Iron Game
Veteran
Branched-chain amino acids (BCAAs) were once thought to just be a major amino acid found in muscle and thus we should consume them to build muscle. This overly simple thought process led many bodybuilders in the ‘80s and ‘90s to recommend their nutritional supplementation for muscle growth. Little did they know that these essential amino acids valine, isoleucine and leucine would prove to be signaling molecules, almost hormones if you will, for muscle growth and metabolism.
There are many hormones that regulate the metabolism of various nutrients. Among these, insulin is the master regulator affecting the metabolism of all of the macronutrients: proteins, carbohydrates and fats. Without insulin we could not grow, develop or survive for that matter. Insulin is very anabolic and is a key stimulant to muscle protein synthesis and inhibition of protein breakdown. In a very similar way, the BCAA leucine functions to stimulate muscle protein synthesis and inhibit the breakdown of muscle proteins.
Recent research on leucine has greatly overshadowed the research on the biological functions of isoleucine and valine, beyond their incorporation into muscle proteins. Particularly isoleucine has also been found to have functions in regulating glucose metabolism very similar to insulin— such as stimulating the uptake of glucose by muscle cells and inhibition of gluconeogenesis (production of more glucose).1 Valine also has actions similar to insulin in that it seems to regulate the metabolism of fatty acids. A study looking into the physiology of liver regeneration found that valine enhanced the uptake of fatty acids from the blood and stimulated regeneration of liver tissue.2
If we put the data about leucine, isoleucine and valine together, we get a very interesting story. The data backs up the theory that BCAAs regulate the metabolism of all three of the macronutrients just as insulin does. Other studies support the ability of BCAAs to maintain muscle mass in aging and enhance protein synthesis around exercise. Amongst any of the essential macronutrients including essential fatty acids and essential amino acids, BCAAs play a unique role in anabolic biology and are essential to the bodybuilding lifestyle. Often our elders in sport were surprisingly right, even though they didn’t really know why that which they recommended worked.
References:
1. Doi M, et al. Hypoglycemic effect of isoleucine involves increased muscle glucose uptake and whole body glucose oxidation and decreased hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 2007;292:E1683-93.
2. Chida A, et al. The effect of valine on lipid metabolic homeostasis in regenerating remnant liver after hepatectomy. J Surg Met Nutr 2003;37:179-88.
Leucine and Metformin
Metformin is a drug often used as a first-line treatment for diabetes. There is a consistent finding with the use of metformin in the treatment of obese type 2 diabetics in that it significantly affects weight loss in a beneficial way. Thus, bodybuilders have tried to take advantage of its fat-loss effects. The major action of metformin in diabetes is thought to depend on decreased liver glucose output, increased intestinal glucose breakdown to lactate, as well as peripheral tissue insulin-dependent glucose uptake. With less glucose for energy, fat burning for energy may be favored and thus the “leaning out” effect.
Metformin has been shown to act through a reduction in mitochondrial metabolism and thus a reduction in ATP production (ATP is used by muscle to create the energy of contraction). When ATP is lower, this activates an enzyme called AMPK. AMPK inhibits mTORC1 activity, which is a key regulator responsible for initiating muscle protein synthesis. Many studies have demonstrated how leucine is capable of stimulating the initiation of muscle protein synthesis through mTORC1.1 Essentially, what occurs is the following: when energy availability is low (i.e., glucose deprivation) this activates AMPK, which inhibits the use of proteins for growth so that the body doesn’t go into energy debt.
Relatively recent studies suggest that metformin can directly inhibit the actions of leucine on mTOR.2 Not only does this not bode well for muscle growth, but the inhibitory effect of metformin on mTOR is believed to be a major player in its correlation with reduced risk of deadly cancers in diabetic patients.3 Interestingly, Dr. Melnik of the University of Osnabrück in Germany, postulated that metformin may be a direct competitor with leucine for binding and activation of mTORC1. He noted in his article that the usual daily dose of metformin (2 grams per day) is in the range of the 2 grams of leucine derived from daily consumption of 100 grams of meat or cheese. Since these two compounds are similar in structure and size, they may be competing for the same sites in mTOR activation.
There is a great deal of conflicting data as to how leucine and high-protein western diets may contribute to exacerbation of obesity and the type 2 diabetes epidemic. Activation of mTOR signaling by leucine is thought to cause oversecretion of insulin, early cell death of insulin producing beta cells, and perpetuation of infant obesity via its high content in cow’s milk-derived infant formula. However, the exercise and sports supplementation literature paints a better picture of leucine and its strong ability to enhance muscle protein synthesis, limit muscle atrophy and improve insulin resistance. There may be a happy medium here for the scientists to hammer out in future studies.
References:
1. Melnik BC. Leucine signaling in the pathogenesis of type 2 diabetes and obesity. World J Diabetes 2012;March 15:3(3)38-53.
2. Kalender A, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010;11:390-401.
3. Bo S, et al. Cancer mortality reduction and metformin: a retrospective cohort study in type 2 diabetic patients Diabetes Obes Metab 2012;Jan;14(1):23-9.
