How Does Testosterone Increase Protein Synthesis?
Written by Ben Bunting: BA, PGCert. (Sport & Exercise Nutrition) // British Army Physical Training Instructor // S&C Coach.
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Testosterone is a male hormone made mainly in the testes (part of the male reproductive system). It stimulates the development of sexual characteristics in men, including growth of body hair, deepening of the voice and muscle development.
It also plays a role in the production of sperm and helps men store fat and build bone. However, testosterone levels naturally decline as a man ages.
Amino Acid Transport
Amino acid transport is a major component of intracellular amino acid homeostasis, as it facilitates the movement of intracellular amino acids into the cytosol to be used for protein synthesis. This process is regulated by multiple pathways, including amino acid sensing and intracellular signaling mechanisms. However, more research is needed to explore these mechanisms and to understand the role that amino acid transporters play in this process.
In mammalian cells, amino acid transport is mediated by 60 different secondary active transporters. These include uniporters, symporters and antiporters. Most active transporters are uniporters, which equilibrate the amino acid concentrations in the cytosol and plasma. A few amino acid transporters are cationic, which accumulate their substrates due to a positive charge on the substrate. The most widely expressed transporters are CAT1 and SNAT1/2/4.
When a cell is depleted of amino acids, amino acid uptake is enhanced via an adaptation known as the amino acid transport system. This system is composed of a set of transporters that have overlapping substrate reactivities and compete for the uptake of neutral amino acids. The amino acids involved in this adaptation are leucine, glutamine and alanine.
The transporters have a range of activities, including AA net uptake into the cell, symports and antiports that equilibrate amino acid concentrations in the cytosol, and antiporters that protect against excessive accumulation or binding. In addition, there are a small number of inactive transporters that prevent amino acid accumulation.
During a systems level simulation of amino acid uptake in U87-MG and A549 cells, removal of one or several transporters can dramatically change the amount of amino acids in the amino acid pool. The effects are visible as changes in the final cytosolic amino acid concentrations (Figure 4), with red indicating an increase and blue indicating a decrease of the cytosolic amino acid concentration.
These effects must be taken into account when performing hormonal stimulation of amino acid transport. Hormones can amplify the uptake of amino acids into the cell, but these increases can also be reversed by inhibiting amino acid transport. In addition, hormonal stimulation may induce the release of other hormones that produce secondary effects on amino acid transport and metabolism.
Intracellular Amino Acids
The cellular amino acid concentrations in both intracellular and extracellular pools are very different. These differences are a direct cause of the lack of correlation between intracellular and plasma protein synthesis. To determine the relationship of these intracellular amino acid concentrations to the underlying physiological processes that drive protein synthesis, a model was developed to examine simultaneous protein synthesis in the cell and the plasma using viable leukocytes as an in vitro cell model.
The model used a two-step looping algorithm. In the first step, a model of the metabolic conversions that result in an increase or decrease in the cellular amino acid concentration was constructed. The second step was to use a model of the physiological effects of the increased and decreased cellular amino acid concentrations on protein synthesis. The results showed that the intracellular concentration of threonine, phenylalanine, tryptophan, alanine, valine, methionine, histidine, and citrulline were related to the simultaneous increase or decrease in these amino acids in the plasma.
Several types of transporters are responsible for net amino acid uptake into cells. Some mediate net uptake through uniporters, whereas others are able to exchange a neutral amino acid with Na+ or K+ against a cationic amino acid. Examples include LAT1 (SLC7A5, large neutral AA), y+LAT2 (SLC7A6, neutral and cationic AA), ASCT1 (SLC1A4, small neutral AA), and ASCT2 (SLC7A5, polar neutral AA).
These transporters have a wide range of functionalities that vary depending on the amino acid type and size. They can act as a loader, a mediator of net uptake, a regulator, or a controller of cellular reactivity. They can also serve as a loader, mediate a reversible net uptake, or act as an antiporter.
In one study, a single dose of BME plus nonessential amino acids stimulated net muscle protein synthesis in elderly men. This increase was independent of a specific inhibitor of LAT1 or SNAT1/2. Moreover, the net balance between synthesis and breakdown was increased. Despite this increase, the total amino acid uptake was not higher than the amount necessary to stimulate net muscle protein synthesis in healthy adults.
Extracellular Amino Acids
Extracellular amino acids are essential for cellular growth and development. They are present at cytosolic concentrations several-fold higher than blood plasma levels and support protein biosynthesis and contribute to osmotic pressure in the cytosol. They are also found in high concentrations within the nucleus, where they regulate a number of cellular processes. These include nutrient and oxygen transport, as well as the production of adenylate cyclase. The constant relationship between cytosolic and intracellular amino acid concentrations is the basis of homeostasis.
When the extracellular supply of amino acids is depleted, cells maintain a pool of charged tRNAGlns in the lysosome. This ability is largely mediated through the lysosomal tRNAGln-protein complex, which facilitates tRNAGln charging and maintains tRNAGln levels during a prolonged period of amino acid deprivation. This capability is critical for sustaining adaptive translational capacity, as it allows the cell to maintain a functional mTORC1 in the absence of vascular free amino acid supply.
To examine the effect of amino acid depletion on tRNAGln pools, we used MiaPaCa2 cells. We measured tRNAGln charging and mTORC1 activity after culturing these cells in medium containing either 5% amino acid depletion or a combination of 5% AA and bafilomycin A1 (BAF).
