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Amino Acids - the Building Blocks of the Body That Guides Metabolism

Amino Acids - the Building Blocks of the Body That Guides Metabolism

Posted By Rupa Jaiswal Posted on Oct 29, 2021

Am I now going to get diabetes and heart disease?" asked a 37year-old high school math teacher to the doctor, as his medical V test reports showed raised levels of blood sugar , serum triglycerides and Low Density Lipoprotein (LDL) cholesterol . Additionally, he also had excess fat accumulation around the waist. With this ominous combination, his doctor indeed could understand that he was gradually moving towards a Health condition called "Metabolic syndrome".

Amino Acids - the Building Blocks of the Body That Guides Metabolism

Dangers of Metabolic Syndrome (MS) The Metabolic Syndrome is a set of disorders that increases the risk of obesity , diabetes and heart diseases. Most notably-abdominal obesity or a waist circumference of at least 35 inches in women and 40 inches in men is worrisome. That is because abdominal fat is metabolically more active than fat in rest of the body, which means it is more likely to trigger heart attack or stroke. With an increased concern about obesity, people who are lean might feel complacent. So, if excess weight pancreas means disease, then normal weight indicates good health, isn't it? Not always. Being lean does not preclude anything. Metabolic Syndrome is a silent killer and can strike anyone, be it overweight or not. Among its major components are excess weight,insulin dyslipidemia (high levels of triglycerides and low levels of HDL in the blood), high blood pressure leading to plaque build-up in blood vessel walls and insulin resistance (the inability of muscle, fat and liver cells to absorb glucose in response to insulin, leading to excess glucose in the blood). Its biochemical underpinnings are still being worked upon to understand the intricacies.

A Glance at Global Scenario! Metabolic Syndrome burdens major portions of the world's population. Globally, around 30-40% people above the age of 65 years are affected, reason being obesity in adulthood. Research suggests that in India, more than 20800 adults are bearing the brunt of this condition, though most of us do not realize it and remain in the darkness till adverse consequences are witnessed.

What Causes Metabolic Syndrome?
The occurence of Metabolic Syndrome is not yet clear, but it involves a cluster of medical conditions that probably can be a cause of it. Some of them are mentioned below:
Insulin resistance. Insulin is a hormone responsible for escorting glucose from our blood into cells, where it is used as fuel for energy. In people with insulin resistance, the insulin does not function well, so the body keeps making more and more of it to cope with the rising level of glucose. In fact, it is often a prelude to type 2 diabetes. Insulin resistance is closely associated with central obesity.

Obesity (especially abdominal obesity)Experts say that the prevalence of Metabolic Syndrome has increased because of rising obesity rates. Having extra fats in the abdomen as opposed to anywhere else in the body seems to increase its risk.

Unhealthy lifestyle Not getting enough physical activity and eating unhealthy processed foods in diet also play a role in triggering metabolic syndrome.

Association of Amino acids with Metabolic Syndrome A common perception is that, this constellation of maladies is driven principally by increased fat consumption in the diet. Whether a star athlete or an individual just starting out the fitness journey, it is likely that a person understands the importance of proteins , fats and carbohydrates in the diet. Proteins are required for normal well -being, but once the body uses protein to build and maintain healthy muscles, bones and skin, only the essential amino acids are left.

These essential amino acids cannot be produced by your body and must be acquired through a healthy and well balanced diet. Whole food such as meat, fish, poultry, beans, dairy products, nuts and seeds are the best sources of protein and thus, for essential amino acids as well. Rightly named due to the fact that they are required for survival, these essential amino acids are overlooked inspite of playing a pivotal role in maintaining overall health.

Recent studies have rekindled interest in understanding the potential role of proteins and amino acid metabolism in development of metabolic syndrome. Amino acids are basic structural protein units composed of nitrogen, carbon, hydrogen and oxygen, along with a variable side chain group. They display a remarkable metabolic and regulatory versatility. Serving as essential precursors for the synthesis of a variety of molecules, they also regulate key metabolic pathways and processes that are vital for the health, growth , development, reproduction and homeostasis in the body.

Although more than 300 amino acids have been found, only 20 of them are standard and contain a specific sidechain. Three Branched Chain Amino Acids (BCAAs), including isoleucine, leucine and valine, have unique properties with diverse physiological and metabolic roles. BCAAs are primarily oxidized in the peripheral tissue, particularly in skeletal muscle, whereas the other amino acids catabolize in the liver.

