Bodybuilding.com Information Motivation Supplementation
in:
Exercise & AMPK Activation.

Long-term participation in endurance exercise leads to skeletal muscle adaptations, which occur by altering transcription of exercise-responsive genes. This article takes an in depth look.

By: Derek Beast Charlebois

Acute endurance exercise produces short-term benefits such as increased glucose uptake and fatty acid oxidation in skeletal muscle. Long-term participation in endurance exercise leads to skeletal muscle adaptations, which occur by altering transcription of exercise-responsive genes.

Examples of such adaptations include increased mitochondria[Define] density and glycogen storage. These adaptations increase the maximal rate at which skeletal muscle can produce ATP and therefore sustain exercise.

It is believed that an enzyme called 5' adensine monophosphate-activated protein kinase (AMPK) plays a very important role in the adaptations seen from exercise. Maintaining optimal levels of ATP is of prime importance for a cell's survival, as ATP is its source of energy.

ATP: Energy's Currency!
If one has ever wondered just how we are able to summon the energy to perform a number of activities under a variety of conditions, the answer, in large part, is ATP. Without ATP, ones body would simply fail to function. Learn why ...
[ Click here to learn more. ]

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[Define] tissue, the liver, heart, and pancreas. This article will primarily address AMPK's effects in skeletal muscle.


Activation Of AMPK

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 various energetic pathways to maintain cellular ATP levels, such as the glycolysis[Define] 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.

AMPK is activated by any stress that inhibits ATP production or increases ATP consumption15. This includes hypoxia, heat shock, exercise, and glucose deprivation. AMPK is also activated by the hormones leptin and adiponectin15. 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 deficit1. AMP can directly activate AMPK, but can also bind to AMPK causing it to become a more efficient substrate (the substance acted upon by an enzyme) for the upstream AMPK kinase (AMPKK); AMP can also activate AMPKK directly2. AMPKK activates AMPK by phosphorylation (adding a phosphate).

Phosphocreatine serves as an inhibitor of AMPK activation; therefore decreased PCr levels can cause AMPK activation2. Increased levels of muscle glycogen also inhibit AMPK1, as sensed by a glycogen-binding domain on the  subunit of AMPK.

It is theorized that this glycogen-binding domain serves as a sensor of glycogen levels15. 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 AMPK2.

AMPK can also be experimentally activated by the nucleoside analogue 5-amino-4-imidazolecarboxamide riboside (AICAR) and Â-guanadionopropionic acid (Â-GPA). Once AICAR enters a muscle cell, it is metabolized into ZMP, an analogue of AMP. Â-GPA, is a creatine analogue which depletes cellular phophsocreatine and ATP3. Both compounds create an energy-stress signal and thereby activate AMPK.

When AMPK is activated, ATP-consuming pathways, such as protein and fat synthesis, are shut off and ATP-producing pathways, such as fatty acid oxidation, are turned on in order to spare ATP as well as restore diminished levels. AMPK accomplishes this by direct phosphorylation of regulatory proteins and by indirect effects on gene expression14.

Activation Of AMPK Results In15:


Click To Enlarge

Adapted from: D. Grahame Hardie, John W. Scott, David A. Pan, Emma R. Hudson Management of cellular energy by the AMP-activated protein kinase system. FEBS Letters 546 (2003) 113-120.


Metabolic Effects Of AMPK Activation

Glucose Uptake

    Glucose enters muscle cells by being transported in by the glucose transporter GLUT-4. During the basal state (no contraction/low insulin) the GLUT-4 transporters lie beneath the muscle cell's sarcolemma and T-tubule membranes and cannot transport any glucose.

    Contraction and insulin can independently and additively cause the GLUT-4 transporters to translocation from below the membranes and insert into the membrane where they can now transport glucose into the muscle cell. It is believed that AMPK plays a part in the contraction-induced translocation of GLUT-4 transporters1 and has been shown to increase skeletal muscle glucose uptake4, 5.

    AMPK has also been shown to increase GLUT-4 mRNA gene transcription, which would increase the total number of receptors available to transport glucose15.

    Studies using AICAR to activate AMPK has shown increased glucose uptake independent of insulin. Insulin stimulated glucose uptake is inhibited by using the phosphatidylinosityol 3 kinase (key molecule of insulin signaling) wortmannin. Neither AICAR nor contraction stimulated glucose uptake is effected by wortmannin1.

    When insulin was added with AICAR treatment, glucose uptake was increased above AMPK activation alone1. When AMPK activation by AICAR was coupled with muscle contraction, no further increase in glucose uptake was seen, which suggest AMPK and contract share a common mechanism of action1.

