Archive for September 2014

AICAR, GW1516 Are An Exercise In A Pill

AICAR, GW1516 Are An Exercise In A Pill

AICAR and GW1516 experiments suggest that these two drugs, also called exercise in a pill, might protect against gaining weight on a high-fat diet, which might make it useful for treating obesity.

Researchers have identified two drugs, AICAR and GW1516, that mimic many of the physiological effects of exercise. The drugs increase the ability of cells to burn fat and are the first compounds that have been shown to enhance exercise endurance.

Both AICAR and GW1516 can be given orally and work by genetically reprogramming muscle fibers so they use energy better and contract repeatedly without fatigue. In laboratory experiments, mice taking the drugs ran faster and longer than normal mice on treadmill tests. Animals that were given AICAR, one of the two drugs, ran 44 percent longer than untreated animals. The second compound, GW1516, had a more dramatic impact on endurance, but only when combined with exercise.

Ronald M. Evans, the Howard Hughes Medical Institute investigator who led the study, said drugs that mimic exercise could offer potent protection against obesity and related metabolic disorders. They could also help counter the effects of devastating muscle-wasting diseases like muscular dystrophy. Evans and his colleagues, who are at the Salk Institute for Biological Studies, published their findings on July 31, 2008, in an advance online publication in the journal Cell.

Concerned about the potential for abuse of the two performance-enhancing drugs AICAR and GW1516, Evans has also developed a test to detect the substances in the blood and urine of athletes who may be looking for way to gain an edge on the competition.

In 2004, Evans and his colleagues genetically engineered mice that had altered muscle composition and enough physical endurance to run twice as far as normal mice. These “marathon mice” had an innate resistance to weight gain, even when fed a high-fat diet. “We made these mice and they had low blood sugar, they resisted weight gain, they had low fats in their blood. They were much healthier animals,” Evans said. “And when we put them on a treadmill, the engineered mice ran twice as far than normal mice – they transformed into remarkable runners.”

The scientists achieved these effects by modifying a gene called PPAR-delta, a master regulator of numerous genes. Evans and his colleagues showed that by enhancing PPAR-delta’s activity, they had shifted the genetic network in muscle cells to favor burning fat over sugar as their energy source. But the effects seen in the marathon mice were caused by a genetic manipulation that was present in their bodies as their muscles were developing. Evans’s group began to wonder whether they could duplicate these effects by turning on PPAR-delta in adult mice.

“We had shown that we could pre-program muscle using genetic engineering. If you express this gene while the muscle is being formed, you can increase the amount of non-fatiguing muscle fibers,” Evans says. “But what about reprogramming in an adult? When all the muscles are in place, can you give a drug that washes over the muscle for a few hours at a time and reprograms existing muscle fibers? That’s a very different question.”

PPAR-delta has long been an attractive drug target because of its central role in metabolism, so Evans and his colleagues had no shortage of chemical compounds available to test. They began by testing a compound called GW1516. They treated young adult mice with the drug for five weeks. “We measured gene changes and the muscles looked like they were responding, so we knew the drug was working.”

Thus, while fully expecting the drug to dramatically increase endurance – Evans says, “There was no change at all in running performance. Nothing — not even a percent.”

Surprised by this spectacular failure, Evans and his colleagues decided to try a different approach, based on real-life experience. “If you’re out of shape – and most of us are – and you want to change, you have to do some exercise. The way we reprogram muscle in adults is by training.”

So the scientists subjected two groups of mice — one that received the drug and one that did not — to interval training. The mice ran for 30 minutes on a slow treadmill five days a week for a total of four weeks. At the end of the training period, all of the mice – regardless of whether they had received GW1516 – had improved their performance. Those that had received GW1516, however, ran 68 percent longer than those that had only done the exercise training. “The dramatic effect of the drug was stunning,” Evans said.

The scientists were intrigued by this synergistic interaction and wanted to know how exercise allowed the drug to work. One possibility was an enzyme called AMP kinase (AMPK). During exercise, cells burn ATP as their primary source of energy. In the process, they create a by-product called AMP. When cells sense the presence of AMP, they activate AMPK. Activation of AMPK creates more ATP for the cell to burn. AMPK also triggers changes that lower blood sugar, sensitize cells to insulin, enable cells to burn more fat, suppress inflammation, and otherwise influence metabolic pathways. This is one reason that exercise is so beneficial.

Evans’s team found that in addition to replenishing the cell’s energy stores, AMPK also assists PPAR-delta in activating its gene targets. “It hops onto PPAR-delta in the nucleus and turbo-charges its transcriptional activity,” Evans explained. “We think AMPK activity is the secret to allowing PPAR-delta drugs to work.”

