16 replies to this topic

[tom a]

A very interesting new result reported in the NY Times.

...The second drug, called Aicar, improves endurance without any training. Dr. Evans believes it both mimics the effects of exercise and activates PPAR-delta, thus being able to switch on both sets of genes needed for the endurance signal.

Aicar works by mimicking a by-product of energy metabolism, signalling the cell that it has burned off energy and needs to generate more. The drug is “pretty much pharmacological exercise,” Dr. Evans said.

He said the drugs work off a person’s own genetics, pushing the body to an improved set-point that is otherwise gained only by strenuous training. “This is not just a free lunch, it’s pushing your genome toward a more enhanced genetic tone that impacts metabolism and muscle function. So instead of inheriting a great set-point you are using a drug to move your own genetics to a more activated metabolic state.”

Aicar is a well known chemical that has been tested for various diseases since 1994. But neither Aicar nor GW1516 has been tested in people for muscle endurance so the health effects of the drugs, particularly over the long term, are not precisely known.

This may change if pharmaceutical companies pursue Dr. Evans’s findings. “The drugs’ effect on muscle opens a window to a world of medical problems,” Dr. Evans said. “This paper will alert the medical community that muscle can be a therapeutic target.”

The new drugs activate at least one of the pathways triggered by resveratrol, a substance found in red wine though in amounts probably too low to significantly affect muscle.

In 2006 Dr. Auwerx and colleagues showed that large doses of resveratrol would make mice run twice as far as usual on a treadmill before collapsing. It is unclear just how resveratrol works, but one of its effects may be to bind with a protein that helps activate PPAR-delta. Dr. Auwerx’s resveratrol-treated mice remodeled their muscle fibers into a type that contains larger numbers of the energy-producing mitochondria.

This is the same result that Dr. Evans has found can be obtained with Aicar.

[maxwatt]

here is a paper that seems to show that resveratrol does the same thing as one of the drugs in the article, Aicar (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside.)

Resveratrol stimulates AMP kinase activity in neurons

[manofsan]

A discovery of a gene-controlling protein PPAR-delta could lead to muscle-toning drugs

http://www.nytimes.c...e/01muscle.html

This pathway apparently relates to the SIRT1 pathway triggered by resveratrol

[niner]

A discovery of a gene-controlling protein PPAR-delta could lead to muscle-toning drugs

http://www.nytimes.c...e/01muscle.html

This pathway apparently relates to the SIRT1 pathway triggered by resveratrol

Cool. Auwerx gets a mention too. So there are two drugs discussed in the article, along with resveratrol. One of the drugs has been around for a while, and is called Aicar. I wondered if it was a misprinted ALCAR, but it's not. AICAR is a nucleotide analog. Here's the structure.

[Shepard]

AICAR is used in rodents to raise AMPK. For some reason, it's not used in humans that I've seen. But, metformin sure is.

[Mind]

Potentially good news for fat couch potatoes, but not so much for those of us who are already in good shape and/or enjoy exercise. I see in different discussions about this finding that researchers and doctors are cautioning that exercise carries a lot more benefit than you could ever get from a pill. Good advice.

[marcopolo]

It seems almost too simple, a pill that mimics going to the gym. Hopefully it works in humans as well as mice. Medical science has done great things for mice, too bad everything that works in mice doesn't seem to work on us. I read about that muscle effect in Resveratrol and wondered why more people were not reporting fat loss with Resveratrol, since exercising your muscles to make them more efficient fat burners would burn more fat correct?

Edited by marcopolo, 02 August 2008 - 10:29 PM.

[TianZi]

here is a paper that seems to show that resveratrol does the same thing as one of the drugs in the article, Aicar (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside.)

Resveratrol stimulates AMP kinase activity in neurons

When I first read this article a few days ago, my first thought was, "Did Glaxo purchase Sirtris not out of a desire to fully exploit Sirtris's discoveries and developments, but rather to bury them, so as to remove a potential competitor to drugs it has already spent time and money developing?" But that's probably not the case, so just idle speculation on my part.

[maxwatt]

here is a paper that seems to show that resveratrol does the same thing as one of the drugs in the article, Aicar (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside.)

Resveratrol stimulates AMP kinase activity in neurons

When I first read this article a few days ago, my first thought was, "Did Glaxo purchase Sirtris not out of a desire to fully exploit Sirtris's discoveries and developments, but rather to bury them, so as to remove a potential competitor to drugs it has already spent time and money developing?" But that's probably not the case, so just idle speculation on my part.

You have to stand to lose a great deal of money to buy a potential competitor to bury it; otherwise it makes no financil sense. Glaxo needs new products, the drugs responsible for their income stream will lose patent protection in a few years. They need new products.