Nerdy Intermission of Amino Acids in Metabolic Syndrome Evidence suggests that BCAAs and aromatic amino acids (phenylalanine and tyrosine) are associated with insulin resistance and hyperglycemia at a single time point. Amino acids can, under appropriate conditions, enhance insulin secretion from primary islets of langerhans cells and B-cell lines. Already several decades ago, research found that obese individuals have elevated concentrations of BCAAs and aromatic amino acids, which predicts future impairment in insulin sensitivity in young adults.

Type 2 Diabetes mellitus (DM) is a common metabolic disorder predisposing diabetic cardiomyopathy and atherosclerotic Cardiovascular Disease (CVD), leading to heart failure through a variety of mechanisms. The close relationship between type 2 DM and CVD has led to the common hypothesis, that postulates both the conditions share common genetic and environmental factors influencing this association. However, the common risk factors of both are obesity, insulin resistance, dyslipidemia, inflammation and thrombophilia that can be very well identified in the majority of affected patients. Less is known about how these factors influence both conditions, so efforts are still needed for a more comprehensive understanding of this relationship.

Amino Acid Perturbations in Progression of Metabolic Syndrome
a) Impact of amino acids on gut microbiota The Gastrointestinal (GI) tract is the habitat of a highly diverse and dynamic microbial community, predominantly composed of bacterial species. As a part of the major nutrients in the diet, amino acids should be particularly taken into account since they not only support the growth and survival of bacteria in the GI tract, but also regulate energy and protein homeostasis in organisms. The most prevalent amino acid fermenting bacterial species in small intestine belongs to BacillusLactobacillus-Streptococcus group, Clostridium clusters and Proteobacteria, whereas Clostridia and Peptostreptococci are mostly involved in amino acid fermentation in large intestine.

b) Inborn errors of metabolism Inborn Errors of Metabolism (IEM) represent a group of inherited disorders in which a genetic defect leads to a block on metabolic pathway, resulting in a single enzyme dysfunction. Amino acid disorders are a group of IEM caused due to inherited defects in pathways involved in amino acids metabolism. As a downstream consequence of lack or a partial enzyme activity involved in amino acids metabolism, there is an accumulation of toxic metabolites in the proximity of the metabolic block or a deficiency of an essential metabolic product that leads to the clinical presentation of the condition. Amino acid disorders, are therefore, biochemically characterized by abnormal levels of single or several amino acids and their downstream plasma or urine metabolites. These disorders are presented with variables and often show non-specific clinical symptoms. This category of IEMs can be diagnosed and monitored by amino acid analysis. In conjunction with medical support, they can be managed by nutritional restrictions and supplemental help.

Approach to investigate IEM- The "omic" approach involves biological information capture and data management that provides new innovative tools for screening, rapid diagnosis, monitoring and treatment of IEM. The most advanced and recently used technologies delivering global, unbiased and comprehensive chemical information from complex mixtures include Nuclear Magnetic Resonance (NMR) spectroscopy and Mass Spectrometry (MS).

Approaches that use another gas phase separation, lon Mobility Spectrometry (IMS), has been gaining interest in metabolomics recently. Coupled with high resolution mass spectrometry and chromatography (LC-IM-MS), IMS provides additional analyte selectivity without compromising the rate of measurements Pharmacological chaperones aid in binding misfolded proteins specifically, stabilizing their conformation, thereby preventing early degradation and allowing proper cellular trafficking and localization.

Insulin resistance Comprehensive metabolic profiling, also known as "metabolomics", has recently provided unique insights into mechanisms underlying development of insulin resistance. These studies demonstrate a strong and preferential association of the BCAA-related metabolite cluster with insulin resistance and coronary artery disease. Interactions of excess BCAA and lipids in the development of B-cell dysfunction drives the transition from the obese, insulin-resistant state to type 2 diabetes . The compendium provides the impetus for gaining better understanding of the potential synergies between this group of metabolites and lipids in development of metabolic dysfunction in multiple tissues.

