Metabolic Autophagy

by Siim Land

  Improved endurance exercise includes increased capillary supply, mitochondrial biogenesis, and improved transport of electrons in the mitochondrial transport chain. With higher aerobic fitness you’ll also use less muscle glycogen and produce less lactate, which allows you to perform at greater intensities.

  Both aerobic and anaerobic training contributes to the development of cardiovascular fitness. It means you can improve your endurance even without necessarily training it. There are much more effective and healthier ways of training your aerobic system than just cardio.

  Long hours of cardio are not that beneficial because of how the repetitive motions begin to tear down your tendons and promote joint pain. Excess aerobic training also increases the risk of oxidative damage in the muscles which may speed up sarcopenia, especially when dieting. On top of that, the prolonged stress hormones and free radicals in the blood may damage the mitochondria.

  The worst thing about too much cardio is that it’s not even the best way to lose fat or become fit. How many people you know who’ve been exercising for a long time doing different runs, spin classes, and cardio sessions but they haven’t gotten any fitter? They’re exercising like maniacs but they’re still fat or worse skinny fat. That’s because the body receives an inefficient stimulus that would enforce proper adaptation.

  Easy-going endurance releases the chemical BDNF in the brain, which makes us feel good and more cognitively sharp. That’s why people experience this runner’s high after hitting the zone. Their mind literally tells them that cardio is good whereas it might not be. The danger is that it may also become addictive because of the same very reason. This is called Black Hole Training.

  Black Hole Training

  Black Hole Training is a nightmare exercise zone somewhere between a piece of cake and a Navy SEAL workout. The pace is vigorous but not painful, which is enjoyable for your mind. You get an endorphin rush, which makes you think I’m getting a good workout but it’s still stressful for the body.

  Basically, the Black Hole is a heart rate zone that exceeds your aerobic capacity just a tiny bit. Once you can’t hold a conversation anymore and have to breathe through your mouth, then you’re using more glycogen and less fat for fuel. For a few minutes, that’s fine, but most people never go running for 10. They hit runner’s flow because of the adrenaline rush and can easily empty their glycogen tank. Once this happens, the body still needs glucose to perform at such intensity. As a result, it begins to break down the protein.

  Figure 45 Heart Rate Zones

  This running craze became popular in the 70s and 80s. Although the joggers ran themselves into burnout, they couldn’t stop because they had become addicted to the endorphin high. Nowadays, running and jogging are considered by many to be the healthiest form of exercise and it’s the average person’s first choice for working out. Unfortunately, they are mistaken.

  While cardio is beneficial and has its place, you shouldn’t make it the focus of your training. At least you’d want to avoid the Black Hole as much as possible.

  If you’re doing cardio for 30+ minutes, then you should stay aerobic for the majority of the time. That’s when your heart rate is below 60-70% of your VO2 max. At that intensity, you’re using fat not glucose as fuel. Going higher than that will simply make you more glycolytic. When you burn through your glycogen stores and you keep exercising, then at that point you may end up sacrificing a bit of the lean tissue by converting some protein into glucose. With keto-adaptation, you can protect yourself against that to a certain extent but it’s simply not worth it.

  I’m also not trying to judge people who love to do long hours of cardio just for this zen-running kind of pursuits. Instead, I’m trying to show you a more effective way of exercising and relieve you from the perceived obligation of doing primarily aerobics, which you might have.

  The 80/20 to exercise is to focus on resistance training and strength because it’s what gives you the most results in terms of longevity. Endurance work can also be good but not if done excessively or for too long. Of course, you don’t want to get winded because of climbing a flight of stairs. There are other more effective and time-efficient ways of doing aerobic conditioning than just cardio.

  High-Intensity Interval Training

  In 1996, a Japanese researcher Dr. Izumi Tabata conducted a study on two groups to assess the differences between training intensities on aerobic fitness[272]. All the subjects used cycling ergometers to train on for 6 weeks.

  The control group did 60 minutes of moderate-intensity exercise 5 times per week at 70% of their VO2 max. It’s called low-intensity steady state cardio (LISS).

