What exactly is? EP1 - AMPK Signalling Pathway (Basic overview)

Seth Walsh

Seth Walsh

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AMPK stands for AMP activated protein kinase. AMP stands for Adenosine Monophosphate. As you know, if you're familiar with creatine and ATPs, ATP stands for Adenosine Triphosphate. ATP is needed by the mitochondria for energy. AMPs are unusuable phosphates that need to bond with an ADP to make usable energy.

So, AMPK is looked at as an "energy sensor", and is activated by being in an energy deficit. How this energy deficit is measured is through the AMP:ATP ratio.

AMPK is the master regulator of energy metabolism.

Exercise activates AMPK. This should make sense now, because during exercise you are using up your ATPs. Since the AMP:ATP ratio grows bigger, AMPK gets activated.

AMPK is a negative regulator of mTOR, meaning it inhibits the mTOR pathway as AMPK itself is activated. Creatine provides more ATPs during exercise, possibly delaying or minimizing the inhibition of mTOR, which is the pathway responsible for protein synthesis. I hope this adds some insight as to why creatine is an effective supplement for keeping muscle mass and optimizing performance.

What does AMPK activate?:

ULK1 (Serine/threonine-protein kinase). ULK1 is a protein responsible for macroautophagy.

ATGL (Adipose triglyceride lipase). This is an enzyme responsible for the release of fatty acids from a triglyceride, which eventually leads to fatty acid catabolism.

What else does AMPK inhibit?:

ACC (Acetyl-CoA Corboxylase). This enzyme is responsible for fatty acid synthesis. AMPK is responsible for inhibiting fatty acid synthesis.
HMG-CoA Reductase. This enzyme is responsible for Cholesterol synthesis.
GS (Glycogen Synthase). The enzyme responsible for glycogen synthesis. In an energy deficit (with AMPK active), you won't be able to store new glycogen in your liver or muscle tissue.

What else is AMPK responsible for activating?:

TBC1D1: A very interesting channel. TBC1D1 helps insulin sensitive cells uptake glucose in the absence of insulin by recruiting GLUT4 vesicles.

GLUT4 translocalisation is an insulin mimicking process. You should not be worried about glucose not being able to enter your cells during AMPK activation during exercise, because TBC1D1 takes care of this process. (Do not buy post workout carb supplements as they're just a waste of money. You don't need an "insulin spike post workout", TBC1D1 is doing insulin's job for your cells during your exercise).

Glycolysis occurs after the GLUT4 translocalisation. Glycolysis is just the breakdown of glucose within your cells.

Summary of AMPK signalling

Increases glucose uptake and utilization
Increases fatty acid oxidation through ATGL
Increases autophagy through ULK and the negative regulation of mTOR (huge subject for another day. too extensive to even briefly explain here)
Decreases glycogen synthesis through inhibition of the GS enzyme
Decreases protein synthesis through the negative regulation of mTOR. (mTOR -> p70s6k -> s6 synthesis)
Decreases cholesterol synthesis through the enzyme HMG-CoA Reductase
Decreases fatty acid synthesis through the enzyme ACC

What you should know

AMPK signalling increases catabolism and decreases anabolism. Why is this the case? AMPK signalling aims to decrease energy expenditure and while increasing energy production, in it's own attempt to reverse the AMP:ATP ratio so our body can regain energy.

AMPK in and of itself is an energy pathway and has many many benefits which I will talk about in the future. Do not fall under the impression that AMPK signalling is bad because it promotes catabolism whilst decreasing anabolism.

Sometime soon I will go into detail about the benefits of increased catabolism (autophagy) and the benefits of decreased anabolism.
 
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Great, I needed a good explanation on AMPK.

makes complete sense why one wouldn't want this pathway active during puberty, lowered androgens due to lowered cholesterol synthesis and a higher rate of catabolism due to lowered protein synthesis.

but sounds like a godsend for anti-aging.
 
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Great, I needed a good explanation on AMPK.

makes complete sense why one wouldn't want this pathway active during puberty, lowered androgens due to lowered cholesterol synthesis and a higher rate of catabolism due to lowered protein synthesis.

but sounds like a godsend for anti-aging.
It really is a godsend for anti-aging. The main purpose of intermittent fasting is to enter AMPK. Once AMPK is activated, mTOR gets shut off. Metformin and Rapamycin are so highly regarded in anti-aging because they shut off mTOR. Achieving more homeostatis between mTOR and AMPK, ie: balancing your body's anabolism and catabolism will improve your longevity. Because look at it this way. Too much catabolism = death by malnutrition/starvation. Too much anabolism = obesity/tumor growths, (not to mention diabetes from all the insulin). Balancing them avoids these potential ailments and helps your body's essential survival adaptations.