BCAAs and Green Tea Protect the Liver
In a recent review, Japanese researchers evaluated a nutraceutical approach utilizing BCAAs and green tea catechins (GTCs) to limit the formation of colorectal and liver cancers.1 The metabolic abnormalities associated with obesity, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1) receptor axis and the state of chronic inflammation increase the risk of colorectal and liver cancers.
In recent years, GTCs have received considerable attention because of their beneficial effects: they improve metabolic abnormalities and prevent cancer development. A recent meta-analysis of clinical trials reported that GTCs help reduce bodyweight.2 Contributing mechanisms include an increase in energy expenditure, stimulation of fatty acid oxidation and reduction of nutrient absorption.3 In animal studies, green tea or its constituents were found to significantly reduce bodyweight and, therefore, improve hyperglycemia, hyperinsulinemia, hyperleptinemia and liver dysfunction.4
Dietary supplementation with branched-chain amino acids (leucine, isoleucine and valine) can prevent progressive liver failure in patients with chronic liver disease by improving insulin resistance.1 BCAAs can also reduce the risk of liver cancer in liver failure patients who are obese. An animal model suggested that the cancer-suppressing effects of the BCAAs may have been through the inhibition of new blood vessel formation normally modulated by vascular endothelial growth factor (VEGF).5
Whether or not BCAAs and GTCs can improve liver function in otherwise healthy individuals has not been substantiated, but the protective effect in liver disease and colorectal cancers in promising. Based on the studies presented by the Shimizu et al., GTCs and BCAAs might be an effective approach for the prevention of cancers of the GI system.
References:
1. Shimizu M, et al. Nutraceutical Approach for Preventing Obesity-Related Colorectal and Liver CarcinogenesisInt. J Mol Sci 2012;13:579-595.
2. Hursel R, et al. The effects of green tea on weight loss and weight maintenance: A meta-analysis. Int J Obes 2009;33:956-961.
3. Rains TM, et al. Antiobesity effects of green tea catechins: A mechanistic review. J Nutr Biochem 2011;22:1-7.
4. Grove KA, Lambert JD. Laboratory, epidemiological, and human intervention studies show that tea (Camellia sinensis) may be useful in the prevention of obesity. J Nutr 2010;140:446-453.
5. Yoshiji H, et al. Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats. J Gastroenterol 2009;44:483-491.
Dr. Victor Prisk is a board certified Orthopaedic Surgeon and IFBB Professional Bodybuilder. Dr. Prisk is an active member of the GNC Medical Advisory Board and creator of the “G.A.I.N. Plan.” He is an NCAA All-American gymnast, champion swing dancer and NPC Welterweight National Champion.
There are many hormones that regulate the metabolism of various nutrients. Among these, insulin is the master regulator affecting the metabolism of all of the macronutrients: proteins, carbohydrates and fats. Without insulin we could not grow, develop or survive for that matter. Insulin is very anabolic and is a key stimulant to muscle protein synthesis and inhibition of protein breakdown. In a very similar way, the BCAA leucine functions to stimulate muscle protein synthesis and inhibit the breakdown of muscle proteins.
Recent research on leucine has greatly overshadowed the research on the biological functions of isoleucine and valine, beyond their incorporation into muscle proteins. Particularly isoleucine has also been found to have functions in regulating glucose metabolism very similar to insulin— such as stimulating the uptake of glucose by muscle cells and inhibition of gluconeogenesis (production of more glucose).1 Valine also has actions similar to insulin in that it seems to regulate the metabolism of fatty acids. A study looking into the physiology of liver regeneration found that valine enhanced the uptake of fatty acids from the blood and stimulated regeneration of liver tissue.2
If we put the data about leucine, isoleucine and valine together, we get a very interesting story. The data backs up the theory that BCAAs regulate the metabolism of all three of the macronutrients just as insulin does. Other studies support the ability of BCAAs to maintain muscle mass in aging and enhance protein synthesis around exercise. Amongst any of the essential macronutrients including essential fatty acids and essential amino acids, BCAAs play a unique role in anabolic biology and are essential to the bodybuilding lifestyle. Often our elders in sport were surprisingly right, even though they didn’t really know why that which they recommended worked.
References:
1. Doi M, et al. Hypoglycemic effect of isoleucine involves increased muscle glucose uptake and whole body glucose oxidation and decreased hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 2007;292:E1683-93.
2. Chida A, et al. The effect of valine on lipid metabolic homeostasis in regenerating remnant liver after hepatectomy. J Surg Met Nutr 2003;37:179-88.
Leucine and Metformin
Metformin is a drug often used as a first-line treatment for diabetes. There is a consistent finding with the use of metformin in the treatment of obese type 2 diabetics in that it significantly affects weight loss in a beneficial way. Thus, bodybuilders have tried to take advantage of its fat-loss effects. The major action of metformin in diabetes is thought to depend on decreased liver glucose output, increased intestinal glucose breakdown to lactate, as well as peripheral tissue insulin-dependent glucose uptake. With less glucose for energy, fat burning for energy may be favored and thus the “leaning out” effect.