  The other group did high-intensity interval training (HIIT) with 20/10 sessions repeated 8 times at 170% VO2 max. They basically ran through a wall. 20 seconds beyond-maximum exertion followed by 10 seconds of rest. In total, the workout lasted for 4 minutes.

  Results of the study were quite astonishing. Over the course of 6 weeks, the control group trained for 1800 minutes vs the 120 minutes of the HIIT group. The subjects who did LISS increased their VO2 max from 53 +/- 5 ml.kg-1 min-1 to 58 +/- 3 ml.kg-1.min-1 but their anaerobic capacity didn’t improve significantly. The individuals who did HIIT increased their VO2 max by 7 ml.kg-1.min-1 while their anaerobic fitness also improved by 28%!

  The Tabata study shows that high-intensity training is much more effective in inducing physiological adaptations and is a more time-efficient way of exercising. It also makes sense from the perspective of the body. You won’t get stronger by lifting a pillow off the ground for millions of times. Lift a 400-pound barbell just twice and you’ll get a much bigger response from the body.

  Strength and fitness are the result of adapting to stressors. There needs to be a very good reason for your body to build muscle or get faster. Making a hole in the wall with a spoon will take an eternity. Hit it with a sledgehammer and you’ll get out of jail in no time.

  However, there are some implications about the Tabata study that need to be covered.

  First of all, the aerobic group did improve their VO2 max quite significantly. They did get fitter because the body became more efficient at running on lower intensities and thus they could ramp it up a notch.

  Secondly, although the HIIT-ers increased their mean VO2 max slightly more, they started off with a lower value and may have had more room for “newbie-gains”. The LISS group was already fitter and thus it was more difficult for them to see improvements. See Figure 46 Below.

  Thirdly, the HIIT group still ended up at a lower VO2 point than the LISS group. They didn’t become exponentially fitter although their relative fitness increased more.

  Figure 46 Note that the endurance training (ET) group started off from a higher baseline level of fitness than the intensity group (IT)

  Despite that, the HIIT group did improve their anaerobic fitness as well as their aerobic, whereas the LISS cyclers didn’t. Unless you’re training specifically for endurance, then you don’t have to do hours of cardio. For an average person trying to be fit and healthy, doing high-intensity training is still a much more effective and time-efficient way of exercising. It saves time, preserves joints, and maintains a better metabolic rate.

  High-intensity interval and Tabata training also coincide with resistance training. Both of them are more intense, they burn muscle glycogen, improve insulin sensitivity, and stimulate the sympathetic nervous system. In fact, HIIT may lead to similar physiological adaptations in terms of muscle growth than resistance training. Not entirely but it’s not going to hinder the beneficial muscle building signals as much as cardio would.

  Combining a lot of endurance with strength training may make you good at none of them because the body won’t have enough time or resources to adapt properly. Confucius a Chinese philosopher said: “The man who chases two rabbits, catches neither.” That’s why doing primarily resistance training and HIIT will give you better results and improve your overall fitness in the long term.

  Moreover, it
resembles the aboriginal hunter-gatherer way of living, where people would walk around at low intensities for the majority of the day and then for a very short amount of time face extreme exertion while running from a lion or chasing their own prey. This is what our primal physiology has become adapted to.

  Next to fasting, exercise can also increase mitochondrial biogenesis and function through the same pathways of AMPK and FOXO proteins. High-intensity interval training increases the ability of mitochondria to produce energy by 69% in older people and 49% in younger[273]. Even just acute exercise increases FOXO1 phosphorylation, improves insulin sensitivity and promotes mitochondrial biogenesis[274]. Exercise also increases NAD+ and sirtuins[275][276].

  There are many ways to improve your aerobic fitness but the main tenet is increased muscle quality. The best way to protect against sarcopenia and muscle-wasting is to combine both resistance training with HIIT cardio and then get a minimalistic dose on endurance. That’s the main way to improve the quality of your life with exercise.

  Chapter VI

  HyperTORphyc Growth

  „You underestimate the Power of The Dark Side.

