Couch Mouse to Mr. Mighty by Pills Alone
- 08-01-2008, 10:41 AM
Couch Mouse to Mr. Mighty by Pills Alone
From the NYT:
Work w/ PPAR-delta leads to a drug that increases the percentage of Type 2 fiber; called 'exercise in a bottle'
- 08-01-2008, 10:46 AM
I wonder which target enzyme (if any) they are activating to exert transcriptional control over PPAR-delta? I know that AMPk directly activates PPAR-alpha b-oxidation, and also upregulates Alpha in response to resistance training.
08-01-2008, 10:47 AM
Ah, I knew it. They're mimicking extracellular fluctuations in the ATP:AMP ratio in order to have AMPk mitigate fatigue accordingly! Funny thing is, Anabolic Pump already directly modulates AMPk in myocytes!t would appear that GW1516 alone only boosted endurance and affected the muscle fibres when combined with some exercise. Narkar said they wondered if this was because of ATP, the chemical that delivers energy to muscles. When the body's demand for energy is high, ATP releases all its energy and becomes AMP, and when AMP goes up, it triggers AMPK, a metabolic regulator that increases production of ATP. They wondered if perhaps PPAR delta only got involved once the AMPK switched on.
AMPK normally resides in the cytoplasm that surrounds the nucleus of each cell, but closer inspection revealed that in this experiment, some exercise-activated AMPK molecules had got into the nucleus, interacted with the PPAR delta and increased its effect on endurance.
"It essentially puts a turbo charge on PPAR delta, which explains why exercise is so important," explained Evans.
So all that remained was to find a way to produce the same ATP-AMP effect without exercise. In a further experiment, the investigatos fed untrained mice a substance called AICAR, a synthetic vesion of AMP that triggers the AMPK switch directly.
After four weeks, with no training, the mice on synthetic AMP were able to run 44 per cent longer than untreated, untrained mice. Narkar said that was about the same improvement we can get with regular exercise.
The researchers concluded that:
" These results demonstrate that AMPK-PPAR delta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise."
08-01-2008, 10:55 AM
Incidentally, I was having a very similar conversation on another board:
You may need to update your research on lipogenic transcriptional factors.
In fact, the latest research I have seen contradicts your point, and has elucidated that malonyl-CoA - and thereby its rate-limiting inhibition of CPT-1 - is not necessarily under transcriptional control of PPAR. Of course, this is based on your comments, and the mistaken assumption that the actions of PPAR-Alpha, in a myocardial respect, is directly corollary to the actions of PPAR-Gamma2 in a skeletal muscle respect (which AP's ingredients are known to modulate); which, of course, it is not. Most of the leading research has not, and most likely will not, reflect what you are implying here (in respects to PPAR-Gamma2 - remembering the PPAR-Family is diverse).
If it were, most of the research surrounding B-Oxidation in respects to these compounds would reflect inhibition; such is not the case.
Further, I think you're missing a key step in terms of 5-AMPk synthesis, and its relationship with the PPAR-Family and fatty acid synthesis and oxidation. It's pretty key to your implication that b-oxidation is inhibited. But, you seem smart, so I'll let you extrapolate that further.No: Most of the research on Berberine - and to an extent Lagerstroemia - has reflected antilipogenic activity via PPAR-Gamma2, and not Alpha. However, AMPk does play a role in the upregulation of PPAR-Alpha in skeletal muscle in the context of oxidative energy demands in endurance training sessions; that is beside the point, though. I merely pointed out PPAR-Alpha, in order to point out the fallacy of your CPT-1 comment. AP predominantly mediates Gamma, which does not have transcriptional control over either malonyl-COA or the target enzyme CPT-1. In reality, most of the research concerning upregulated malonyl-CoA and subsequent lessened mRNA CPT-1 expression surrounded Alpha's activity in smooth muscle; the context is different.
My comments towards AMPk are vital to the discussion at hand, though; energy homeostasis, and by extension Anabolic Pump's MOA, cannot be fully understood without a concomitant understanding of AMPk mediated FA oxidation, glucose metabolism, protein synthesis, and so on. AMPk responds to extracellular fluctuations (AMP:ATP ratio) in order to meet intracellular demand for energy. It is especially responsible for the transferring between glycolytic and oxidative manners of energy expenditure during anaerobic exercise (see above comment). It directly controls the expression of GLUT4, and the processes of glycolysis and vasculogenesis, as well as mediating several other glucose uptake enzymes. It is highly responsible for the efficient storage and expenditure of glucose - hence my comments towards your 'excess glucose' storage comment.
Further, AMPk inactivates ACC, and upregulates levels of MCD (malonyl-CoA-decarboxylase) which as you know leads to increased levels of CPT-1 and subsequent mitochondrial FA oxidation. So, as I said earlier, CPT-1 is not an issue in this respect, and AP is - very efficiently so - antilipogenic. This is one of the primary mechanisms through which AP produces body composition changes: Ensuring the efficient transfer and storage of glucose, as well as increasing the cell's oxidative capacity. The risk of FA 'restorage' and subsequent lipogenesis/lipid hypertrophy is therefore reduced, and AMPk by its nature prevents plasma triglyceride, and lipid synthesis.
I appreciate your healthy skepticism, but I also appreciate my reps being allowed to conduct their activities without overzealous posters harassing them with condescending tones and questions they do not fully understand. Your confrontational attitude isn't necessary, and I hope in further USP Labs related threads you participate in, you are much more cordial.
08-01-2008, 10:57 AM
08-01-2008, 11:00 AM
08-01-2008, 11:04 AM
08-01-2008, 11:06 AM
08-01-2008, 11:22 AM
A poetic license would permit you to operates mixed metaphors and vivid imagery on public thoroughfares (like this one).
(a reference to you being "balls-deep in AMPk pathways", above)
So, good morning - hope that was gentle enough (I, of course, have been up for hours & have had ALL my coffee...).
08-01-2008, 11:28 AM
My poetic license is a Class-6: permitted to execute the most vivacious pentameter vernacular whilst operating a motor vehicle.
And I am glad no female I would ever hope to intimate with is reading this particular exchange.
08-01-2008, 12:33 PM
08-01-2008, 12:34 PM
Especially I've heard of AICAR before so it didn't seem all that new what this research was reporting. Still very interesting none the less. Although I don't buy that it's going to be as good as exercise.
08-01-2008, 12:41 PM
I saw this on the news yesterday. Very interesting read.
Thanks for the post BW.
Thanks for the insightful comments Mullet.
\\ USPlabs Alpha Ginger //
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