low-intensity exercise., Am J Physiol Endocrinol Metab, volume 284, issue 6, pages E1162-71, Jun 2003, doi [http://dx.doi.org/10.1152/ajpendo.00425.2002 10.1152/ajpendo.00425.2002], PMID [http://www.ncbi.nlm.nih.gov/pubmed/12604505 12604505]</ref>
<ref name="Miller-2002">BF. Miller, JA. Fattor, KA. Jacobs, MA. Horning, F. Navazio, MI. Lindinger, GA. Brooks, Lactate and glucose interactions during rest and exercise in men: effect of exogenous lactate infusion., J Physiol, volume 544, issue Pt 3, pages 963-75, Nov 2002, PMID [http://www.ncbi.nlm.nih.gov/pubmed/12411539 12411539]</ref>
<ref name="Mazzeo-1986">RS. Mazzeo, GA. Brooks, DA. Schoeller, TF. Budinger, Disposal of blood [1-13C]lactate in humans during rest and exercise., J Appl Physiol (1985), volume 60, issue 1, pages 232-41, Jan 1986, PMID [http://www.ncbi.nlm.nih.gov/pubmed/3080398 3080398]</ref>
<ref name="Kelley-2002">KM. Kelley, JJ. Hamann, C. Navarre, LB. Gladden, Lactate metabolism in resting and contracting canine skeletal muscle with elevated lactate concentration., J Appl Physiol (1985), volume 93, issue 3, pages 865-72, Sep 2002, doi [http://dx.doi.org/10.1152/japplphysiol.01119.2001 10.1152/japplphysiol.01119.2001], PMID [http://www.ncbi.nlm.nih.gov/pubmed/12183479 12183479]</ref>
<ref name="Stanley-1986">WC. Stanley, EW. Gertz, JA. Wisneski, RA. Neese, DL. Morris, GA. Brooks, Lactate extraction during net lactate release in legs of humans during exercise., J Appl Physiol (1985), volume 60, issue 4, pages 1116-20, Apr 1986, PMID [http://www.ncbi.nlm.nih.gov/pubmed/3084443 3084443]</ref>
<ref name="Gladden-1991">LB. Gladden, Net lactate uptake during progressive steady-level contractions in canine skeletal muscle., J Appl Physiol (1985), volume 71, issue 2, pages 514-20, Aug 1991, PMID [http://www.ncbi.nlm.nih.gov/pubmed/1938723 1938723]</ref>
<ref name="Stainsby-1966">WN. Stainsby, HG. Welch, Lactate metabolism of contracting dog skeletal muscle in situ., Am J Physiol, volume 211, issue 1, pages 177-83, Jul 1966, PMID [http://www.ncbi.nlm.nih.gov/pubmed/5911036 5911036]</ref>
<ref name="Brooks-2000">GA. Brooks, Intra- and extra-cellular lactate shuttles., Med Sci Sports Exerc, volume 32, issue 4, pages 790-9, Apr 2000, PMID [http://www.ncbi.nlm.nih.gov/pubmed/10776898 10776898]</ref>
<ref name="Nielsen-2001">OB. Nielsen, F. de Paoli, K. Overgaard, Protective effects of lactic acid on force production in rat skeletal muscle., J Physiol, volume 536, issue Pt 1, pages 161-6, Oct 2001, PMID [http://www.ncbi.nlm.nih.gov/pubmed/11579166 11579166]</ref>
<ref name="Bangsbo-1996">J. Bangsbo, K. Madsen, B. Kiens, EA. Richter, Effect of muscle acidity on muscle metabolism and fatigue during intense exercise in man., J Physiol, volume 495 ( Pt 2), pages 587-96, Sep 1996, PMID [http://www.ncbi.nlm.nih.gov/pubmed/8887768 8887768]</ref>
<ref name="Westerblad-2002">H. Westerblad, DG. Allen, J. Lännergren, Muscle fatigue: lactic acid or inorganic phosphate the major cause?, News Physiol Sci, volume 17, pages 17-21, Feb 2002, PMID [http://www.ncbi.nlm.nih.gov/pubmed/11821531 11821531]</ref>
<ref name="Sahlin-1992">K. Sahlin, Metabolic factors in fatigue., Sports Med, volume 13, issue 2, pages 99-107, Feb 1992, PMID [http://www.ncbi.nlm.nih.gov/pubmed/1561513 1561513]</ref>
<ref name="Hermansen-1981">L. Hermansen, Effect of metabolic changes on force generation in skeletal muscle during maximal exercise., Ciba Found Symp, volume 82, pages 75-88, 1981, PMID [http://www.ncbi.nlm.nih.gov/pubmed/6913479 6913479]</ref>
<ref name="Gladden-2004">LB. Gladden, Lactate metabolism: a new paradigm for the third millennium., J Physiol, volume 558, issue Pt 1, pages 5-30, Jul 2004, doi [http://dx.doi.org/10.1113/jphysiol.2003.058701 10.1113/jphysiol.2003.058701], PMID [http://www.ncbi.nlm.nih.gov/pubmed/15131240 15131240]</ref>
<ref name="Richardson-1998">RS. Richardson, EA. Noyszewski, JS. Leigh, PD. Wagner, Lactate efflux from exercising human skeletal muscle: role of intracellular PO2., J Appl Physiol (1985), volume 85, issue 2, pages 627-34, Aug 1998, PMID [http://www.ncbi.nlm.nih.gov/pubmed/9688741 9688741]</ref>
<ref name="Wasserman-1984">K. Wasserman, The anaerobic threshold measurement to evaluate exercise performance., Am Rev Respir Dis, volume 129, issue 2 Pt 2, pages S35-40, Feb 1984, PMID [http://www.ncbi.nlm.nih.gov/pubmed/6421216 6421216]</ref>
<ref name="HillLupton1923">A. V. Hill, H. Lupton, Muscular Exercise, Lactic Acid, and the Supply and Utilization of Oxygen, QJM, volume os-16, issue 62, 1923, pages 135–171, ISSN [http://www.worldcat.org/issn/1460-2725 1460-2725], doi [http://dx.doi.org/10.1093/qjmed/os-16.62.135 10.1093/qjmed/os-16.62.135]</ref>
<ref name="Mizock-1992">BA. Mizock, JL. Falk, Lactic acidosis in critical illness., Crit Care Med, volume 20, issue 1, pages 80-93, Jan 1992, PMID [http://www.ncbi.nlm.nih.gov/pubmed/1309494 1309494]</ref>
<ref name="Connett-1986">RJ. Connett, TE. Gayeski, CR. Honig, Lactate efflux is unrelated to intracellular PO2 in a working red muscle in situ., J Appl Physiol (1985), volume 61, issue 2, pages 402-8, Aug 1986, PMID [http://www.ncbi.nlm.nih.gov/pubmed/3745033 3745033]</ref>
</references>