  If you will not fight, then you will meet your destiny.“

  Darth Vader, Star Wars Episode VI: Return of the Jedi

  Cellular growth requires adequate amounts of energy and biosynthetic precursors such as essential amino acids and lipids or fatty acids. Because of that, your cells’ energy and nutrient status are constantly monitored and regulated by the body wanting to maintain homeostasis.

  One of the main mechanisms that makes the body grow and turn anabolic is the mammalian target of rapamycin (mTOR). It’s mostly activated by nutrients and growth factors that activate muscle protein synthesis (MPS).

  The process of growing new cells and tissue is called hypertrophy, which translates from Greek into ‘excess-nourishment’. That’s how muscles get bigger, that’s how you grow as a child, and that’s also how you conciliate entropy. Growth and expansion are just an extra step away from aging and death.

  mTOR is connected to protein synthesis and cellular growth via many pathways and it affects hypertrophy at least indirectly. It’s a piece of the puzzle and probably one of the most important ones but not the only one.

  In this chapter, I’m going to give an overview of the main functions of the mTOR pathway and how it affects muscle growth and longevity. Let’s begin with the basics!

  Enter TOR

  Mechanistic Target of Rapamycin or Mammalian Target of Rapamycin or mTOR is a protein kinase fuel sensor that monitors the energy status of your cells[277]. It’s involved in every aspect of cellular life and existence.

  There are two mTOR complexes – mTORC1 and mTORC2. They stimulate cell growth, proliferation, DNA repair, protein synthesis, new blood vessel formation (angiogenesis), muscle building, the immune system and everything related to anabolism[278].

  mTORC1 functions as a nutrient sensor that controls protein synthesis[279]. mTORC1 is regulated by insulin, growth factors, amino acids, mechanical stimuli, oxidative stress, oxygen levels, the presence of energy molecules (ATP), phosphatidic acid, and glucose[280]. It’s a key factor in skeletal muscle protein synthesis[281].

  mTORC2 regulates the actin cytoskeleton, which is a network of long chains of proteins in the cytoplasm of eukaryotic cells[282]. It also phosphorylates IGF-1 receptor activity through the activity of the amino acid tyrosine protein kinase[283].

  mTOR is involved with anabolic pathways such as insulin, insulin-like growth factors (IGF-1 and IGF-2) and amino acids[284][285].

  Figure 47 The mTOR complexes and their effects

  The mTOR Pathway

  The story of how mTOR was discovered is also quite an interesting one.

  In 1975, scientists were collecting soil bacteria on the Pacific islands. On The Easter Island, they found that these bacteria called Streptomyces hygroscopicus secreted a particular compound with powerful immunosuppressing effects. They named the compound Rapamycin after the Polynesian name of the island Rapa Nui.

  During the 1990s, Rapamycin was found to bind with a certain complex of proteins in the cells. That protein was named mTORC1. However, rapamycin doesn’t bind to mTORC2[286].

  mTORC1 detects many extra- and intracellular signals and growth factors[287], whereas mTORC2 is known to be activated only by growth factors[288]. Growth factors would be things like insulin, mechanical muscle stimulus, while nutrient factors would be things like amino acids and glucose that promote growth factors such as insulin and IGF-1.

  After several studies, it was discovered that mTOR functions like an on and off switch for cellular growth. Simply put, if mTOR detects energy in the body, it’s going to upregulate processes related to growth and ATP production. Elevated mTOR may not be the sole cause of hypertrophy but it’s a catalyst nonetheless.

  Here’s a simple explanation of the mTOR pathway and how it works:

  Whenever your body detects excess energy in the system, it’ll try to direct it into the right places.

  The mTOR complexes are activated by growth factors, primarily insulin and IGF-1, but also nutrient factors like amino acids and protein.

  Insulin Receptor (IR) and IGF-1 Receptor (IGF-1R) are in the class of tyrosine kinase receptors. Tyrosine is an amino acid. Activating these receptors leads to the phosphorylation of insulin substrate receptor proteins (IRS)[289].

  IRS activates a protein called phosphatidylinositol-3-kinase (PI3K) which further phosphorylates inositol phospholipids like PIP3. PIP3 interacts with proteins PDK1 and Akt.