Metformin has been shown to act through a reduction in mitochondrial metabolism and thus a reduction in ATP production (ATP is used by muscle to create the energy of contraction). When ATP is lower, this activates an enzyme called AMPK. AMPK inhibits mTORC1 activity, which is a key regulator responsible for initiating muscle protein synthesis. Many studies have demonstrated how leucine is capable of stimulating the initiation of muscle protein synthesis through mTORC1.1 Essentially, what occurs is the following: when energy availability is low (i.e., glucose deprivation) this activates AMPK, which inhibits the use of proteins for growth so that the body doesn’t go into energy debt.
Relatively recent studies suggest that metformin can directly inhibit the actions of leucine on mTOR.2 Not only does this not bode well for muscle growth, but the inhibitory effect of metformin on mTOR is believed to be a major player in its correlation with reduced risk of deadly cancers in diabetic patients.3 Interestingly, Dr. Melnik of the University of Osnabrück in Germany, postulated that metformin may be a direct competitor with leucine for binding and activation of mTORC1. He noted in his article that the usual daily dose of metformin (2 grams per day) is in the range of the 2 grams of leucine derived from daily consumption of 100 grams of meat or cheese. Since these two compounds are similar in structure and size, they may be competing for the same sites in mTOR activation.
There is a great deal of conflicting data as to how leucine and high-protein western diets may contribute to exacerbation of obesity and the type 2 diabetes epidemic. Activation of mTOR signaling by leucine is thought to cause oversecretion of insulin, early cell death of insulin producing beta cells, and perpetuation of infant obesity via its high content in cow’s milk-derived infant formula. However, the exercise and sports supplementation literature paints a better picture of leucine and its strong ability to enhance muscle protein synthesis, limit muscle atrophy and improve insulin resistance. There may be a happy medium here for the scientists to hammer out in future studies.
References:
1. Melnik BC. Leucine signaling in the pathogenesis of type 2 diabetes and obesity. World J Diabetes 2012;March 15:3(3)38-53.
2. Kalender A, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010;11:390-401.
3. Bo S, et al. Cancer mortality reduction and metformin: a retrospective cohort study in type 2 diabetic patients Diabetes Obes Metab 2012;Jan;14(1):23-9.
BCAAs and Green Tea Protect the Liver
In a recent review, Japanese researchers evaluated a nutraceutical approach utilizing BCAAs and green tea catechins (GTCs) to limit the formation of colorectal and liver cancers.1 The metabolic abnormalities associated with obesity, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1) receptor axis and the state of chronic inflammation increase the risk of colorectal and liver cancers.
In recent years, GTCs have received considerable attention because of their beneficial effects: they improve metabolic abnormalities and prevent cancer development. A recent meta-analysis of clinical trials reported that GTCs help reduce bodyweight.2 Contributing mechanisms include an increase in energy expenditure, stimulation of fatty acid oxidation and reduction of nutrient absorption.3 In animal studies, green tea or its constituents were found to significantly reduce bodyweight and, therefore, improve hyperglycemia, hyperinsulinemia, hyperleptinemia and liver dysfunction.4
Dietary supplementation with branched-chain amino acids (leucine, isoleucine and valine) can prevent progressive liver failure in patients with chronic liver disease by improving insulin resistance.1 BCAAs can also reduce the risk of liver cancer in liver failure patients who are obese. An animal model suggested that the cancer-suppressing effects of the BCAAs may have been through the inhibition of new blood vessel formation normally modulated by vascular endothelial growth factor (VEGF).5
Whether or not BCAAs and GTCs can improve liver function in otherwise healthy individuals has not been substantiated, but the protective effect in liver disease and colorectal cancers in promising. Based on the studies presented by the Shimizu et al., GTCs and BCAAs might be an effective approach for the prevention of cancers of the GI system.
References:
1. Shimizu M, et al. Nutraceutical Approach for Preventing Obesity-Related Colorectal and Liver CarcinogenesisInt. J Mol Sci 2012;13:579-595.
2. Hursel R, et al. The effects of green tea on weight loss and weight maintenance: A meta-analysis. Int J Obes 2009;33:956-961.
3. Rains TM, et al. Antiobesity effects of green tea catechins: A mechanistic review. J Nutr Biochem 2011;22:1-7.
4. Grove KA, Lambert JD. Laboratory, epidemiological, and human intervention studies show that tea (Camellia sinensis) may be useful in the prevention of obesity. J Nutr 2010;140:446-453.
5. Yoshiji H, et al. Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats. J Gastroenterol 2009;44:483-491.
Dr. Victor Prisk is a board certified Orthopaedic Surgeon and IFBB Professional Bodybuilder. Dr. Prisk is an active member of the GNC Medical Advisory Board and creator of the “G.A.I.N. Plan.” He is an NCAA All-American gymnast, champion swing dancer and NPC Welterweight National Champion.
