Dangers of Metabolic Syndrome (MS)
The Metabolic Syndrome is a set of disorders that increases the risk of obesity
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
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
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.
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)
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
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
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
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
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
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
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
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
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
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
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
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.
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