d) Atherogenic dyslipidemia The key features of atherogenic dyslipidemia are high plasma triglyceride levels, low HDL cholesterol levels and an increase in LDL. Insulin resistance leads to atherogenic dyslipidemia in several ways. Insulin normally suppresses lipolysis in adipocytes, so impaired insulin signaling increases lipolysis, resulting in increased Free Fatty Acid (FFA) levels. In the liver, FFAs serve as substrates for synthesis of triglycerides."

e) Endothelial dysfunction Endothelial dysfunction is the final common pathway between many cardiovascular risk factors and the development of atherosclerosis. It occurs when the endothelium fails to serve its normal physiological and protective mechanisms. This might occur due to the damaged or missing endothelium. It also senses and responds to physiological and pathological stimuli, and produces vasoactive substances. The endothelium modulates the response of the vascular smooth muscle layer, that contributes to intima formation during the atherosclerotic plaque development. Normal endothelial function protects against these processes, and endothelial dysfunction is central to the pathogenesis of atherosclerotic lesion development.

It may occur when the normal responses of the endothelium are affected by hyperglycemia, oxidative stress, FFA , inflammatory cytokines or adipokines .

f) Development of Type 2 DM and CVD Insulin resistance is a core defect in the pathogenesis of type 2 DM, and the condition is associated with increased risk for Diabetes in early adulthood. Type 2 DM is caused by relative or absolute lack of insulin activity, which disrupts the regulation and balance of many metabolic pathways. In addition, impaired insulin sensitivity in young adults frequently precedes a dyslipidemic profile and contributes to development of CVD .

Nonetheless, several studies have indicated a prominent amino acid signature of insulin resistance, even in normoglycemic individuals. Furthermore, the circulating concentrations of BCAAs and aromatic amino acids are associated with the risk of future hyperglycemia and overt diabetes. However, it remains incompletely understood how these amino acids mediate the risk for development of diabetes

Looking for Metabolic Syndrome Most doctors look for the presence of three or more of these componentsd .
Central or abdominal obesity (measured by circumference)
a) Men - greater than 40 inches
b) Women-greater than 35 inches

Triglycerides greater than or equal to 150 milligrams per deciliter of blood (mg/dL) HDL cholesterol:
a) Men - Less than 40 mg/dL
b) Women - Less than 50 mg/dL
Blood pressure greater than or equal to 130/85 millimeters of mercury (mmHg)
fasting glucose levels greater than or equal to 100 mg/dL

Coming back to the 37-year-old high school math teacher. He decided to switch to a better lifestyle including adequate physical activity and to follow balanced diet that consisted of nuts, whole grains, fruits, vegetables, olive oil and fish. All these efforts of him resulted in greater weight loss, improved insulin sensitivity and blood lipids as compared to earlier levels. He also limited his alcohol intake and cut off unhealthy food. Each morning prior to classes, he undertook a 45-minute workout, alternating aerobics with strength training. In the course of one year, he lost 17 percent of his body weight. By regular blood checkups, he kept a track on his cholesterol levels which revealed normal levels of HDL cholesterol, blood sugar and triglycerides. His blood pressure is under control and his new waistline now measures 38 inches, down from 44 inches. He pledged to keep his enthusiasm for his new exercise and diet regimen to lead a healthy life!

Linking Amino Acids with Insulin Resistance Amino acids are basic unit of proteins that play a role in gene expression. These are known to be the building blocks of body as they are required for the normal growth and, development. They are generally classified as essential and non-essential on the basis of their source of origin. Few of the essential ones are leucine, isoleucine and valine, and are named as Branched Chain Amino Acids (BCAAs). They are rich in dietary proteins and account for 15-20% of the total protein intake.' Dietrich in proteins are popularly correlated with impaired glucose tolerance, insulin resistance and increased risk of type 2 diabetes.