The critical question was whether chemical activation of AMPK is sufficient to trick the muscle into thinking it has been exercised. The second drug, called AICAR, enabled them to answer that question. AICAR mimics AMP, Evans said, “so muscle thinks it’s burning fat.” The researchers were encouraged when they found that when they gave the drug to mice, they activated many of the genes in muscle that are turned on by exercise.

After four weeks of treatment with AICAR, Evans and his colleagues once again challenged sedentary mice to run on the treadmill. They found that mice that had received AICAR were able to run 44 percent longer than untreated mice. “This is a drug that is like pharmacological exercise,” Evans says. “After four weeks of receiving the drug, the mice were behaving as if they’d been exercised.” In fact, he says, those that got the drug actually ran longer and further than animals that received exercise training.

The animals receiving AICAR improved their running performance and their ability to burn fat. None of these effects, however, were as strong as they were in the animals that received both exercise and activation of PPAR-delta via GW1516.

Evans said this indicates that the benefits are likely due to collaboration between cells’ AMPK and PPAR-delta signaling pathways. The team’s genetic analyses supported this hypothesis; they found that AICAR and GW1516 alone activated a subset of exercise-induced genes, but activating both pathways (by combining GW1516 with exercise) activated a larger group of genes. Many of those genes regulate metabolism and muscle remodeling. Evans and his colleagues called this the “endurance gene signature.”

Like exercise, AICAR and GW1516 trigger a variety of changes that contribute to muscles cells’ improved endurance and ability to burn fat. These changes include an increase in mitochondria, the structures responsible for producing energy; a shift in metabolism that takes advantage of lipids as an energy source; and an increase in blood flow, which enables the steady delivery of fat to burn. While the scientists only examined the drugs’ effects on muscle cells in this study, Evans says it is likely that they confer benefits on other systems impacted by exercise, such as the heart and lungs.

Based on his group’s findings, Evans is optimistic about using small molecules that mimic exercise to treat and prevent a variety of common conditions. For example, the way in which AICAR and GW1516 transformed the muscle fibers of mice suggests they might help reverse the muscle frailty associated with aging or diseases like muscular dystrophy. “We have now created the potential for a really simple intervention in an area of major health problems for which there is no intervention,” he says.

More broadly, AICAR and GW1516 could offer the benefits of exercise to people who do not get enough. “Almost no one gets the recommended 40 minutes to an hour per day of exercise,” he says. “For this group of people, if there was a way to mimic exercise, it would make the quality of exercise that they do much more efficient. This might be enough to move people out of the `danger zone’ toward a lower risk, healthier set point. By intervening early, you may forestall the emergence of more serious problems.”

Evans expects these types of drugs will be attractive to a variety of individuals. “If you like exercise, you like the idea of getting more bang for your buck,” he says of GW1516. “If you don’t like exercise, you love the idea of getting the benefits from a pill,” as with AICAR. So, while Evans sees tremendous opportunities for health benefits from drugs that mimic exercise, he also sees serious potential for abuse.

“Drugs that improve health are not only going to be used by people who have medical problems. They may also be used by people who are healthy – or by athletes who want an edge,” said Evans. He noted that the sports world has long been aware of his lab’s work demonstrating a link between PPAR-delta and endurance. What’s more, GW1516 has a relatively simple chemical structure and can be synthesized easily. Evans anticipates that athletes will seek their own sources of the drug – if they haven’t already.

Concerned about the potential for abuse, Evans thought it was important to develop a test that could detect whether the drug was being used as a performance-enhancing substance. With HHMI support, his group has created a highly sensitive test that uses mass spectrometry to detect the two drugs and their metabolic by-products in the blood or urine. While the test is very reliable in mice, Evans says that further analyses are needed to ensure that it is accurate in humans. Evans, HHMI and the World Anti-Doping Agency are now working to certify the detection system and make it available in time to retroactively test athletes who compete in the 2008 Olympics

Submitted by Armen Hareyan

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Bodybuilding PEGylated MGF

Bodybuilding PEGylated MGF

I was originally going to wait until the end of my trail with PEG-MGF (herein further referred to as pmgf) before posting my results and information, but my PM box has been flooded with information requests, so instead of waiting, I am going to post a blog that will be updated weekly.

Let’s start with an explanation of Mechano Growth Factor (MGF) and what it does. The C-terminal peptide of mechano-growth factor (MGF), an alternatively spliced variant of insulin-like growth factor 1 (IGF-1), was found to function independently from the rest of the molecule. At any rate, IGF-I exists in multiple isoforms (tissue-specific proteins of functional and structural similarity). One isoform, which differs from the systemic or liver type, happens to be particularly sensitive to mechanical signals such as the gamut of exercise overload. This important isoform, called mechano-growth factor (MGF), is a local splice variant of IGF-I produced by damaged or loaded skeletal muscle.