[dachshund]

http://www.physorg.c...s136967597.html

[Shepard]

It seems almost too simple, a pill that mimics going to the gym. Hopefully it works in humans as well as mice.

I doubt it. Elevating AMPK is only part of the adaptation process, and chronically elevating it interferes with the rest.

Also note that there are tons of things that increase AMPK in various tissues through various mechanisms.

Edited by shepard, 03 August 2008 - 05:43 PM.

[neogenic]

Couch Mouse to Mr. Mighty by Pills Alone


By NICHOLAS WADE
Published: August 1, 2008
For all who have wondered if they could enjoy the benefits of exercise without the pain of exertion, the answer may one day be yes — just take a pill that tricks the muscles into thinking they have been working out furiously.

Researchers at the Salk Institute in San Diego reported that they had found two drugs that did wonders for the athletic endurance of couch potato mice. One drug, known as Aicar, increased the mice’s endurance on a treadmill by 44 percent after just four weeks of treatment.

A second drug, GW1516, supercharged the mice to a 75 percent increase in endurance but had to be combined with exercise to have any effect.

“It’s a little bit like a free lunch without the calories,” said Dr. Ronald M. Evans, leader of the Salk group.

The results, Dr. Evans said, seem reasonably likely to apply to people, who control muscle tone with the same underlying genes as do mice. If the drugs work and prove to be safe, they could be useful in a wide range of settings.

They should help people who are too frail to exercise and those with health problems like diabetes that are improved with exercise, Dr. Evans said.

The chemicals involved are already available, and such muscle-enhancing drugs would also have obvious appeal to athletes seeking to gain an edge in performance. Dr. Evans said athletes often showed up at public lectures he had given and asked him about the drugs.

With money from the Howard Hughes Medical Institute, Dr. Evans has devised a test to detect whether an athlete has taken the drugs and has made it available to the World Anti-Doping Agency, which prepares a list of forbidden substances for the International Olympic Committee. Officials at the anti-doping agency confirmed that they were collaborating with Dr. Evans on a test but could not say when they would start using it.

Experts not involved in the study agreed that the drugs held promise for treating disease. Dr. Johan Auwerx, a specialist in metabolic diseases at the University Louis Pasteur in Strasbourg, France, said the result with Aicar looked “pretty good” and could be helpful in the treatment of diabetes and obesity. “The fact you can mimic exercise is a big advantage,” he said, “because diet and exercise are the pillars of diabetes treatment.”

Dr. Richard N. Bergman, an expert on obesity and diabetes at the University of Southern California, said the drugs might prove to have serious side effects but, if safe, could become widely used. “It is possible that the couch potato segment of the population might find this to be a good regimen, and of course that is a large number of people.”

The idea of a workout in a pill seems almost too good to be true, but Dr. Evans has impressive research credentials, including winning the Lasker Award, which often presages a Nobel Prize. He is an expert on how hormones work in cells and on a powerful gene-controlling protein called PPAR-delta, which instructs fat cells to burn off fat.

Four years ago he found that PPAR-delta played a different role in muscle. Muscle fibers exist in two main forms. Type 1 fibers have copious numbers of mitochondria, which generate the cell’s energy and are therefore resistant to fatigue. Type 2 fibers have fewer mitochondria and tire easily. Athletes have lots of Type 1 fibers. People with obesity and diabetes have far fewer Type 1 and more Type 2 fibers.

Dr. Evans and his team found that the PPAR-delta protein remodeled the muscle, producing more of the high-endurance Type 1 fiber. They genetically engineered a strain of mice whose muscles produced extra amounts of PPAR-delta. These mice grew more Type 1 fibers and could run twice as far as on a treadmill as ordinary mice before collapsing.

Given that people cannot be engineered in this way, Dr. Evans wondered whether levels of the PPAR-delta protein could be raised by drugs. Pharmaceutical companies have long tried to manipulate PPAR-delta because of its role in fat metabolism, and Dr. Evans found several drugs were available, although they had been tested for different purposes.

In a report in the Friday issue of Cell, he described the two drugs that successfully activate the muscle-remodeling system in mice, generating more high-endurance Type 1 fiber. The drug GW1516 activates the PPAR-delta protein but the mice must also exercise to show increased endurance. It seems that PPAR-delta switches on one set of genes, and exercise another, and both are needed for endurance.

Aicar improves endurance without training. Dr. Evans believes that it both activates the PPAR-delta protein and mimics the effects of exercise, thus switching on both sets of genes needed for the endurance signal.