Link between carbohydrate and fat metabolism with insulin is well known, however, there seems to exist a link between protein metabolism and insulin resistance as well. The BCAAs being the vital nutrient signals, influence metabolic health either directly or indirectly thereby gaining interest from researchers. The elevated levels of BCAAs are well observed in individuals with obesity, impaired fasting glucose and type 2 diabetes,

How does Amino Acids Affect Metabolic Health?
The elevated levels of amino acids are known to have positive effects on the metabolic health, Leucine, an essential amino acid, can act as a potent signal which helps in the less intake of food. This is done by activating mammalian target of rapamycin (mTOR). Further, BCAAs regulate the release of hormones in both the intestinal tract as well as fat deposits. Intake of BCAAs in the form of supplements are useful in certain liver diseases as they enhance protein synthesis and secretion of hepatic growth factor, and inhibit proteolysis. Apart from the beneficial effects, amino acids also carry a negative impact. In a study conducted by Fiehn, the levels of leucine and valine was increased in women with type 2 diabetes. Several other studies revealed that increased BCAA levels were observed in individuals developing insulin resistance or type 2 diabetes, BCAA can act as a predictor for insulin resistance. In all explaining the strong interlink between BCAA and insulin resistance. The raised levels of BCAAs also reduce the level of aromatic amino acid, causing reduction in release of neurotransmitter and finally leading to a possible risk of depression. Low levels of BCAA along with glycerol are predictive of insulin sensitivity.

Activation of mammalian target of rapamycin (mTOR) by Amino Acids MTOR is a serine or threonine kinase belonging to the protein kinase family, and is known to regulate vital developmental processes like cell growth, differentiation and metabolism. It occurs in two forms namely: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), of which the former controls protein synthesis and cell growth; influenced by extracellular and intracellular signals including growth factors, cell's energy status, oxygen level of the cells and the availability of amino acid, and the latter has role in glucose metabolism in the brain, liver and fat tissues.' mTORC1 also consists of a protein (raptor) that helps in the localization of mTOR, thereby controlling protein synthesis.

Tuberous Sclerosis Complex (TSC) 1/2 and GTP are a hub for transducing the signal to mTOR. TSC is known to negatively regulate mTORC1 by increasing the rate of hydrolysis of GTP of Ras homologous enriched in brain (Rheb). GTP activates mTORC1. On the other side, amino acid signaling independently regulates mTORC1, without the need for TSC and GTP regulation.

Linking mTOR and Insulin Resistance (IR) Insulin is a hormone secreted by the beta cells of Langerhans; high glucose levels in the blood stimulate the release of insulin. On its release, it binds to receptor by phosphorylating it, which in turn activates insulin receptor tyrosine kinase. The activated tyrosine kinase recruits substrates IRS1 and IRS2, and follows insulin signaling thereby regulating the blood glucose levels. Tyrosine kinase is inhibited by protein tyrosine phosphatases (PTPs), which disrupts the insulin signaling and causes insulin resistance. The link between mTOR and insulin resistance can be well understood by the following description: mTORCI BCAAs BCAAs, particularly leucine, stimulates mTOR and its downstream effector. Activated mTOR stimulates 56 kinase 1 by phosphorylation at the S6K1 S6, either mTOR or S6 kinase 1 phosphorylates insulin receptor substrate-1 (IRS 1) found on serine residues, this autophosphorylation interrupts with the insulin signaling and results in insulin resistance. Several other mechanisms have been proposed that explain the mTOR induced insulin resistance. mTOR directly phosphorylates IRS 1/2 and causes its degradation inducing insulin resistance. mTORC1 is also known to add phosphate group to Growth Factor Receptor Bound Protein 10 (GRB10) which breaks the interaction between insulin molecule and its substrate ultimately leading to insulin resistance. mTORC1 can phosphorylate mTORC2 and inhibits its activity and AKT signaling leading to insulin resistance.

Amino Acid Levels: Association with Insulin Action The concentration of amino acids in the body rampants after consuming a protein-rich diet or because of the breakdown of muscle proteins. Of which, the BCAAs are known to regulate protein degradation of protein by decreasing autophagy or by proteasomal activity. Contrary to this, the level of BCAA is observed to be elevated in obese individual even after fasting overnight suggesting that the high levels are not only due to dietary intake, but other related mechanisms. In this view, the gut microbiota plays a role in influencing the BCAA levels in the plasma. They use amino acids for synthesizing bacterial components or for breaking it down to use the metabolic products that leads to obesity. In all, they are known to increase the BCAA levels by de novo synthesis or by influencing the nutrient absorption in the body. From many supported studies, it is very clear that the increased levels is an

between BCAA levels and insulin sensitivity. By reducing the levels of available BCAA in the body, improvisation in insulin sensitivity has been reported."