The physiological function of a recently cloned splice variant of insulin-like growth factor-I (IGF-I; mechano growth factor (MGF)) was studied using an in vitro cell model. Unlike mature IGF-I, the distinct E domain of MGF inhibits terminal differentiation whilst increasing myoblast proliferation. Blocking the IGF-I receptor with a specific antibody indicated that the function of MGF E domain is mediated via a different receptor. The results provide a basis for localized tissue adaptation and helps explain why loss of muscle mass occurs in the elderly and in dystrophic muscle in which MGF production is markedly affected.
Yang SY, Goldspink G. FEBS Lett. 2002 Jul 3;522(1-3):156-60.

So what is pegylation? In simple terms it is the process of attaching one or more chains of a substance called polyethylene glycol (PEG) to a protein molecule such as IGF or in this case MGF. Since the body does not react to PEG, it helps provide a protective barrier around an attached protein so it can survive in the body longer. This is highly beneficial for systemic products that must survive repeated attacks by enzymatic exposure. PEG is an inert non-toxic substance that can provide protection to amine groups since they are flexible and allow attachment by bioengineered processes to the receptor bearing cell.

Finally a quick explanation of polyethylene glycol; Any of a family of high molecular weight compounds that can be liquid or waxlike in consistency and are soluble in water and in many organic solvents.

Alright, now that you have sifted through my semi-scientific yet easy to read explanation of pmeg, let’s get to the main point of the article, my experience. First off, I was asked to test this new product. They supplied me the product and requested I use it at 200mcg, two times per week. I agreed on the condition that no matter what the results, good or bad, my review would be brutally honest. If they were looking for someone to just promote their product, I was not their guy. They agreed unconditionally and shipped the product out immediately.

Let me preface what follows below are my results but they will not be typical for most users. Having already accumulated up to 270lbs of mass over the years, my muscle memory is outstanding and I am easily able to rebound when using products. At this time, I have been off cycle for 2 months, using only 500mg test enanthate per week as HRT. This is my first time off cycle in over 8 years. I was also using 2iu gh per day but stopped using it at the request of IBE. My diet and training did not change, I was trying to create as stable an environment to test this product as would allow.

I started at a current bodyweight of 227lbs with my bodyfat measured at 14.8% and 55% water balance. I have some sophisticated test equipment at home so I can be sure my stats and my ability to track results are fairly accurate. I have been using this product for 4 weeks now, still having 4 weeks to go. After that, I will cycle off for a few weeks and then resume with a new test trial using mgf, igf, slin, and gh with small amount of anabolics in a very androgen rich environment. I will utilize many small injections with specific timing to maximize my results, but that is for another article.

My first week of use was a tough one for me, I had to come off the gh and immediately notice a decrease in lean mass, as well as longer recovery between workouts. This subsided very quickly though with the introduction of pmeg. My current workout schedule is on Tues, Thurs, and Friday. I decided to use the pmeg on Tues and Thurs, my two biggest bodypart workout days. I was instructed by IBE to test it sub-q since it is systemic anyway and the injection method was somewhat irrelevant. On my next trial, I will be using it IM in a specific sequence with other peptides.

My first week of use, my weight stabilized as did my body fat percentage. I was quickly able to stop my wasting from coming off cycle and gh, and reintroduce beneficial cell growth potential. The changes from my first to second week were dramatic to say the least. Not only was I getting skin tight pumps, my vascularity was up, but the scale was most telling off all. I went from 227lbs to 232lbs by the end of the second week. At this time my water balance and body fat were still the same. The third week was another major change, even more so than the first two weeks. My weight jumped up to 235lbs but most incredible of all was the fat loss. Let me remind you that I did not make any diet changes; I just added this product in mostly as a pct product while coming off cycle. So what impressed my most was my body fat dropping from 14.8% to 12.9%. I just finished my 4th week yesterday so I jumped back on the scale to see what changes were in store for me now!

This was the best week yet. Before you get all freaked out, please remember that I just came off an 8 year cycle, my body fat jumped up from the estrogen increase and I was gaining back weight I had lost from not bulking anymore. Ok, with that out of the way again, here is week 4: Weight backed off a bit to 234lbs, but my body fat melted down to 10.9%, a drop of almost 4% since starting this just 4 weeks ago. The other awesome gain was my cellular water balance was up to 58% which is an indication of intra-cellular water balance for overall health, condition, and prevention from muscle and joint tissue damage.
PegMGF Journal by “Almost Pro”
My Pegylated Mechano Growth Factor trial
By Gavin Kane

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