    An interesting note is while AMPK turns off anabolic pathways and turns on catabolic, ATP producing pathways, AICAR treated rats have been shown to possess increased glycogen stores1. AMPK has an inhibitory effect on glycogen synthase, the enzyme used in glycogen storage, yet glycogen storage is not diminished, but rather enhanced.

    AMPK activation has been shown to decrease glucose oxidation rates by 50% in rats6. Because of this and other findings, it is proposed that AMPK's action in restoring ATP levels in mainly accomplished by promoting fatty acid oxidation over glucose oxidation.

Fatty Acid Oxidation

    Beta-oxidation of fatty acids (in the form of fatty acyl-CoA) in the mitochondria supplies a significant source of ATP regeneration during exercise, specifically endurance-type exercise. A protein called carnitine palmitoyltransferase-1 (CPT-1), which is found on the outer membrane of mitochondria, regulates fatty acid oxidation.
    The Lowdown On EFA's.
    Personally when I first heard that there were types of fats that actually helped your body and helped you lose weight, I did not believe it. After doing a pretty good amount of reading and some research, I found out that the myth was true.

    CPT-1 carries fatty acids across the membrane into the mitochondria by binding to the acyl end of the fatty acyl-CoA. CPT-1 is in turn regulated by malonyl-CoA, which is synthesized by acetyl-CoA carboxylase (ACC) in skeletal muscle. Malonyl-CoA prevents fatty acid oxidation by competitively binding with CPT-1, which prevents fatty acids from binding to it. Malonyl-CoA concentrations are lowered by malonyl-CoA decarboxylase.

    In order to take the brakes off fatty acid oxidation, malonyl-CoA levels must be decreased; inhibiting ACC or activating malonyl-CoA decarboxylase can accomplish this.

    Exercise inhibits ACC and rapidly decreases malonyl-CoA in skeletal muscle7, 8. This effect has been linked to AMPK activation. AICAR treatment has been shown to deactivate ACC, reduce malonyl-CoA levels, and increase fatty acid oxidation9.

    Activation of AMPK, by exercise, electrical stimulation, and AICAR, has also been shown to activate malonyl-CoA decarboxylase1. The combination of deactivated ACC and activated malonyl-CoA decarboxylase supports AMPK's roll in fatty acid oxidation in skeletal muscle.

    The above would agree with AMPK's proposed action of increasing fatty acid oxidation while decreasing glucose oxidation since increased fatty acid oxidation would suppress glucose oxidation at the PFK-1 and pyruvate dehydrogenase level10. This is supported by in-vitro findings, which showed AICAR to increase fatty acid oxidation and inhibit glucose oxidation simultaneously11.


Gene Expression

Chronic endurance training causes many skeletal muscle adaptations. Some examples are increased mitochondria and GLUT-4 density, expression of oxidative enzymes, and increased glycogen storage.

Chronic AMPK activation by AICAR has been shown to cause the same adaptations as well as increased protein expression of the following mitochondrial enzymes: malate dehydrogenase, citrate synthase, cytochrome C, hexokinase II, succinate dehydrogenase, d-aminoevulinate synthase, and uncoupling protein-3 (UCP-3)12. All of these enzymes are involved in fatty acid oxidation.

To further support the idea that glucose metabolism is secondary to fatty acid oxidation, no glycolytic enzymes have been found to be up regulated by AMPK activation1.

AMPK has been shown to play a role with mitochondria biogenesis in skeletal muscle. A study using Â-GPA injections on mice to induce an energy-deprived state found that GPA caused a significant increase in mitochondrial DNA and density in skeletal muscle in wild mice (normally functioning AMPK), but not in mice expressing an inactive dominant-negative AMPK, which shows AMPK is essential component of mitochondria biogenesis13.

An increased number of mitochondria would allow more total fatty acids to be oxidated by increasing the body's capacity to do so.

Blood Sugar & Insulin.
Lately I've received a whole bunch of questions about the benefits and drawbacks of insulin, so why not straighten out the issue, once and for all? Learn the straight forward facts on insulin!
[ Click here to learn more. ]


Summary And Application

AMPK serves to make one's body more efficient in producing ATP. It does this by increasing glucose uptake (GLUT-4 translocation and gene expression) and insulin sensitivity, promoting fatty acid oxidation and mitochondria biogenesis, as well as a host of other effects. The adaptations caused by AMPK make the body more efficient in producing ATP and therefore survival.

The easiest and most economical way to activate AMPK is through exercise, but supplement induced activation may prove useful for those looking to lose weight or improve different aspects of overall health. An example of such a supplement is Avant Labs' Phenogen. Phenogen targets AMPK to aid in fat loss by use of Â-GPA. Phenogen also contains SesaThin and Salvia Miltiorrhiza, which will both enhance fat loss.

