Download AMPK and mTOR: Antagonist ATP Sensors

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.
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  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  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).
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.
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.
Creatine + Citrulline Malate
Maintaining Glycogen Levels
Leucine
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 directacting 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.