Aicar signals to the cell that it has burned off energy and needs to generate more. The drug is “pretty much pharmacological exercise,” Dr. Evans said.

He said the drugs worked off a person’s genetics, pushing the body to an improved set-point otherwise gained only by strenuous training. “This is not just a free lunch,” he said. “It’s pushing your genome toward a more enhanced genetic tone that impacts metabolism and muscle function. So instead of inheriting a great set-point you are using a drug to move your own genetics to a more activated metabolic state.”

Aicar has been tested for various diseases since 1994 and is in advanced trials for treating a heart condition known as ischemic reperfusion injury. But neither Aicar nor GW1516 has been tested in people for muscle endurance, so the side effects of the drugs, particularly over the long term, are not precisely known.

That may change if pharmaceutical companies pursue Dr. Evans’s findings. “The drugs’ effect on muscle opens a window to a world of medical problems,” he said. “This paper will alert the medical community that muscle can be a therapeutic target.”

The drugs activate at least one of the chemical pathways triggered by resveratrol, a substance that also showed increased endurance in mice. Resveratrol is found in red wine though in amounts probably too low to significantly affect muscle.

In 2006 Dr. Auwerx and colleagues at University Louis Pasteur showed that large doses of resveratrol would make mice run twice as far as usual on a treadmill before collapsing. It is unclear just how resveratrol works, but one of its effects may be to bind with a protein that helps activate PPAR-delta. Dr. Auwerx’s resveratrol-treated mice remodeled their muscle fibers into the Type 1, with greater endurance.

That is the same result Dr. Evans has found can be obtained with Aicar. The relationship between the two drugs is not yet clear. Dr. Evans believes that resveratrol acts on so many pathways in the cell, particularly at high doses, that it is hard to know how it is achieving any given effect, whereas the role of Aicar and GW1516 is well defined. But Dr. Auwerx said he did not think Aicar was necessarily working in the way Dr. Evans described.

[neogenic]

Cell. 2008 Jul 30. [Epub ahead of print]
AMPK and PPARdelta Agonists Are Exercise Mimetics.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.
Gene Expression Laboratory.

The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARbeta/delta agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1alpha, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.

[neogenic]

J Clin Endocrinol Metab. 2005 Mar;90(3):1791-7. Epub 2004 Dec 21. Links
Peroxisome proliferator activated receptor delta (PPARdelta) agonist but not PPARalpha corrects carnitine palmitoyl transferase 2 deficiency in human muscle cells.Djouadi F, Aubey F, Schlemmer D, Bastin J.
Institut National de la Santé et de la Recherche Médicale Unité 393, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75015 Paris, France.

Type 2 carnitine palmitoyl transferase (CPT2) is involved in the transfer of long-chain fatty acid into the mitochondria. CPT2-deficient patients carry gene mutations associated with different clinical presentations, correlating with various levels of fatty acid oxidation (FAO) and residual CPT2 enzyme activity. We tested the hypothesis that pharmacological stimulation of peroxisome proliferator-activated receptors (PPAR) can stimulate FAO in CPT2-deficient muscle cells. Accordingly, we show that a 48-h treatment of CPT2-deficient myoblasts by bezafibrate restored FAO in patient cells. Specific agonists of PPARdelta (GWdelta 0742), and, to a lower extent, PPARalpha (GWalpha 7647) also stimulated FAO in control myoblasts. However, when tested in CPT2-deficient myoblasts, only the delta-agonist was able to restore FAO, whereas the alpha-agonist had no effect. GWdelta 0742 increased CPT2 mRNA levels, whereas no change in CPT2 transcripts was found in response to GWalpha 7647. Bezafibrate and GWdelta 0742 increased residual CPT2 activity and normalized long-chain acylcarnitine production by deficient cells. Finally, CPT1-B mRNA was also stimulated after PPAR agonist treatment, and this likely takes part in drug-induced increase of FAO in control muscle cells. In conclusion, this study clearly suggests that PPARs could be therapeutic targets for correction of inborn beta-oxidation defects in human muscle. Furthermore, these data also illustrate a selective control of beta-oxidation enzyme gene expression by PPARdelta, with no contribution of PPARalpha.

[neogenic]

Diabetes. 2008 Feb;57(2):332-9. Epub 2007 Nov 16. Links
Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men.Risérus U, Sprecher D, Johnson T, Olson E, Hirschberg S, Liu A, Fang Z, Hegde P, Richards D, Sarov-Blat L, Strum JC, Basu S, Cheeseman J, Fielding BA, Humphreys SM, Danoff T, Moore NR, Murgatroyd P, O'Rahilly S, Sutton P, Willson T, Hassall D, Frayn KN, Karpe F.
Churchill Hospital, Oxford OX3 7LJ, UK.

