Immunohistochemical images demonstrating some components of the lactate oxidation complex in L6, cultured rat muscle cells. This complex involves the mitochondrial constituent cytochrome oxidase, the lactate transport protein, lactate dehydrogenase (LDH) and other constituents. Shown is co-localization of Lactate dehydrogenase (LDH) (and mitochondrial cytochrome oxidase (COX) where most oxygen is actually used in cells are imaged. Superposition of signals for LDH (red, B-1) and COX (green) shows co-localization of LDH in the mitochondrial reticulum (yellow) of cultured L6 rat muscle cells. Depth of field ~1 mm, scale bar = 10 mm.
Professor George A. Brooks (email@example.com)
5101 Valley Life Sciences Building
510 642 2861
Jill A. Fattor
Michael A. Horning
Gregory C. Henderson
The Lactate Shuttle: The Shuttling of lactate between cell compartments, cells, tissues and organs is a major means of distributing carbohydrate energy, supporting glycemia via gluconeogenesis, and intracellular as well as cell-cell signaling. Lactate is formed continuously, but especially after carbohydrate nutrition and during physical exercise. Most (70-80%) of lactate formed during exercise is oxidized and used as a fuel energy source. Working red skeletal muscle and heart are fueled by lactate during exercise. Other tissues, such as brain, also use lactate as a fuel during exercise. The remainder of lactate disposal (20-30%) during exercise is for conversion to glucose in the liver and kidneys, but the magnitude of lactate turnover during exercise is so great that lactate is the main gluconeogenic precursor. As well, in it’s role as a signaling molecule, lactate has been characterized as a “Lactormone.” In our laboratory we study the regulation of Cell-Cell and Intracellular lactate Shuttles and of the cell protein constituents that facilitate functioning of lactate shuttles. Micrographs at the Top of the page show organization of components of the Mitochondrial Lactate Oxidation Complex in cultured mammalian muscle fibers.
The Crossover Concept: Information on the relative use of fuel energy substrates (carbohydrates, fats, proteins) has been used to develop a model of Energy-Substrate Partitioning in which the effects of exercise intensity, gender, endurance training and nutrition are coordinated and regulated. The Crossover Concept holds that during post-absorptive resting conditions, in muscle and at the whole body in general, fats are the major fuel sources. But, as exercise intensity increases, in working muscle there occurs a switch (Crossover”) from dependence on fats to carbohydrate energy forms as fuel sources. In this context, some amino acids, such as the essential amino acid leucine are used, but in general most amino acids are not important muscle energy sources. A model of the Crossover Concept in which the effect of relative exercise intensity is depicted is shown below.
Figure: Results of an extensive literature search showing blood glucose and free fatty acid flux rates (Ra) and net muscle glycogenolysis as functions of relative exercise intensity as given by % VO2max. This form of analysis indicates exponential increments in muscle glycogenolysis and glucose Ra's as functions of relative exercise intensity. In contrast, the analysis shows multi-component polynomial response of plasma FFA flux, with easy to moderate intensity exercise (i.e., 25-40% VO2max) eliciting a large rise in flux, but crossover and decreasing flux at approximately 55% VO2max. Plasma FFA flux is predicted to reach minimal values as VO2max is approached.
Recent Papers on the Lactate Shuttle
Brooks, G.A, H. Dubouchaud, M. Brown, J. P. Sicurello, and C.E. Butz. Role of mitochondrial lactate dehydrogenase and lactate oxidation in the ‘intra-cellular lactate shuttle.’ Proc. Natl. Acad. Sci. USA 96: 1129-1134, 1999.
Brooks, G.A. Lactate shuttles in nature. Biochemical Society Transactions. 30: 258-264, 2002.
Hashimoto, T., S. Masuda, S. Taguchi, and G. A. Brooks. Immunohistochemical analysis of MCT1, MCT2 and MCT4 expression in rat plantaris muscle. J. Physiol. (London) 567: 121-129, 2005.
Hashimoto, T., R. Hussien and G.A. Brooks. Colocalization of MCT1, CD147 and LDH in mitochondrial inner membrane of L6 cells: Evidence of a mitochondrial lactate oxidation complex. Am J Physiol Endocrinol Metab 290: 1237-1244, 2006.
Hashimoto, T, R. Hussien, S. Oommen, K. Gohil, and G. A. Brooks. Lactate sensitive transcription factor network in L6 myocytes: activation of MCT1 expression and mitochondrial biogenesis. FASEB Journal Mar 29, 2007; [Epub ahead of print].
Recent Papers on the Crossover Concept
Kuo, C.C., J. A. Fattor, G. C. Henderson, and G.A. Brooks. Effect of exercise intensity on lipid oxidation in fit young adults during exercise recovery. J Appl Physiol 99: 349-356, 2005.
Fattor, J.A., B.F. Miller, K.A. Jacobs, and G.A. Brooks. Catecholamine response is attenuated during moderate intensity exercise in response to the “lactate clamp.” Am J Physiol (Endocrinol Metab) 288: E143-E147, 2005.
Jacobs, K.A., R.M. Krauss, J. A. Fattor, M. A. Horning, A.L. Friedlander, T. A. Bauer, T. A. Hagobian, E. E. Wolfel and G. A. Brooks. Endurance training has little effect on active muscle fatty acid, lipoprotein, or triglyceride net balances. Am J Physiol Endocrinol Metab. 29: E656-665, 2006.
Friedlander, A.L., K. A. Jacobs, J. A. Fattor, M. A. Horning, T. A. Hagobian, T. A. Bauer, E. E. Wolfel and G. A. Brooks. Contributions of working muscle to whole body lipid metabolism vary with exercise intensity and training. Am J Physiol Endocrinol Metab. 292: E107-E116, 2007
Wallis, G.A., A.L. Friedlander, K.A. Jacobs, M.A. Horning, J.A. Fattor, E.E. Wolfel, G.D. Lopaschuk, and G.A. Brooks. Augmented working leg glycerol turnover after short-term endurance training in men. Am J Physiol Endocrinol Metab.
Response to Criticisms on Discovery of the Mitochondrial Lactate Oxidation Complex: (https:// )