AICAR Peptide And The Energy Metabolism Of Different Cell Types

Researchers believe AICAR peptide (5-Aminoimidazole-4-carboxamide ribonucleotide) to be a synthetic analog of adenosine monophosphate (AMP). Both AICAR and AMP are thought to belong to a class of molecules called nucleotides, which serve as the basic building blocks of DNA and RNA. It is thought that nucleotides may play a key role in storing and transferring energy within cells. Because AICAR peptide mimics AMP, it may activate an enzyme called AMP-activated protein kinase (AMPK), which is believed to help ensure that cells have the energy they need while limiting excessive energy storage. By stimulating AMPK, AICAR peptide is suggested to exert a wide range of relevant research implications when exposed to research models, such as:

• possibly supporting insulin resistance by making glucose more readily available to muscle cells
• potentially boosting the breakdown of stored energy, especially under conditions such as ischemia
• Believed to potentially reduce lipid accumulation inside various cells, such as liver cells

AICAR peptide may also influence fatty acid oxidation, mitochondrial biogenesis, and the maintenance of slow-twitch, fatigue-resistant muscular tissue fibers, thereby influencing muscle cell endurance.

 

Research

AICAR Peptide and Muscle Cell Metabolism

Research by Cuthbertson et al. has posited that AICAR peptide may support muscle-cell insulin sensitivity through mechanisms related to its intracellular conversion into ZMP, aka 5-aminoimidazole-4-carboxamide ribonucleoside.⁽¹⁾ ZMP is thought to resemble AMP, an endogenous regulator of AMP-activated protein kinase (AMPK). Researchers have hypothesized that once AICAR peptide enters a muscle cell, it is metabolized into ZMP. ZMP is believed to bind AMPK to possibly induce a set of downstream signals. This cascade is thought to potentially contribute to relocation and better-supported functionality of glucose transporters, possibly allowing more efficient glucose uptake in muscle cells under laboratory conditions.

Although ZMP’s AMP-like properties suggest an AMPK-linked pathway, Cuthbertson et al. also mention other studies where AICAR peptide led to minimal activation of AMPK, or none at all, despite an apparent rise in glucose uptake. This implies that alternative or accessory routes, including pathways associated with ERK1/2 phosphorylation, might also be involved. ERK1/2 activation has been posited to mediate aspects of glucose transport in muscle cells, presumably through phosphorylation events that may complement or bypass AMPK signaling. Cuthbertson et al.also mention a possible role of AMPK subunits in mediating AICAR peptide-induced glucose uptake. Knocking out specific AMPK isoforms or the upstream kinase LKB1 that regulates them apparently abolishes the usual increase in glucose uptake that occurs when muscle cells are exposed to AICAR peptide. Yet there remains a possibility that these genetic manipulations might eventually yield variable outcomes, especially concerning contraction-induced glucose uptake.

Researchers have posited that glycogen depletion might also play a role in supporting glucose transport, though this appears to be only partially responsible. In addition, when AICAR peptide apparently activates AMPK, one event that might occur is the phosphorylation (and therefore inhibition) of acetyl-CoA carboxylase (ACC).⁽²⁾ ACC is an enzyme that usually helps generate malonyl-CoA, an intermediate in fatty acid synthesis. This may potentially lower malonyl-CoA levels, which might encourage more oxidization of fatty acids rather than storage in muscle cells. Some researchers posit that this shift in lipid usage might play a role in muscle cells responding better to insulin. Boon et al. observed higher levels of ACC phosphorylation after AICAR peptide exposure, possibly reflecting a better-supported AMPK cascade. In turn, this mechanism may partly explain how AICAR peptide might influence muscle cell insulin sensitivity. However, ongoing experiments continue to evaluate the full extent of its potential actions on glucose handling.