The result was that tRNAGln charging was significantly reduced after 1 hr of amino acid deprivation, but not at 6 hr (Figure 2A), and was nearly completely uncharged after 6 hr of treatment (Figure 2C). This contrasts with the maintenance of tRNAMet, tRNALeu, tRNAArg, and tRNAVal charging in amino-acid-depleted medium at 1 hr (Figure 2--figure supplement 1A) or after 6 hr of treatment (Figure 2--figure supplement 1D). Conclusion: These results indicate that a sustained period of amino acid depletion results in a selective and profound reduction of tRNAGln charges that significantly reduces adaptive translation. Moreover, this effect is specific to polyQ-containing proteins.
Testosterone
Testosterone is the male hormone made mainly in the testes (part of the male reproductive system). It is needed for the development of male sex characteristics, including facial hair, a deep voice and muscle growth. It also helps sperm develop and mature.
Normally, men produce about 6-7 milligrams of testosterone per day. It is stored in a special cell called the Leydig cells. When these cells secrete the hormone, it is released into the blood. It can also be produced by other tissues.
The amount of testosterone in the body changes as you get older. Low levels may cause symptoms such as decreased sexual desire and erectile dysfunction. They can also affect your physical appearance and lead to swollen or tender breasts (gynecomastia).
When a man has low testosterone, he may become infertile, which means that he cannot have children. This can happen because low testosterone causes sperm to become less mature.
Many men can increase their levels of testosterone by taking certain drugs or supplements, such as tamoxifen or aromatase inhibitors. However, these drugs can cause serious health problems. They can also cause liver and kidney damage, and they can affect your mood.
Another type of medication that can increase your testosterone levels is a synthetic form of the hormone. This type of drug is called anabolic steroids, and it can help to build muscle mass. It can also help to improve your endurance and performance.
These drugs can also increase your cholesterol levels and make you more likely to develop heart disease, diabetes and high blood pressure. They can also increase your risk for certain cancers.
Some people can have higher than normal testosterone levels because of a condition called polycystic ovary syndrome. This can cause irregular menstrual cycles and increases in body and facial hair, balding at the front of your head and a deepening voice.
Testosterone can be found in your blood in two forms: bound and free. Most of it is bound to proteins. The proteins prevent your tissue from using the testosterone right away.
Muscle Protein Synthesis
It promotes the synthesis of proteins in cells, including myofibrils which are muscle cells. It increases muscle cell size and the number of myofibrils, resulting in increased strength, muscle mass, and metabolism.
When testosterone is low, myofibrils shrink in size and myofibril dissolution occurs. This may lead to decreased muscle size, loss of strength and body fat.
The hormone luteinizing hormone from the pituitary gland regulates testosterone production. If the luteinizing hormone is too low, then the pituitary gland sends signals to stimulate the testicles to produce more testosterone.
A high-protein diet increases LH secretion in men, leading to higher testosterone levels. This is especially true for those who consume a lot of protein in the form of meat and fish, as well as foods rich in lignans, such as flaxseed oil.
Myofibrils
Testosterone increases muscle size (hypertrophy) by stimulating androgen receptors in skeletal muscle cells. It also increases the number of muscle protein strands in each fiber, known as myofibrils.
Muscle fibers are the structural components of skeletal muscle that produce active force by contractile proteins, such as actin and myosin. These proteins interact with neural receptors to generate a specific amount of force during isometric contractions.
Myofibrils increase in thickness and density during training to create muscle hypertrophy. This occurs because your body is forced to recruit more muscle fibers than it normally does during a workout.
During myofibril hypertrophy, the volume of sarcoplasm within muscle cells increases and the volume of ATP, glycogen, creatine phosphate, and water within skeletal muscles increases as well. Sarcoplasmic hypertrophy is a type of muscle growth that increases size while myofibrillar hypertrophy increases strength.
Myofibrillar hypertrophy is more dominant in bodybuilders and Olympic weightlifters than sarcoplasmic hypertrophy.
In myofibril hypertrophy, there is an increase in the number of myosin and actin contractile proteins within the sarcomeres. This is a result of sarcomerogenesis.
Multiple studies have shown that sarcomerogenesis produces stronger, more robust sarcomeres than the muscle cells alone. This suggests that myofibril hypertrophy can contribute to increased strength by increasing the sarcomere's capacity to contract with greater force.
Conclusion
In men, signals sent from the brain's hypothalamus to the pituitary gland control the production of testosterone. The pituitary gland then relays the message to the testes, which produce the hormone. This "feedback loop" closely regulates testosterone levels.
As a result, great differences in the amounts of testosterone that occur during prenatal development, at puberty and throughout life contribute to many biological and behavioral variations between males and females.
These variations are likely caused by a variety of factors, such as diet, body composition and exercise. When these factors are manipulated, testosterone levels in the blood rise, resulting in increased skeletal muscle protein synthesis.
To determine the effects of testosterone on protein synthesis, the serum concentrations of several amino acid tracers were measured before and after the injection of testosterone in healthy elderly men who had low serum testosterone levels. The results showed that a single injection of testosterone led to increases in both mixed and myofibrillar muscle protein synthesis.
This increase was accompanied by a decrease in net amino acid efflux from skeletal muscle tissue. These results suggest that the synthesis of intramuscular testosterone improves net muscle protein synthesis and ameliorates catabolism and protein breakdown in the face of a low level of amino acids in the body.