Amino Acid-A Predictor for Insulin Action Insulin, a pancreatic secretion, is known for the uptake and utilization of glucose, thereby signifying its action However, in obese individuals, the elevated BCAA levels in the skeletal muscles as well as the deposition of lipid by products like acylcarnitines impairs or damages the insulin action, thus the acylcarnitines can be used as a marker to check insulin action. Additionally, higher BCAA concentration in blood can be a better indicator of prediabetic state than the plasma glucose levels. Also, there is an increase in the occurrence of other metabolic abnormalities such as metabolic syndrome and diabetes . The higher levels in children and adolescents predict the future occurrence of insulin resistance

Hence, BCAA levels are potential indicators of both glucose uptake as well as insulin sensitivity,

Scrutinizing the Abnormality As there seems to be a strong association between BCAAs level and the insulin action, this can be used in the diagnosis of type 2 diabetes. Accordingly, it was reported that the levels of BCAA along with Glutamic acid, Proline and Tyrosine were significantly increased in individuals with high insulin. Additionally, the high amino acid levels had a strong correlation with visceral obesity. Not only amino acids are important and useful biomarkers of insulin resistance, they also can give feedback about the drug effect.

The only limitation is that it is complex and expensive when compared to the other available biomarkers for insulin action

Amino Acids in Muscle and Collagen Metabolism Muscles, which are a major part of musculoskeletal system, are indispensable to our human body. Life is nothing without muscles as its absence is inconceivable. Our human heart, which is the first and foremost organ, itself is a muscle. Muscles attach to the bones and governs every locomotion of the body. They also help in joint stabilization, heat generation during movement and maintain our postures.

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Collagen is the main structural protein of extra-cellular matrix found in con muscles and skin. It fosters skin elasticity, contributes tensile strength to tendons and ligaments, and also assists in bone strengthening. Major muscle diseases and disorders include Muscular Dystrophy (MD), tendinosis, fibromyalgia, mitochondrial myopathy, mysthenia gravis and tetanus. Duchenne muscular dystrophy is the most common and dreadful form of MD with an incidence rate of about 1 out of every 3,600 boys'. Collagen vascular diseases refer to a group of hereditary and autoimmune disorders that cause inflammation of collagen and its surrounding joints. They are more prevalent in women than in men. One such diseases, Systemic Lupus Erythematosus (SLE) affects women more frequently than men, with a ratio of approximately nine women to every one man

Muscle and Collagen-What is the Framework?" Muscles are the framework of various tissues and proteins. The three types of muscles found in human body are:
Skeletal muscles- A form of voluntary striated muscles that are attached to the bones to provide support and movement
Cardiac muscles-Involuntary, striated muscles of the heart whose contraction helps in pumping blood
Smooth muscles. Involuntary, non-striated muscles found in the walls of hollow organs to provide pressure to the vessels and organs

The skeletal muscle is made up of many muscle tissues bundled together and surrounded by epimysium. Perimysium is a connective tissue sheath that groups muscle fibers into bundles or fascicles. Endomysium is another protective layer that ensheaths individual muscle fibers. Each muscle fiber consists of myocytes that are formed by the combination of muscle fibers which itself consist of myofibrils. Myofibrils are made up of two major protein filaments-thick filament containing a protein called myosin and thin filament containing a protein called actin. This actin filament is twisted around protein strands called tropomyosin that blocks the binding site; thereby preventing contraction. Actin filaments are bound to a structure called Z-line which are the borders of sacromere; the functional unit for muscle contraction. Myosin binding sites of actin are released by troponin, which is a complex of three regulatory proteins, present between the actin filaments. Sarcomere contraction is regulated by both troponin and tropomyosin via calcium binding. Actin and myosin filaments slide over each other (cross-bridge cycle) using ATP for the muscle contraction to occur. Also, the skeletal muscles serves as a storage pool for amino acids which can be utilized by various organs of the body for organspecific proteins synthesis.

Collagen is made up of amino acids with the primary sequence being glycine-proline-X or glycine-Xhydroxyproline, where X may be any of the other 17 amino acids and every third amino acid is glycine. Proline or hydroxyproline accounts for at least 1/6 of the sequence whereas glycine accounts 1/3 of the sequence. It is triple stranded helical protein with three polypeptide a-chains. Being the smallest amino acid, glycine permits tight configuration of the chains thereby withstanding the stress. There are 28 different types of collagen that have been discovered; however, the most common are type I to IV, while type constitutes over 90% of collagen in the human body .