AICAR Peptide and Muscle Cell Endurance

Research by Narkar et al. posits that by activating AMPK, AICAR peptide may potentially influence muscle cell endurance and performance. AMPK is a central metabolic sensor that, when activated, is believed to possibly form a transcriptional complex with PPARδ. This nuclear receptor appears to regulate genes important for lipid metabolism and energy expenditure. Once bound to its co-regulators, PPARδ may coordinate the expression of multiple genes tied to fatty acid oxidation, mitochondrial biogenesis, and the maintenance of slow-twitch, fatigue-resistant muscular tissue fibers. In certain experiments, AICAR peptide was posited to have boosted the expression of oxidative metabolism–associated genes such as Scd1 (steroyl-CoA desaturase 1, an enzyme involved in unsaturated fatty acid synthesis), Fasn (fatty acid synthase, important for lipid biosynthesis), Ppargc1a (the gene encoding PGC1α, a co-activator that may upregulate mitochondrial formation and function), and Pdk4 (pyruvate dehydrogenase kinase 4, which may regulate glucose utilization in cells).

Based on these observations, researchers have proposed that AICAR peptide might foster a metabolic state akin to repeated mechanical stimulation, potentially reprogramming muscle cell gene networks in the absence of physical stimulation. Additional findings suggest that AICAR peptide may not directly increase the phosphorylation of PPARδ. Instead, it is believed to potentially act through co-regulatory proteins like PGC1α, thus possibly amplifying oxidative gene responses. Upon activation by AICAR peptide, AMPK may physically associate with PPARδ, apparently coordinating a suite of downstream transcriptional events that may support endurance-like properties in muscle cells. Specifically, Narkar et al. commented that 4 weeks of experimentation with AICAR peptide alone “induced metabolic genes and better-supported running endurance by 44%.” ⁽³⁾

Bosselaar has also posited that AICAR peptide may exert a vasodilatory action on the vasculature of muscular tissue, possibly through mechanisms tied to nitric oxide (NO). AICAR peptide may lead to a time- and concentration-dependent increase in blood flow, which some have hypothesized involves endothelial NO release. Findings further suggest the involvement of NO, which is thought to inhibit nitric oxide synthase and appears to attenuate the vasodilatory response. Because early work with adenosine receptor antagonists did not blunt the observed changes, it has been proposed that these vascular actions are not strictly mediated by adenosine receptor pathways but rather by intracellular events that depend on NO. Regardless, the better-supported blood flow to muscle cells may further contribute to their better-supported endurance in laboratory studies.⁽⁴⁾

AICAR Peptide and Cardiac Cell Survival

Longnus et al. suggest that the active intracellular forms of AICAR peptide and ZMP mentioned above may promote glycogen breakdown. They may also provide energy and promote survival to cells suffering from ischemia, such as cardiac cells. ZMP may allosterically activate glycogen phosphorylase, thereby supporting glycogenolysis and potentially supporting greater ATP availability during ischemic or otherwise stressful conditions. Because ZMP apparently mimics the action of AMP on phosphorylase activity, an increase in ZMP might be the main factor driving glycogen breakdown. At the same time, AICAR peptide exposure may allosterically activate AMPK without producing strong, easily measured changes in the total phosphorylation state of AMPK in homogenates. Data supporting this phenomenon includes the detection of phosphorylated ACC within the tissue, which hints that AMPK was activated in the intact preparation even if assays did not detect a large rise in kinase activity once the tissue was homogenized.

From a mechanistic standpoint, this apparent link between ZMP and glycogen phosphorylase may be crucial under ischemic stress, when an increased rate of glycogen breakdown might help sustain glycolytic flux in conditions of oxygen limitation. Moreover, other AMPK-mediated processes, such as the potential relief of malonyl-CoA–induced inhibition on fatty acid transport, may coincide with better-supported glucose utilization. Together, these mechanisms might provide a dual pathway for energy production—both glucose- and fatty acid-based—thus potentially helping cardiac cells maintain ATP levels.⁽⁵⁾ Cieslik et al. suggest that by activation on AMPK, AICAR peptide may also trigger non-canonical TGF-β pathways involving p38MAPK, which may help drive fibroblast precursor cells toward becoming fully functional fibroblasts and, later, myofibroblasts in the event of cardiac cell ischemia and injury.

