cyclic adenosine monophosphate (cAMP) second messenger molecule

This article will convey a proven technique of altering diet and exercise that affects the natural processes for muscle gain and fat loss.  Further, the information contained herein will provide a limited understanding of the hormones that activate protein synthesis; the intracellular biochemical pistons that drive energy release and energy reserves; and, diet and exercise that affect these same hormones and intracellular chemicals.  Further information will be provided on how certain chemicals impact hormones (endocrine disrupters) as well as the need for detox programs, which will be the topic of my next paper.

Gaining muscle and losing fat is natural to your body; i.e. innate within your physiology provided that you understand some foundational physiological principles.  All growth, disease and death starts at the cellular level.  Growth and fat burning begin with cellular messengers that cause protein synthesis or fat break down.  The biochemistry behind break down, repair and growth of muscle fiber as well as the breakdown of fat for utilization of energy can be found at the following URL addresses (fat to energy) and,  how muscles grow.

Growth stimulating hormones and inhibition of fat gain occurs at a cellular level, triggered by a nucleotide, cyclic adenosine monophosphate cAMP.1  cAMP triggers the release and actions of certain hormones.  Hormones that are water soluble act on the cell membrane while hormones that are fat soluble act within the cell of the target tissue. Hormones that messenger to the cells of the target tissue will activate adenyl cyclase.  This reaction then produces cAMP, which actually brings the effect of the hormone in the cell.

Other chemical reactions occur in the cell causing enzymes to acquire phosphorous which in turn amplifies the action of cAMP, causing breakdown of glycogen stores in the liver and muscle and lipolysis (fat burning in fat cells).  The reaction continues when cAMP activates protein kinase which catalyzes phosphorylation, activating a ribonucleic acid (RNA) polymerase.  The polymerase will stimulate the production of RNA that acts as a messenger for protein synthesis. Additionally cAMP will cause the production of anabolic hormones such as steroid male hormones and growth hormones.1

When energy is expended the body has innate chemical reactions that cause energy to be resupplied.  The regaining of energy involves an external source, which is food.  Eating the wrong food, causing an imbalance of nutrients will impact the following innate cellular reaction.  “Repairs at the cellular level are regulated by cyclic guanine monophosphate (cGMP).  cGMP is insulin dependent and in turn inhibits the actions of cAMP.  Under normal conditions these two are the pistons that drive the energy/growth cycle at the cellular level.1

The energetics of expenditure and gain drive skeletal muscle growth when challenged by resistance training.   The trauma/injury to the muscle fibers activates satellite cells, which are exterior to the muscle fibers between the basement membrane (basal lamina) and the plasma membrane (sarcolemma) of muscles fibers.  Satellite cells are activated by muscle tears, causing the nucleus to replicate leaving some of the cell organelles on the muscle fiber while others fuse to muscle fibers to form new muscle protein stands (or myofibrils) and/or repair damaged fibers. (Charge and Rudnicki 2004).2

The understanding of muscle gain and fat breakdown is further understood by the actions of certain hormones within our endocrine system.  The endocrine system is the collection of glands that produce hormones that regulate metabolism, growth and development, tissue function, sexual function, reproduction, sleep, and mood, among other things.

Androgens (steroid hormones) are fat soluble, meaning they can pass into the cell’s nucleus, bind to specific receptors and genes and trigger the cell to make proteins.  Steroid hormones moving through the cell cytoplasm will form a hormone/receptor that moves into the nucleus of the cell attaching to the DNA binding sites, activating protein-producing genes.  Steroid hormones have a base structure made from cholesterol.

Corticoids are chemically related steroid hormones, being a fat molecule with a cholesterol polycyclic core.  The adding and removing groups to the cholesterol polycyclic core is spurred by proteins called enzymes, causing the following chain of chemicals: pregnenolone (precursor to corticosteroids, mineral corticosteroids), 11-deoxycorticosterone (a steroid produced by adrenal gland that is a precursor to aldosterone), 17-alpha-hydroxyprogesterone then to corticosterone, cortisol and aldosterone.

The production of glucocorticoids and mineral corticoids occurs in the adrenal glands that sit on top of the kidneys.  Glucocorticoids provide the energy (release glucose) by signaling the liver, fat and muscle to speed the breakdown of stored sugar, fat or protein.  The signaling will soak up muscle proteins and fat from the blood and convert them to glucose.

Mineral corticoids regulate the minerals sodium and potassium and the hydrogen ion to maintain water balance.  Usually sodium is retained while potassium and the hydrogen ion are excreted in the urine.  As sodium is retained so is water, increasing blood volume and blood pressure. As these two increase, sensors in the kidney will turn off mineral corticoids release, creating a balance; i.e. homeostasis within one’s blood pressure.

