Details
Aicar
Introduction
AICAR, an amide-conjugated nucleoside, is an analog of adenosine. The international nonproprietary name (INN) of AICAR is acadesine; the full unabbreviated name is 5-Amino-1-(5-O-phosphono-β-D-ribofuranosyl)-1H-imidazole-4-carboxamide (Chemspider aicar entry. (n.d.), and it is variously referred to as AICA riboside, AICA ribonucleotide, Z-nucleotide, and ZMP (however, it should be noted that ZMP specifically refers to the phosphorylated form – AICA riboside monophosphate – that is converted within cells after administration of AICAR). Its actions are primarily mediated by selective AMPK activation as well as conversion into factors that also act on AMPK.
AMPK: The key to understanding AICAR
Because AICAR induces AMPK signaling through a relatively direct pathway, is used in many studies to study and better understand AMPK itself. At the time of writing (2012), however, there are vastly more published inquiries into AMPK than of AICAR specifically; since AICAR’s effects are similar (or identical to) AMPK, it is possible to better AICAR by closely reviewing AMPK studies to infer AICAR’s effects.
AICAR therapeutic uses
The actions of AICAR vary greatly by method of administration, duration of application, and dosage. Administration of exogenous AICAR orally or by injection shows promise for a plethora of medical problems and disease states: ischemia, hypertension, diabetes, obesity, cancer, Alzheimer’s disease, and even aging may be addressed to varying degrees by use of AICAR as a drug (Salminen et al).
Lifestyle factors such as overeating or under-exercising appear to initiate a cascade of pathological events that are mediated by altered AMPK signaling; AMPK expression is associated with exercise and periods of not eating. Other genetic factors also predispose individuals to AMPK dysregulation. Eventual effects of AMPK dysregulation – such as obesity, diabetes, even Alzheimer’s disease – can be treated or even partially reversed by AICAR-induced AMPK expression, whereas diet or exercise may not exert a major effect past an early or undetectable point in the pathology.
Research uses of AICAR peptides
AICAR is useful in researching the purine synthesis pathways and their downstream effects to better interpret biomarkers for different disease states. Most cancer cells rely on the de novo purine synthesis pathway, while normal cells prefer the salvage pathway; many chemotherapeutic drugs inhibit purine synthesis. A better understanding of these differences between cancer cells and normal cells should lead to more-selective less-toxic chemotherapy drugs, as well as better ability to tailor therapies to individuals via improved understanding of biomarkers related to purine synthesis inhibition in various cell types (Boccalatte et al, 2009).
AICAR, AMPK, and purine synthesis pathways
Roles of AMPK signaling in various physiological systems and states
"Doping,” the use of pharmacological agents to improve athletic performance for competition, is controversial and intrigues the public mind. AICAR improved treadmill performance in untrained mice by 45% (Narkar et al, 2008), leading to speculation that it may work as a performance-enhancing drug (PED) in humans. Tests have been developed for AICAR use in professional athletes, but since the 2008 articles the medical community has focused on AICAR as a way to better understand the profound role of AMPK in health and disease states and on AICAR as a treatment for a variety of pathologies."
AMPK and mTOR in resistance and endurance exercise
In humans, AMPK is increased in response to both endurance and resistance training, but mTOR response is thought to be specific to resistance training (Vissing et al, 2007). Basal concentrations of mTOR and AMPK were not permanently affected in a study of three groups (control, endurance, resistance training) undertaking ten weeks of training (Vissing et all, 2007). Although Nader speculates (2006) that concurrent endurance and strength training may be counterproductive due to the potential of AMPK (expressed with endurance training) to limit mTOR’s effect, Medeiros et al found that in the rat swimming increases transduction activity of proteins involved in insulin-dependent protein synthesis and the mTOR pathway (2011).
"Our recent data show that short-term (2-week), daily treatment of obese (ob/ob) mice with AICAR normalized their hyperactive, fasted-state mTOR signaling. Along with the expected reductions in circulating blood glucose and insulin concentrations, and muscle lipid and glycogen content after AICAR treatment, translational capacity and mass (including muscle fiber areas) of the plantar flexor muscle complex were significantly increased in the obese treated mice. It is our view that the oxidative metabolism/capacity of the muscle and the regulatory processes of muscle growth (i.e. mTOR and translational control) need to be normalized to elicit growth in insulin resistant (e.g. obese, aged) muscle."
Paradoxically, mTOR reduction in certain physiological states by AMPK/AICAR can result in improved protein synthesis and muscle-cross section.
AMPK and Energy Balance
Without proper context, AICAR’s effects would appear detrimental to adaptations to resistance exercise: Lantier et al write about “the crucial role of AMPactivated protein kinase (AMPK) in the inhibition of protein synthesis and cell growth” (2010). mTOR is necessary for muscle hypertrophy (Lantier et al, 2010). AMPK directly inhibits mTORC1, the mTOR complex involved in overloading-induced hypertrophy of muscle cells (Lantier et al, 2010). Lantier et al tested the effect of total AMPK inhibition in myotubes and found that it resulted in myotubes 1.5 times bigger than AMPK-expressing myotubes. However, the AMPK-deficient myotubes failed to respond to mTOR pathway activation: while they started with an initial greater size, they did not increase in size whatsoever when stimulated with mTOR pathway effectors (Lantier et al, 2010).