Collagen synthesis occurs both intracellularly and extracellularly, mainly in the cells of fibroblasts involving several post-translational modifications. Different types of collagen may undergo different post-translational modifications; however, the rudimentary synthesis process is described below:

Proline and lysine are hydroxylated to hydroxyproline and hydroxylysine respectively, in the endoplasmic reticulum, entailing vitamin C (ascorbic acid) as a cofactor. This is followed by glycosylation of the selected hydroxylysine residue. Triple helix configuration is thus, formed from three of the hydroxylated and glycosylated pro-alpha-chains. Procollagen molecule traverses to golgi apparatus for final modifications and they are secreted out of the cells. Now the enzyme, collagen peptidase, cleaves the registration peptides where procollagen molecule becomes tropocollagen. Lysyl oxidase, a copper dependent enzyme, links hydroxylysine and lysine residues, and multiple tropocollagen molecule forms insoluble collagen fibril via covalent bonding.

Vitamin C regulates collagen synthesis without affecting the protein synthesis. Hence, a vitamin C deficiency inhibits the hydroxylation of proline and lysine leading to an intervention in the collagen synthesis which explains the basis for scurvy, a nutritional deficiency disease that has detrimental effects on skin and mucous membranes.

Role of Various Amino Acids and Collagen in Wound Healing Wound healing is a complex process that requires availability of nutrients, especially amino acids, ATP and oxygen. Some of the amino acids also help in wound healing.

Proline: Recent study has confirmed that systemic administration of proline has more positive effects on wound healing that of local administration.
Arginine: It stimulates the release of growth hormone and Insulin-like Growth Factor-1 (IGF-1), which are shown to improve wound healing. Additionally, this improves collagen accumulation, thus accelerating wound healing.
Glutamine: It decreases infectious complications and protects against inflammatory injury; however, its role in wound healing is still under considerable debate.
Ornithine: It is the main metabolite of arginine whose supplementation can enhance wound breaking strength and collagen deposition, thus facilitating wound healing

Beta-hydroxy-beta-methylbutyrate (HMB): It is a metabolite of the essential amino acid leucine whose supplementation in combination with arginine and glutamine can favor wound healing.

Collagen was earlier considered to be functioning as a structural support; however, collagen is involved in all, the steps of wound healing process. Due to its chemotactic property, it attracts cells such as fibroblasts and keratinocytes to the wound site thus, facilitating wound healing. Collagen dressings are widely used in pharmaceutical industry for actively promoting the deposition and organization of newly formed collagen that helps in wound healing.

Amino Acid and Collagen Metabolism During Exercise Exercise modifies amino acid metabolism in our body; especially sustained dynamic exercise stimulates the oxidation of branched chain amino acids providing metabolic energy and production of ammonia with respect to the exercise intensity. Studies proved that the branched chain amino acid, leucine regulates translation initiation of skeletal muscle protein synthesis after exercise Also, studies have shown that acute exercise increases type 1 collagen synthesis

Does Amino Acid Supplementation Help in Building Muscle Mass and Strength in Athletes?
Dietary supplementation of branched chain amino acids are extensively used for muscle strengthening, increasing endurance, reducing mental fatigue and improving performance in sports.

Tryptophan, a precursor of serotonin, is not ergogenic. Its supplementation has been shown to rise serotonin production in order to increase pain tolerance during intense exercise.

Glutamine supplementation has resulted in greater weight reduction; however, several recent studies have demonstrated that both short-term and long-term glutamine supplementation failed to bring ergogenic effect on muscle mass or strength performance.

Potassium and magnesium aspartates are salts of aspartic acid. Ergogenic effect of aspartate supplementation is ambiguous; however, about 50% of the available studies have pointed out enhanced performance in aerobic endurance.

Ornithine, lysine and arginine have been exploited to increase HGH production; but no scientific studies support amino acids supplementation for increasing muscle mass and strength rather than strength training alone.

Tyrosine has been proposed to be ergogenic as its inadequacy could affect optimal physical performance; however, scientific studies have failed to prove that.