Another hormone that impacts energy is built on the amino acid tyrosine, having its structure populated with iodine atoms.  These iodinated amino acids are clipped to form the thyroid hormones thyroxine and triiodothyronine, with thyroxine being the most abundant thyroid hormone and triiodothyronine (T3) is being the most active thyroid hormone.  Thyroid sensitive tissues receive T3 on the cell membrane and inside the cell on the organelle mitochondria or in the nucleus, activating chemical processes and protein producing genes that control cell energy and metabolic functions.

Other hormones include water-soluble polypeptide hormones such as insulin, growth hormone, and prolactin; all consisting of long chains of amino acids.  The water-soluble hormones will bind on protein receptors on the surface of the cell, which in turn will activate enzymes and other cellular proteins affecting gene expression, regulating processes as metabolism, lactation, growth and reproduction.3

The balance (homeostasis) of energy, neuro-hormonal signaling is constantly challenged by environmental toxicants and life style (stress and eating habits).  Therefore, before discussing the muscle gain/fat loss program there is a need to briefly explain how homeostasis is disrupted through chemical exposures and diet.  The subject of toxicology takes years to master, thus restricting the following discussion to a few chemical categories.

The delicate balance and the biological functions of the aforementioned hormones are impacted by external environmental and occupational chemicals known as endocrine disrupters.  These environmental pollutants include but are not limited to pesticides, plasticizers and polychlorinated biphenyls (PCBs).  PCBs will interfere with the body’s energy balance.  They will interfere with iodide use and delivery affecting thyroid hormone processes.  Additionally PCBs will alter thyroid delivery to body tissues by affecting the protein-binding transfer to thyroid sensitive tissues.4   In addition to PCBs interfering with thyroid transport proteins they will boost hormone destroying liver enzymes.5, 6, 7

Another endocrine disrupter is arsenic which interferes with glucocorticoids hormone-receptor complexes, causing inhibition of gene transcription, believed to cause cancer.8,9  In toxicology there is a saying that ‘the dose makes the poison’, meaning there is a threshold dose below which will not cause an adverse effect on one’s physiology.  However, with carcinogens and endocrine disrupters there is no threshold dose.  Carcinogen exposures are structured into probabilistic formulas with acceptance criteria for human exposure to same that equates to a one-in-one million incremental increase of risk above background risk.

The aforementioned material on toxicants and their affect on hormones should stimulate one’s interest toward detoxification.  In today’s environment detox programs are recommended as long as it is under the supervision of a health professional.  Detox will be a topic for my next article.

The next primary factor that impacts homeostasis is diet.  Foods that are ingested such as food altered genetically, having residual pesticides/herbicides, having been processed, containing high fructose, containing the wrong fats, browned to contain advanced glycation end products will affect the body’s innate biochemical program for muscle growth and fat loss.  Therefore, it is important to consult a nutritionist to obtain knowledge on proper foods.

Nutrition will impact the two intracellular chemicals cAMP and cGMP.  Restrictive/under eating coupled with cardio-exercise will cause cAMP to be a dominant factor in the cell, which in turn will cause adrenal and glucagon hormones to activate G-proteins, causing increase of cAMP.

Restoring the expenditure of energy through the ingestion of nutrient dense foods will trigger cGMP to activate cellular repairs.  cGMP being insulin dependent will dampen the activity of cAMP and allow sugar to enter the cell, which in turn is used to produce adenosine triphosphate (ATP), the molecule critical to our inherent energy.

This cycle of energy expenditure and gain driven by cAMP and cGMP can malfunction by simply eating too often, too large of a meal and/or too many carbohydrates causing cGMP to increase which in turn inhibits cAMP.  An increase of cGMP will inhibit the enzymes that break down fat and glycogen, causing fat deposits rather than fat burn.  Prolonged increase of cGMP leads to a sluggish metabolism, weight gain, insulin resistance, fatigue, lack of energy and accelerated aging.

The intracellular chemical imbalance cascades into metabolic decline by involving thyroid hormones which are essential in maintaining and regulating the body’s metabolism.  Triiodothyronine (T3) is the most active of the thyroid hormones. Approximately 85% of circulating T3 is produced by monodeiodination of thyroxine (T4) in tissues such as liver, muscle and kidney. Selenium and zinc are required for this process.  Reverse T3 (rT3) is an inactive form of T3 that is produced in the body particularly during periods of stress.  rT3 differs from T3 in that the missing deiodinated iodine is from the inner ring of the thyroxine molecule compared with outer ring on T3. [rT3 is measured by a blood test.]