NMN is important because it's an NAD+ precursor, and NAD+ is needed in the ATP production process. AMPK is really the master regulator. NMN and Creatine work so well because your body enters AMPK once you exercise, but then there's a flood of ATP that gets created during your exercise, allowing you to work harder because you have more energy than you're supposed to have.

The Creatine Phosphates are AMP-like phosphates which are very readily available to join ADPs. The NMN increases NAD+ in a time when your NADH/NAD+ should also be positive (while exercising and expending energy).
 
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@Don't Forget to mew
AMP = 1 AMP
ADP = 2 AMPs
ATP = 3 AMPs (usable energy source)

Creatine phosphates act like AMPs so that they can bond with ADPs more readily during intense exercise when all the AMPs have already been used up to form ATPs.
@Don't Forget to mew
AMP = 1 AMP
ADP = 2 AMPs
ATP = 3 AMPs (usable energy source)

Creatine phosphates act like AMPs so that they can bond with ADPs more readily during intense exercise when all the AMPs have already been used up to form ATPs.
Energy deficit = AMPK activation which leads to autophagy. So increasing ATP stops us from channeling AMPK. So increasing ATP is not a huge point of concern in the bigger picture. It's a very intricate, trivial and not such an important concern. Your body will never really lack ATP. Because ATP is always created when you need it for energy. But when you lack ATP, and use AMPK as an energy channel, that's also a very healthy hormetic routine.
 
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I saw a user use Creatine to offset the effect of metformin. Wouldn't this render metformin useless?
 
How did I miss this lol
 
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I saw a user use Creatine to offset the effect of metformin. Wouldn't this render metformin useless?
No because Creatine doesn't activate mTOR or kick you out of AMPK. You won't have enough NADH electron donors.
 
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bumping this high iq thread, also what your opinions on astaxanthin and coenzyme q10 for longevity?

also does insulin inhibit AMPK? i have a hard carb addict so even though i fast 19 hours a day my ketone levels are still very low if I even have any present, if it does, is there anyway to counter that? i found this study regarding coenzyme q10 might do something but my knowledge regarding this is quite low and i cant understand shit https://www.hindawi.com/journals/jdr/2016/6384759/

thx bro
 
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Decreases cholesterol synthesis through the enzyme HMG-CoA Reductase
This is the main reason T levels drop when fasted btw. If you're not able to synthesize cholesterol frequently enough you essentially shut off the steroidogenesis cascade temporarily.
 
bumping this high iq thread, also what your opinions on astaxanthin and coenzyme q10 for longevity?

also does insulin inhibit AMPK? i have a hard carb addict so even though i fast 19 hours a day my ketone levels are still very low if I even have any present, if it does, is there anyway to counter that? i found this study regarding coenzyme q10 might do something but my knowledge regarding this is quite low and i cant understand shit https://www.hindawi.com/journals/jdr/2016/6384759/

thx bro
Yeah insulin release will kick you out of AMPK immediately. mTOR is responsible for the insulin signalling cascade and is also like the other side of the switch in terms of AMPK. For example, when there's mTOR signalling, AMPK is shut off, and vice versa. I made some graphs back in 2019 explaining the whole AKT -> PI3K -> mTOR -> insulin system and how/why AMPK can't be active in tandem with mTOR.
 
Yeah insulin release will kick you out of AMPK immediately. mTOR is responsible for the insulin signalling cascade and is also like the other side of the switch in terms of AMPK. For example, when there's mTOR signalling, AMPK is shut off, and vice versa. I made some graphs back in 2019 explaining the whole AKT -> PI3K -> mTOR -> insulin system and how/why AMPK can't be active in tandem with mTOR.
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Also. I don't bother with astaxanthin or COQ10 at all. To me they're a waste of money.
 
So how to activate this ?? Fasting? What else?
 
So how to activate this ?? Fasting? What else?
Moderate to intense exercise while in a semi fasted state works too. Other shit like metformin and berberine work but come with their own set of effects which have negatives/positives too.

Fasting and exercise (or simply... being in an energy deficit), will kick you into AMPK.
 
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