One potential roadblock with AICAR is it does not mimic all the changes seen in high-energy phosphate concentrations seen during exercise2. ATP and PCr levels are not affected and ZTP has been shown to increase, which would interfere with full activation of AMPK12. New substances that activate AMPK will be researched. Conclusion: much more research on AMPK is needed to fully understand its applications and the most effective methods, besides exercise and diet, to activate it.

References:

  1. 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
  2. Winder, W. W. Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle. J Appl Physiol 91: 1017-1028, 2001.
  3. N. Musi, H. Yu and L. J. Goodyear. AMP-activated protein kinase regulation and action in skeletal muscle during exercise AMPK 2002 - 2nd International Meeting on AMP-activated Protein Kinase. Biochemical Society Transactions (2003) Volume 31, part 1
  4. Goodyear LJ. AMP-activated protein kinase: a critical signaling intermediary for exercise-stimulated glucose transport? Exerc Sport Sci Rev 2000; 28 (3): 113-6
  5. Hayashi T, Hirshman MF, Fujii N, et al. Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism. Diabetes 2000; 49: 527-31
  6. Kaushik VK, Young ME, Dean DJ, et al. Regulation of fatty acid oxidation and glucose metabolism in rat soleus muscle: effects of AICAR. Am J Physiol Endocrinol Metab 2001; 281 (2): E335-40
  7. Rasmussen BB, Winder WW. Effect of exercise intensity on skeletal muscle malonyl-CoA and acetyl-CoA carboxylase. J Appl Physiol 1997; 83 (4): 1104-9
  8. Rasmussen BB, Hancock CR, Winder WW. Postexercise recov- ery of skeletal muscle malonyl-CoA, acetyl-CoA carboxylase, and AMP-activated protein kinase. J Appl Physiol 1998; 85 (5): 1629-34
  9. Merrill GF, Kurth EJ, Hardie DG, et al. AICA riboside in- creases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol 1997; 273 (36): E1107-12
  10. Spriet LL, Dyck DJ. The glucose-fatty acid cycle in skeletal muscle at rest and during exercise. In: Maughan RJ, Shisheva A, editors. Biochemistry of exercise. Aberdeen: Human Kinetics Publishers Inc., 2003: 127-56
  11. Kaushik VK, Young ME, Dean DJ, et al. Regulation of fatty acid oxidation and glucose metabolism in rat soleus muscle: effects of AICAR. Am J Physiol Endocrinol Metab 2001; 281 (2): E335-40
  12. Winder WW, Holmes BF, Rubink DS, et al. Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol 2000; 88 (6): 2219-26
  13. Zong H, Ren JM, Young LH, et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A 2002; 99 (25): 15983-7
  14. B. E. Kemp, D. Stapleton, D. J. Campbell, Z.-P. Chen, S. Murthy, M. Walter, A. Gupta, J. J. Adams, F. Katsis, B. van Denderen, I. G. Jennings, T. Iseli, B. J. Michell and L. A. Witters AMP-activated protein kinase, super metabolic Regulator. AMPK 2002 - 2nd International Meeting on AMP-activated Protein Kinase. Biochemical Society Transactions (2003) Volume 31, part 1
  15. D. Grahame Hardie, John W. Scott, David A. Pan, Emma R. Hudson Management of cellular energy by the AMP-activated protein kinase system. FEBS Letters 546 (2003) 113-120.

Exercise & AMPK Activation.
derek@scivation.com

Visitor Reviews Of This Article!
Read Visitor Reviews - Write Your Own Review

Back To Derek Beast Charlebois's Main Page

Back To The Articles Main Page.

Related Articles
Arnold Schwarzenegger Blueprint Trainer: Main Page
How To Gain Weight: 5 Lifts And Techniques For Building Muscle
Research Roundup Vol. 10: Breaking Insights In Training, Nutrition, And Supplementation



RATE THIS ARTICLE
POOR
  • 1
  • 2
  • 3
  • 4
  • 5
  • 6
  • 7
  • 8
  • 9
  • 10
EXCELLENT
OVERALL RATING
N/A

Out of 10

0 Ratings

0

Comments

Showing 0 - 0 of 0 Comments

(5 characters minimum)

      • notify me when users reply to my comment
Showing 0 - 0 of 0 Comments

Featured Product

Give Us Feedback:
Report A Problem
Site Feedback
Follow Us:
Twitter
Facebook
RSS Feeds
Bodybuilding.com Newsletter

Receive exciting features,
news & special offers from Bodybuilding.com