Under normal conditions T4 will convert to both T3 and rT3 continually and the body eliminates rT3 quickly.  Under certain conditions, more rT3 is produced and the desirable conversion of T4 to T3 decreases. This occurs during fasting, starvation, illness such as liver disease and during times of increased stress.  rT3 competes with T3 as a substrate for the 5-deiodinase enzyme. This inhibits the conversion of T4 to T3, with more T4 being converted to more rT3.  In effect prolonged periods of fasting, stress and other environmental factors shifts the cycle to rT3 leading to energy decline, metabolic imbalances, fat deposition, cycling the body into deficits, muscle loss and fat gain.  Specifically, an increased production of rT3 is often seen in patients with disorders such as fibromyalgia, chronic fatigue syndrome (CFS), Wilson’s Thyroid Syndrome and stress.10

The discussion on cAMP and cGMP along with androgens, corticosteroids and thyroid hormones was to favor an approach for maximum muscle gain and fat loss.  The program that will accomplish maximum muscle gain and fat loss involves alternating a short period of restrictive diet concurrent with cardio exercise followed by short period of nutrient splurge and strength exercise cycled over a 30 day period.   This program is summarized by two professionals, Dr. Mercola11 and Mr. Nick Nilsson12.

To lose fat, you need a caloric deficit and to build muscle you need a caloric surplus. If you try to do both at the same time, you may just remain exactly where you are.  The key is to do the program in sessions that are consecutive and not concurrent.  By alternating rapidly back and forth between reduced-calorie/fat loss circuit training and higher-calorie/mass-oriented strength training, you can achieve maximum fat loss and muscle gain.  Proper manipulation of these factors will greatly enhance the body’s hormonal response to this program, which is the real key to maximizing your results.1, 11, and 12

Noteworthy is a precaution specific to imbalances that are caused by protracted fasting or extended carbohydrate loading.  Extended periods of fasting or carbohydrate-loading will damage the biochemical processes that influence muscle gain and fat loss.  For example, fasting for long periods will cause metabolic decline, causing an inactive thyroid (refer to rT3, above).  The thyroid gland regulates energy production, body heat, fat burning and steroid hormone activity.  When the body has a deficiency of energy for long periods there will be a metabolic decline.


1Hofmekler, O.  Maximum Muscle Minimum Fat. North Atlantic Books. 2008.

2Charge, S. B. P., and Rudnicki, M.A. (2004). Cellular and molecular regulation of muscle regeneration. Physiological Reviews, Volume 84, 209-238.

3Cato A, Nestl A, and Mink S. 2002. Rapid actions of steroid receptors in cellular signaling pathways. Science’s STKE 2002: re9

4Howdeshell KL. 2002. A model of the development of the brain as a construct of the thyroid system. Environmental Health Perspectives 110(Supp 3):337-348

5Moccia RD, Fox GA, and Britton A. 1986. A quantitative assessment of thyroid histopathology of herring gulls (Larus argentaltus) from the Great Lakes and a hypothesis on the causal role of environmental contaminants.  Journal of Wildlife Diseases 22:60-70.

6Leatherland JF and Sonstegard RA. 1980. Structure of thyroid and adrenal glands in rats fed diets of Great Lakes coho salmon (Oncorhynchus kisutch). Environmental Research 23(1):77-86.

7Zoeller RT, Bansal R, and Parris C. 2005. Bisphenol-A, an environmental contaminant that acts as a thyroid hormone receptor antagonist in vitro, increases serum thyroxine, and alters RC3/neurogranin expression in the developing rat brain. Endocrinology 146(2):607-612.

8Glennemeller  K. and Denver R. 2001. Sublethal effects of chronic exposure to an organochlorine compound on northern leopard frog (Rana pipiens) tadpoles. Environmental Toxicology 16:287-297.

9Kaltreider RC, Davis AM, Lariviere JP, and Hamilton JW. 2001. Arsenic alters the function of the glucocorticoid receptor as a transcription factor. Environmental Health Perspectives 109(March):245-251.

10Healthscope. Functional pathology. Practitioner Manual 2011

11Mercola, J.  Nine Natural Ways to Boost Testosterone. July 28, 2012.

12 Nielson, N. How to Lose the Most Fat and Build the Most Muscle in 30 Days. Jan. 11, 2013.

David Brancato

Dr. Brancato’s cumulative experience in nutrition, alternative medicine, chemistry, toxicology, physiology directed him to holistic approaches in human physiology to correct system imbalances. He maintains his professional certifications as a Naturopath from the American Naturopathic Medical Certification and Accreditation Board; the National Federation of Professional Trainers; Black belts in Kick Boxing and Kenpo.