AMPK and mTOR:
Antagonist ATP Sensors and Control of Protein Synthesis
By: Derek Charlebois B.S. CPT

Adenosine Triphosphate (ATP)

    Adenosine triphosphate (ATP) is the body’s primary energy source. The molecule of ATP, referred to as a “high-energy phosphate”, is made up of adenine and ribose (adenosine) bonded to three phosphates (Pi- phosphorus and oxygen). The energy stored in ATP is held in the two outermost phosphate bonds. These outermost bonds are referred to as “high-energy bonds.” When water joins with ATP, catalyzed by the enzyme ATPase, the outermost phosphate bond is cleaved, producing adenosine diphosphate (ADP) and a phosphate ion as well as liberating 7.3 kcal of free energy to be used for work. ADP levels increase as ATP is used for energy.

ATP Molecular Structure

    The body uses three energetic pathways to maintain cellular ATP levels, phosphocreatine, glycolysis, and oxidative phosphorylation. Two enzymes are responsible for maintaining ATP levels as soon as muscle contraction begins; more precisely as soon as the muscle starts using ATP at an accelerated rate. The first enzyme is myokinase, also known as adenylate kinase, which catalyzes the reaction in which a phosphate is transferred from one ADP molecule to another ADP molecule, creating one ATP and one AMP molecule:

ADP + ADP à ATP + AMP

    The other enzyme is creatine phosphokinase, which catalyzes the reaction in which a phosphate is transferred from phosphocreatine (PCr) to ADP to form one ATP and creatine (Cr) molecule:

PCr + ADP à ATP + Cr

During exercise, AMP levels increase and PCr decreases in the working muscle, both of which signal a need to produce more ATP.

AMP Activated Protein Kinase (AMPK)

    AMP Activated Protein Kinase (AMPK) is a metabolic-stress-sensing protein kinase; meaning it functions as a cellular fuel gauge. This enzyme serves to maintain cellular energy homeostasis, specifically during times of stress caused by exercise or nutrient intake (diet).

    The activation of AMPK initiates signaling cascades that stimulate changes in glucose, fatty acid metabolism, and gene expression, which ultimately results in an increased ability to produce ATP. These metabolic changes affect mainly skeletal muscle, adipose tissue, the liver, heart, and pancreas. This article will primarily address AMPK’s effects in skeletal muscle.

    AMPK is activated by any stress that inhibits ATP production or increases ATP consumption (Hardie, 2003). This includes hypoxia, heat shock, exercise, and glucose deprivation. As its name suggests, AMP directly activates AMPK. Specifically, AMPK is activated when there is an increase in the AMP/ATP or creatine/phosphocreatine ratio, or more simply, an energy deficit (William, 2004). The actions of AMPK activation are shown below. The + sign means increases and the – sign means decreases.

    Phosphocreatine serves as an inhibitor of AMPK activation; therefore decreased PCr levels can cause AMPK activation (Winder, 2001).  Increased levels of muscle glycogen also inhibit AMPK (William, 2004), as sensed by a glycogen-binding domain on the β subunit of AMPK. It is theorized that this glycogen-binding domain serves as a sensor of glycogen levels (Hardie, 2003). As mentioned, exercise (muscle contraction) causes AMP levels to increase, PCr levels to decrease, and depletion of muscle glycogen and has been proven to activate AMPK (Winder, 2001).

Mammalian Target of Rapamycin (mTOR)

    The Mammalian Target of Rapamycin (mTOR) is one of the body's protein synthesis regulators. mTOR functions as an energy sensor; it is activated when ATP levels are high and blocked when ATP levels are decreased (AMPK is activated when ATP decreases, which works antagonistically to mTOR).

    The main energy-consuming process in a cell is protein synthesis. When mTOR is activated (high ATP levels sensed) protein synthesis is increased and when mTOR is suppressed (low ATP levels are sensed) protein synthesis is blunted. mTOR activation is vital for skeletal muscle hypertrophy.


Insulin signaling cascade [adapted from Laymen (17) amd Anthony et at. (39)]. IRS-1, Insulin receptor substrate 1; Pß-K, phosphatidylinostitol-3 kinase; GLUT4, Insulin-dependent glucose transporter; PKC, proteinkinase C; mTOR, mammial target of rapamycin; el F4, translational factor 4.

Figure 3 - Adapted from: Layman, DK (2003). The role of leucine in weight loss diets and glucose homeostasis. J. Nutr. 133: 261S-267S.

    Interestingly, mTOR is also a nutrient sensor of amino acid availability, specifically of leucine availability. Research has shown that regulation of mTOR by ATP and amino acids act independently through separate mechanisms (Dennis et al., 2001).

    Leucine is the key regulator of the mTOR-signaling pathway (Anthony et al. 2001 & Lynch et al. 2002). According to Laymen (2003), "The increase in leucine concentration is sensed by an element of the insulin-signaling pathway and triggers a phosphorylation cascade that stimulates the translational initiation factors eIF4 and p70S6K."

    Activation of these initiation factors initiates the translation of muscle mRNA components and are vital for skeletal muscle protein synthesis and creation of new contractile proteins (muscle). Leucine directly signals and primes your muscles to grow through the activation of mTOR.

Increasing Protein Synthesis by Controlling AMPK and mTOR
    From the above information, we can insight on how to increase protein synthesis by activating mTOR and suppressing AMPK. Doing so requires keeping ATP levels high, glycogen and phosphocreatine levels elevated, and supplementing with free-form leucine. How to accomplish this will be examined in the next article.

    Derek “The Beast” Charlebois is an ACE certified personal trainer, competitive bodybuilder, and holds a Bachelor’s degree in Exercise Science from The University of Michigan. Derek is the Promotions Coordinator/R&D at Scivation/Primaforce and is involved in coordinating promotions, research and development, advertising, and marketing. Derek is an accomplished author with articles on such websites as Bodybuilding.com, Bulknutrition.com, the online magazines StrengthAndScience.com and MusclesAndCuts.com, and is a contributing author to the book Game Over: The Final Showtime Cut Diet You’ll Ever Need! Derek is available for online personal training. His website is www.beastpersonaltraining.com.

References:

Anthony JC, Anthony TG, Kimball SR, Jefferson LS. Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine. J Nutr. 2001 Mar;131(3):856S-860S.

Dennis, PB. Jaescke, A., Saitoh, M., Fowler, B., Kozma, SC., Thomas, G. (2001). Mammalian TOR: A homeostatic ATP sensor. Science. 294: 1102-1105.
Hardie et. al. Hudson Management of cellular energy by the AMP-activated protein kinase system. FEBS Letters 546 (2003) 113-120.
Layman, DK (2003). The role of leucine in weight loss diets and glucose homeostasis. J. Nutr. 133: 261S-267S.
Lynch CJ, Patson BJ, Anthony J, Vaval A, Jefferson LS, Vary TC. Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. Am J Physiol Endocrinol Metab. 2002 Sep;283(3):E503-13.
William G. Aschenbach, Kei Sakamoto and Laurie J. Goodyear. 5’ Adenosine Monophosphate-Activated Protein Kinase, Metabolism and Exercise. Sports Med 2004; 34 (2): 91-103

Winder, W. W. Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle. J Appl Physiol 91: 1017–1028, 2001.

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