Researchers have proposed that these fibroblast precursors, identifiable by markers such as CD44, may respond more vigorously when AMPK is activated. By supporting fibroblast differentiation and boosting their capacity to produce collagen and α-SMA, AICAR peptide may contribute to forming a sturdier, better-organized scar. These processes might also have the potential to support the overall cellular environment in the healing region. For instance, it has been proposed that a stronger and more coherent extracellular matrix may reduce the mechanical stresses that otherwise worsen damage in compromised cardiac tissue, presumably supporting cellular survival.⁽⁶⁾

AICAR Peptide and Liver Cells

Via AMPK-related mechanisms, mechanisms Tomita et al. suggest that AICAR peptide may be able to decrease the activity of specific lipogenic regulators in liver cells and consequently reduce fat accumulation. One proposed mechanism is that AICAR peptide may reduce sterol regulatory element binding protein-1c (SREBP-1c) expression. Since SREBP-1c is posited to be a major transcription factor controlling de novo lipogenesis, any dampening of its activity might, in theory, curb downstream enzymes such as fatty acid synthase (FAS). Additionally, the researchers commented that the “detection of 4-hydroxy-2-nonenal (4-HNE)-protein adducts showed that the AICAR peptide […] also decreased the products of lipid peroxidation.” This may have occurred possibly because the lower triglyceride burden leads to fewer lipid-derived oxidative byproducts.

Because lipid peroxidation is often linked to progressive cell stress, a decrease in these reactive lipid byproducts may potentially lessen subsequent cellular injury. Overall, by interacting with AMPK, Tomita et al. suggest that AICAR peptide may possibly rewire hepatic metabolism away from lipogenesis, at least under certain experimental conditions. Additional pathways, including interactions with Kupffer cells, are also thought to be involved. Some investigators have posited that examining Kupffer cell responses might reveal further roles for AICAR peptide in regulating liver cell injury and inflammation.⁽⁷⁾

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References:

1. Cuthbertson DJ, Babraj JA, Mustard KJ, Towler MC, Green KA, Wackerhage H, Leese GP, Baar K, Thomason-Hughes M, Sutherland C, Hardie DG, Rennie MJ. 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men. Diabetes. 2007 Aug;56(8):2078-84. doi: 10.2337/db06-1716. Epub 2007 May 18. PMID: 17513706.
2. Boon H, Bosselaar M, Praet SF, Blaak EE, Saris WH, Wagenmakers AJ, McGee SL, Tack CJ, Smits P, Hargreaves M, van Loon LJ. Intravenous AICAR peptide administration reduces hepatic glucose output and inhibits whole-body lipolysis in type 2 diabetic patients. Diabetologia. 2008 Oct;51(10):1893-900. doi: 10.1007/s00125-008-1108-7. Epub 2008 Aug 16. PMID: 18709353.
3. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008 Aug 8;134(3):405-15. doi: 10.1016/j.cell.2008.06.051. Epub 2008 Jul 31. PMID: 18674809; PMCID: PMC2706130.
4. Bosselaar M, Boon H, van Loon LJ, van den Broek PH, Smits P, Tack CJ. Intra-arterial AICA-riboside administration induces NO-dependent vasodilation in vivo in human skeletal muscle. Am J Physiol Endocrinol Metab. 2009 Sep;297(3):E759-66. doi: 10.1152/ajpendo.00141.2009. Epub 2009 Jul 14. PMID: 19602584.
5. Longnus SL, Wambolt RB, Parsons HL, Brownsey RW, Allard MF. 5-Aminoimidazole-4-carboxamide 1-beta -D-ribofuranoside (AICAR peptide) stimulates myocardial glycogenolysis by allosteric mechanisms. Am J Physiol Regul Integr Comp Physiol. 2003 Apr;284(4):R936-44. doi: 10.1152/ajpregu.00319.2002. PMID: 12626360.
6. Cieslik KA, Taffet GE, Crawford JR, Trial J, Mejia Osuna P, Entman ML. AICAR-dependent AMPK activation improves scar formation in the aged heart in a murine model of reperfused myocardial infarction. J Mol Cell Cardiol. 2013 Oct;63:26-36. doi: 10.1016/j.yjmcc.2013.07.005. Epub 2013 Jul 19. PMID: 23871790; PMCID: PMC3820161.
7. Tomita K, Tamiya G, Ando S, Kitamura N, Koizumi H, Kato S, Horie Y, Kaneko T, Azuma T, Nagata H, Ishii H, Hibi T. AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats. Alcohol Clin Exp Res. 2005 Dec;29(12 Suppl):240S-5S. doi: 10.1097/01.alc.0000191126.11479.69. PMID: 16385230