AMPK also limits cardiac hypertrophy, and AMPK deletion results in cardiac hypertrophy (Lantier et al, 2010), a state probably caused in part by mTOR overexpression.
Fatty acid synthesis and oxidation
AMPK is a master lipid metabolism regulator (Lim et al, 2009): high levels of AMPK inhibit cholesterol and fatty acid synthesis. AMPK also acts as a cellular signal to increase fatty acid oxidation by indirectly increasing levels of carnitine palmitoyltransferase-1 (CPT-1), which is the rate-limiting factor in mitochondrial uptake of free fatty acids (FFAs). In other words, AICAR and AMPK increase the upper limit of the body’s ability to burn stored fat for energy.
AMPK dysregulation is implicated in obesity: lipolysis is inhibited and constant low-grade fatty acid synthesis may take place. A steady caloric surplus (energy surplus) suppresses AMPK, resulting in reduced release of fat for fuel usage, and instead resulting in constant low-grade fat storage.
Conclusion
AICAR has yet to be realized as a mainstream treatment, likely because wide-range systemically acting drugs with profound cellular and systemic effects are difficult to press into medical use under current the regulatory climate in the United States, Canada, and EU countries; the wide range of effects raises hard-to-answer questions about the safety and appropriateness of AICAR for any given disease, particularly “lifestyle” conditions such as obesity and insulin resistance, which have accepted “lifestyle” remedies of diet and exercise and accepted medical remedies as they reach a certain point in pathology.
In the case of Type 2 diabetes, further animal and human safety and efficacy studies could prove AICAR to be a viable candidate, but the current drug metformin is a viable AMPK-targeting agent; AICAR could also be a financially risky choice for investors with a viable (if perhaps less-effective) similar drug on the market. In the case of Alzheimer’s disease, AICAR may also prove to be a next-generation treatment; a better understanding is needed, though, as AMPK appears to play a role in advancing late-stage Alzheimer’s.
All products available for purchase are for research purposes only. These laboratory products are not for use in food products or as any type of drug.Aicar peptides are not intended to treat, prevent, mitigate or cure any disease or medical condition.
Southern Research is now offering discounted FedEx shipping rates to domestic and international researchers worldwide! Now you can receive your laboratory products quicker and even more affordably than ever before!
Researchers must be at least eighteen (18) years of age to purchase Aicar peptides.
References
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Boccalatte FE, et al. The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase is enhanced by NPM-
ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL. Blood March 19, 2009 113(12): 2776-2790.
Chemspider aicar entry. (n.d.). Retrieved from http://www.chemspider.com/Chemical-Structure.58620.html
Dhillon T et al. Overexpression of the Mammalian Target of Rapamycin: A Novel Biomarker for Poor Survival in Resected Early Stage Non-small Cell Lung Cancer. J Thoracic Oncol. (2010). 5(3): 314-319.
Gleason CE, et al. The Role of AMPK and mTOR in Nutrient Sensing in Pancreatic β-Cells. J Bio Chem, 282 (2006). 10341-10351.
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Lantier L, et al. Coordinated maintenance of muscle cell size control byAMP-activated protein kinase. (2010) The FASEB Journal, 24:9 3555-3561.
Lim CT, et al. REVIEW AMPK as a mediator of hormonal signalling. J Mol Endocrinol. (2009) 44, 87-97.
López JM, Santidrián AF, Campàs C, Gil J. 5-Aminoimidazole-4-carboxamide riboside induces apoptosis in Jurkat cells, but the AMP-activated protein kinase is not involved. Biochem J. 2003 March 15; 370(Pt 3): 1027–1032.
Medeiros C, et al. Exercise training reduces insulin resistance and upregulates the mTOR/p70S6k pathway in cardiac muscle of diet-induced obesity rats. J Cell Physiol. 2011 Mar;226(3):666-74.
Nader, GA. Concurrent strength and endurance training: from molecules to man. Med Sci Sports Exerc. 2006 Nov;38(11):1965-70.
Narkar VA, et al. AMPK and PPARδ agonists are exercise mimetics. Cell. 2008 August 8; 134(3): 405–415.
Salminen et al. AMP-activated protein kinase: a potential player in Alzheimer's disease. J Neurochem, 118:4. June 2011.
Storey K.B. (ed), Storey J.M. (ed.) Protein adaptations and signal transduction vol. 2. Amsterdam : Elsevier; 2001.
Viollet B, et al. AMPK inhibition in health and disease. Crit Rev Biochem Mol Biol. 2010 August; 45(4): 276–295.
Vissing K, et al. Differentiated mTOR but not AMPK signaling after strength vs endurance exercise in training-accustomed individuals. Scand J Med Sci Sports. 2011 Oct 7.
Williamson DL, Drake JC. AICAR treatment for 14 days normalizes obesity-induced dysregulationof TORC1 signaling and translational capacity in fasted skeletal muscle. Am J Physiol Regul Integr Comp Physiol 299: R1546–R1554, 2010.
Yin, W. "The regulation of 5'AMP-activated protein kinase by the beta-adrenergic signaling pathway in adipocytes" (January 1, 2005). Dissertations available from ProQuest. Paper AAI3179843.
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