A well-balanced diet supplies sufficient protein to fulfill your needs for lysine, proline, glycine and any other amino acids needed for collagen synthesis. In case of inadequate amino acids, supplements can also be used for collagen synthesis.

Amino Acids in Collagen Degradation and Muscle Atrophy Collagen degradation usually occurs with aging, stress and UV exposure. cortisol , a steroid hormones, stimulates this degradation and cleaves collagen into peptides and amino acids.

On the other hand, muscle atrophy occurs as a result of sedentary lifestyle, aging or may be associated with poor prognosis in several diseases. Supplementation of HMB, a metabolite of lysine, has been useful in treating muscular atrophy thereby explaining the beneficial role of amino acids in treating muscle disorders.

Cardiac Metabolism - Do Amino Acids Play a Role?
The human heart is a highly active organ that produces high rate of energy flux. This is required to accomplish the monumental task of pumping over 6500 liters of blood everyday at a relatively constant flow extraordinary amount of work requires a constant supply of Metabolic substrates and oxygen. It is essential to understand the metabolism as it is the fundamental system governing the entire organ's behavior. All cardiac behaviors are highly ATP-dependent and the heart will cease to function in a matter of minutes without ATP. In many types of heart diseases and dysfunctions, metabolism is the first area that is affected, which can lead to decreased contractile function, ion imbalance, increased free radical production and cardiac death. It is important to recognize heart as a metabolic omnivore as it is capable of utilizing glucose, lactate, ketone bodies, fatty acids and certain amino acids as metabolic substrates.

Amino acids play a pivotal role in cardiac metabolism. This ability is especially important under conditions of prolonged stress or ischemia. The heart's reliance on amino acids increase oxygen supply makes cardiomyocytes deprived of fatty acid oxidation and derive energy from amino acids. Amino acids are now becoming more widely appreciated as cardio-protective substrates. Glucose, fatty acids and other substrates require oxygen for full energy yield and produce significant levels of acidic by-products, one of them being amino acids. Amino acids have potential for non-oxidative metabolism and contribute less to cellular acidification Anabolic activity of the ventricle wall is induced by high levels of ventricular pressure ATP can directly be produced from glutamine and glutamate through substrate level phosphorylation and hence, these amino acids are important for ischemic and hypertrophied heart.

Recently, specific amino acids have been associated with incident cardiovascular disorders, that suggest their significant role in the pathogenesis of Cardiovascular Disease (CVD). Since the plasma values of leucine, isoleucine and valine are frequently found in high concentrations in individuals with CVD risk, special attention has been paid to this group of Branched-Chain Amino Acids (BCAAs). Nevertheless, dietary BCAA, leucine in particular, has been used as an indicator of atherosclerosis. Apart from this, amino acids are also associated with macrophage foam cell formation which in turn leads to the development of atherosclerosis.

How do amino acids help in heart metabolism?
Amino acids, also, have an indirect role in regulating ATP production or utilization in impairing myocardial processes, by several different mechanisms. As amino acids lose the amino group, the remaining carbon skeleton is converted to glucose, and the intermediates of the Tricarboxylic Acid Cycle (TCA) are produced. In addition, specific amino acids such as aspartate influence ATP formation from Adenosine Monophosphate (AMP) via the action of auxiliary enzymes. The role of aspartate is to shuttle amino groups, derived from other amino acids, to inosine monophosphate, which further yields AMP. The AMP is further hydrolyzed to yield free NH3 and inosine, monophosphate, or transformed into ATP. This cycle has important regulatory and metabolic functions in myocardial cells. NH3 can buffer hydrogen ion production during ischemia, thereby maintaining intracellular pH. This effect is important because myocardial acidosis has several deleterious consequences, including inhibition of various metabolic pathways and aggregation of nuclear chromatin. Amino acids are not only precursors of the adenosyl moiety of AMP, ADP and ATP, but also of important molecules involved in cardiac ATP metabolism, such as carnitine and creatine,