OBJECTIVE: Pharmacological use of peroxisome proliferator-activated receptor (PPAR)delta agonists and transgenic overexpression of PPARdelta in mice suggest amelioration of features of the metabolic syndrome through enhanced fat oxidation in skeletal muscle. We hypothesize a similar mechanism operates in humans. RESEARCH DESIGN AND METHODS: The PPARdelta agonist (10 mg o.d. GW501516), a comparator PPARalpha agonist (20 mug o.d. GW590735), and placebo were given in a double-blind, randomized, three-parallel group, 2-week study to six healthy moderately overweight subjects in each group. Metabolic evaluation was made before and after treatment including liver fat quantification, fasting blood samples, a 6-h meal tolerance test with stable isotope fatty acids, skeletal muscle biopsy for gene expression, and urinary isoprostanes for global oxidative stress. RESULTS: Treatment with GW501516 showed statistically significant reductions in fasting plasma triglycerides (-30%), apolipoprotein B (-26%), LDL cholesterol (-23%), and insulin (-11%), whereas HDL cholesterol was unchanged. A 20% reduction in liver fat content (P < 0.05) and 30% reduction in urinary isoprostanes (P = 0.01) were also observed. Except for a lowering of triglycerides (-30%, P < 0.05), none of these changes were observed in response to GW590735. The relative proportion of exhaled CO(2) directly originating from the fat content of the meal was increased (P < 0.05) in response to GW501516, and skeletal muscle expression of carnitine palmitoyl-transferase 1b (CPT1b) was also significantly increased. CONCLUSIONS: The PPARdelta agonist GW501516 reverses multiple abnormalities associated with the metabolic syndrome without increasing oxidative stress. The effect is probably caused by increased fat oxidation in skeletal muscle.


Diabetologia. 2006 Nov;49(11):2713-22. Epub 2006 Sep 8. Links
Activation of PPAR-delta in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids.Brunmair B, Staniek K, Dörig J, Szöcs Z, Stadlbauer K, Marian V, Gras F, Anderwald C, Nohl H, Waldhäusl W, Fürnsinn C.
Department of Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.

AIMS/HYPOTHESIS: GW501516, an agonist of peroxisome proliferator-activated receptor-delta (PPAR-delta), increases lipid combustion and exerts antidiabetic action in animals, effects which are attributed mainly to direct effects on skeletal muscle. We explored such actions further in isolated rat skeletal muscle. MATERIALS AND METHODS: Specimens of rat skeletal muscle were pretreated with GW501516 (0.01-30 mumol/l) for 0.5, 4 or 24 h and rates of fuel metabolism were then measured. In addition, effects on mitochondrial function were determined in isolated rat liver mitochondria. RESULTS: At concentrations between 0.01 and 1 mumol/l, GW501516 dose-dependently increased fatty acid oxidation but reduced glucose utilisation in isolated muscle. Thus after 24 h of preincubation with 1 mumol/l GW501516, palmitate oxidation increased by +46+/-10%, and the following decreased as specified: glucose oxidation -46+/-8%, glycogen synthesis -42+/-6%, lactate release -20+/-2%, glucose transport -15+/-6% (all p<0.05). Reduction of glucose utilisation persisted independently of insulin stimulation or muscle fibre type, but depended on fatty acid availability (the effect on glucose transport in the absence of fatty acids was an increase of 30+/-9%, p<0.01), suggesting a role for the glucose-fatty acid cycle. At higher concentrations, GW501516 uncoupled oxidative phosphorylation by direct action on isolated mitochondria. CONCLUSIONS/INTERPRETATION: GW501516-induced activation of PPAR-delta reduces glucose utilisation by skeletal muscle through a switch in mitochondrial substrate preference from carbohydrate to lipid. High concentrations of GW501516 induce mitochondrial uncoupling independently of PPAR-delta.

[neogenic]

I am suprised this discussion ended. This is really groundbreaking. People that were turned off by the exercise in a bottle stuff...look closely. You need to exercise for this to work, it just potentiates it. I'd like to discuss drugs or supplements that could mimics these effects to some degree along the lines of the aforementioned mechanisms.

[Shepard]

Until there is a human trial, it can hang in the category of everything that works great in rodents but not in people.

Which mechanisms would you like to discuss? GW501516 works via AMPK and PPAR beta/delta. Even though PPAR agonists tend to activate AMPK via increased adiponectin, this and the TZDs (maybe fibrates, too) seem to activate AMPK independently of PPAR activation.