  Akt is thought to be one of the main upstream regulators of mTOR[290]. Akt is a family of proteins that comprise of Akt1, Akt2, and Akt3. Akt1-2 are expressed in skeletal muscle while Akt3 is not[291].

  Akt inhibits protein breakdown by regulating FoxO proteins. FoxO proteins regulate protein breakdown and autophagy-related pathways[292]. They are inhibited by Akt, which prevents cell death[293].

  When there are plenty of nutrients around, mTORC1 binds to ULK1, which is an autophagy activating kinase and inhibits the formation of autophagosomes which would initiate autophagy[294]. When energy gets depleted, mTORC1 becomes inactive and releases itself from the ULK1 complex, thus freeing up the formation of autophagosomes.

  Myostatin is a growth factor that inhibits muscle growth by suppressing hypertrophy[295]. It’s basically your body’s attempt to not build too much muscle as a way to preserve energy from an evolutionary perspective. Myostatin reduces Akt/mTORC1/p70S6K activity and protein synthesis, which blocks muscle cell copying[296]. Therefore, for muscle growth, you need the Akt/mTORC1/p70S6K pathway to be active.

  AMPK, mTORC1, and ULK1 form The Kinase Triad, which maintains energy and nutrient homeostasis[297] (See Figure 48). These protein kinases and fuel sensors are in constant correlation and they’re balancing each other out based on the energetic conditions of the body.

  Figure 48 The Protein Kinase Triad of nutrient sensing

  What Activates mTOR?

  mTOR regulation is mostly mediated through AMP-activated kinase (AMPK). AMPK monitors the energy status of the cells through their glycogen content and ATP to AMP to ADP ratios. It’s called the adenylate energy charge that measures the energy status of cells.

  Adenosine Triphosphate (ATP) is often referred to as the molecular currency of cells that’s needed for energy production. Thus it’s essential to life and anabolism. When ATP gets produced by the mitochondria, it converts into either adenosine diphosphate (ADP) or adenosine monophosphate (AMP). This process can be recycled several times, creating more ATP from its by-products.

  Whether or not the body becomes anabolic or catabolic depends upon the energy charge. In an abundance of ATP, the body has more resources to conduct repair and growth. If ATP levels are low or depleted, ADP and AMP ratios increase and they’ll get converted into ATP to maintain homeostasis. In that case, there isn’t enough excess energy for additional growth thus the body remains either at a balance or, if energy depletion c
ontinues, becomes catabolic.

  A reduction in energy activates AMPK which promotes catabolic pathways for maintaining energy homeostasis[298]. AMPK inhibits muscle growth by suppressing mTORC1.

  Here are the other mTOR activating nutrients and factors:

  Amino acids promote mTORC1 activity[299] without affecting mTORC2 activity[300]. Leucine specifically activates mTORC1 the most[301]. Some evidence also hints that leucine’s by-product HMB may have a similar anabolic effect through the signaling pathway of mTORC1[302]. Although I’d say you’d get the same effect directly from leucine.

  Mechanical stimuli from resistance exercise, especially eccentric contractions, increases the levels of mTORC1[303]. That’s why cold exposure can sometimes also activate mTOR in muscles – you freeze up and contract the muscles. Phosphatidic acid gets regulated by exercise which activates mTORC1[304].

  Phosphatidic acid enhances mTOR signaling and resistance exercise-induced hypertrophy[305]. It’s found the most in cabbage leaves, radish leaves, and herbs[306] or can be taken as a supplement.

  Ursolic acid stimulates mTORC1 after resistance training in mice[307]. It stimulates anabolism via PI3K/Akt pathways. Ursolic acid can be taken as a supplement or found in foods like apples, bilberries, rosemary, lavender, thyme, oregano and many more.

  Creatine may potentially promote mTORC1 by increasing IGF-1 activity after exercise but doesn’t further potentiate mTORC1 several hours after exercise[308]. So, the best time to take it is with your post-workout meal. It’s one of the most well-studied supplements that actually seems to work. Plus it’s very cheap and effective.