Amino acids: Role in cardiovascular diseases and atherosclerosis development Over the past few years, individual or clusters of amino acids have been identified as novel biomarkers and metabolic signatures that revealed multiple circulating metabolites associated with cardiovascular risks through metabolomics. Glutamate and glutamine have been associated with atherosclerosis development and CVD risk, and have been related to cardio-metabolic disorders as well. Furthermore, glutamine is associated with increased risk for both plaque development and increased intima thickness which are linked with the clinical manifestations of atherosclerosis. Along with these two amino acids, other potential atherogenic amino acids are methionine and its metabolic intermediate, homocysteine, which have been found to promote atherosclerosis development in humans. It has been found that arginine, the main precursor for nitric oxide production in the vascular endothelium, improves endothelial function in CVD. Recent studies have described a strong positive correlation between the levels of plasma BCAA and metabolic diseases, and recognized them as biomarkers for CVD risk, while others claim the potential role of BCAA catabolism in cardiac pathophysiology

Biomarkers for Cardiovascular Disorder risk Biomarkers not only help in risk stratification, but also highlight the pathways which can be targeted to lower the risk. The availability of less biased molecular profiling technologies such as proteomics and metabolomics, have advanced biomarker discovery efforts, BCAAs in particular, have been consistently observed as strongly associated with higher CVD risk. Leucine, isoleucine and valine constitute the group of BCAA due to similar structural features of their side-chain and a distinct catabolic pathway in the first two steps of their catabolism. Unlike other amino acids, BCAA are primarily catabolized in the extrahepatic tissues, primarily in the cardiac muscle. They are essential for normal growth and functions at cellular and organ levels. However, an excess amount of free BCAA or their catabolic products can also be cytotoxic. Elevated concentrations of each or total BCAA in individuals increase cardiovascular risk factors.

Macrophage foam cell formation- a key feature during atherosclerosis development Macrophages are recognized as significant pathophysiological agents in diseases associated with Chronic inflammation and aging, including atherosclerosis. A critical early step in atherosclerosis development is the infiltration of monocytes from the circulation into the arterial wall, where they are differentiated into macrophages and accumulate lipids in a process known as macrophage foam cell formation, this is the hallmark feature of early atherogenesis (formation of fatty deposits in the arteries) The balance between lipoprotein uptake by macrophages, lipid biosynthesis rate within the macrophages, and the cholesterol efflux can help in determining the initiation and progression of the atherosclerotic lesions. However, the amino acid contribution to macrophage foam cell formation, and the setting of the inflammatory diseases, remains underexplored.

Ways to monitor and quantify amino acids The levels of amino acids in heart are monitored by measuring the difference in their concentrations between coronary arterial input and coronary venous output across the whole heart. Many pioneering studies in cardiac physiology employed this method to establish the foundation of cardiac metabolism. There are many methods that are now in use for precisely quantifying the amino acid flux in the myocardium as well as in identifying the metabolic fates of the molecules.

The most accurate and widely employed amino acid monitoring technique is the radio-labeled tracer study These labels can be detected using Positron EmissionTomography (PET-CT scan) for imaging amino acid accumulation in the tissues as well as quantifying media depletion in a a culture setting. Similarly, NMR studies detect and track the labeled carbon or nitrogen through its many conversions to determine how the amino acid was metabolized. Mass spectrometry is a highly sensitive method for quantifying amino acid flux and is capable of rapid processing of large numbers of samples.

Diagnostic aid All cardiac behaviors are highly ATP-dependent and imbalance in ATP supply and deficit in oxygen supply leads to heart failure. Although diet is indisputably of importance in modulating overall disease risk, the application of metabolite profiling is an important step forward. A better understanding of the environmental and genetic determinants of plasma BCAA signaling would aid in the advancement of the investigation and unravel the complex relationship between diet influenced metabolites, disease-related metabolic signaling and cardio-metabolic risk. Thyrocare offers amino acid profile for detection of amino acids for preventive and diagnostic screening at affordable rates, using highly sensitive and automated technology.

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Managing the risk Cardiovascular disorders are considerably affected by exogenous dietary factors. While lipids have been designated as the main dietary contributors to the onset of this inflammatory condition, novel data indicated potential involvement of some specific amino acids in the process of macrophage foam cell formation, the hallmark feature of early atherogenesis. Echocardiography is a simple and relatively inexpensive diagnostic method that uses both conventional and more recent modalities and is a primary diagnostic tool for the assessment of early cardiac dysfunction. A strong professional liaison between echocardiologists and occupational physicians helps the process to offer effective support and management to the cardiovascular patients .

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