Building High-Performance Muscle™

Anabolic Resistance

How Mass Diets Can Hurt You

   09/23/13
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Here's what you need to know...

Eating more calories to bulk up is only helpful to a certain point. Soon you reach "nutrient overload" where fatty acids, triglycerides, and glucose become toxic.

Eat too many calories for too long and you experience anabolic resistance, which is the reduced ability to increase muscle protein synthesis in response to amino acids, mechanical loads, or other anabolic agents such as insulin or IFG-1.

Those who alternate periods of increased calorie intake with dieting phases have physiques that continually evolve over time.


Bulking Gone Bad

Bulking Gone Bad

Picture this scenario: You've dieted hard for months, getting completely shredded. Although you're in great condition, you also lost some size. Now the diet is over and you're fired up to do some big eating. This year, you tell yourself, you'll be bigger than ever.

You start to eat big to get big. You take in a huge surplus of calories and train like an animal. Over the next several weeks, all is well: strength levels are way up, you're getting unbelievable pumps in the gym, and you're hungry all the time. This is what "anabolic" feels like. You just know that you're growing.

After some time, things start to change, however. You're starting to look a little softer as the body fat starts to accumulate. That full and muscular look you had starts to fade. You're increasingly soft and bloated, your abs are fading fast, and manatees start to look at you amorously.

Fast forward several more weeks. You can't seem to get a pump in the gym like you used to, gains are coming more and more slowly, and the scale is barely moving. What now? Must. Keep. Growing. You suck it up and devise a way to throw down more food. Eat to grow, right?

You add a few cheat meals here and there and turn (over) eating into a second full-time job. The good news is that the scale starts to move again, but not like before. Strength gains are less than impressive, those legendary pumps are long-gone, and your joints and your body in general are starting to ache, a sign of chronic, low-grade inflammation. Worse, there's that manatee thing.

What went wrong? The simple answer is that tsunami of fat-gain caused by your bulk-up diet induced a state of anabolic resistance. I don't want to be mistaken here; a surplus of calories is needed to fuel new muscle growth. Fail to eat enough and you'll certainly fail to grow. On the other hand, a calorie surplus is only helpful up to a certain point, after which excess fatty acids, triglycerides, and glucose become toxic. At that point, you're in "nutrient overload" and you've reached the point of diminishing returns.

Many people have experienced this, at least to some degree, usually when in "bulking" mode. Taken to the extreme, the same metabolic changes that limit muscle growth during periods of nutrient overload are also causes of metabolic syndrome, diabetes, and cardiovascular disease.

This isn't to say that you're in danger of becoming morbidly obese and diabetic the next time you decide to "bulk". The majority of T-Nation readers who train hard are metabolically resilient enough to avoid becoming diabetic when the calories go up for extended periods of time.

Prolonged nutrient overload does cause negative metabolic adaptations that cause varying degrees of anabolic resistance, however.


Three Steps to Anabolic Resistance

Anabolic Resistance

The reason muscle growth slows down when body fat creeps out of your optimal range is important to understand. Nutrient overload causes a cascade of negative effects that ultimately throw a metabolic wrench in the muscle growth process. This has recently been termed anabolic resistance, which is technically defined as the reduced ability to increase muscle protein synthesis in response to amino acids, mechanical loads, or other anabolic agents such as insulin or IFG-1.

Importantly, this is irrespective of insulin, IGF-1, or growth hormone availability (1), so excessive fat accumulation can make you more resistant to muscle growth even in the context of normal anabolic hormone levels. Although training plateaus are inevitable, "metabolic plateaus" caused by misguided gluttony in an attempt to put on extra muscle are completely avoidable with smart nutrition.

There are three important factors associated with bulk-up-diet induced nutrient overload that work together to create anabolic resistance:


Step 1: Insulin Resistance

Insulin resistance may be the most important, because it tends to be induced early-on. The link between obesity and insulin resistance in skeletal muscle is well established (2, 3). What isn't commonly known, however, is that you don't need to be morbidly obese for several years to develop insulin resistance.

Take any relatively young, perfectly healthy individual, put them in a state of nutrient overload, and insulin resistance develops within a few weeks time (4). Insulin resistance increases the tendency to store carbs as fat, rather than packing them into muscle tissue as glycogen. It also causes the accumulation of triglycerides in muscle tissue, which contributes to muscle insulin resistance (3, 5, 6).

As muscle insulin sensitivity decreases, so does glucose uptake (5, 7-9). The result is less stored glycogen, reduced muscle fullness, and less of a pump from training. So the bulk-up diet only works so good for so long – until you start to become less insulin sensitive. As body fat starts to creep out of the optimal range, you become increasingly insulin resistant. At this point, things start to go downhill fast, metabolically speaking. Fat stores expand, training progress slows, and it becomes difficult, if not impossible, to get a good pump in the gym.

Step 2: Leptin Resistance

You've now reached the point of diminishing returns. As you become less insulin sensitive, you gain more and more fat. This is where leptin resistance comes into the picture. Leptin is a peptide hormone produced in fat cells (adipocytes) that functions as a controller of metabolism and as a hunger regulator. Technically speaking, it links changes in body fat stores to CNS control of energy homeostasis (10-13).

It helps to think of leptin as sort of a whole-body fuel gauge. Leptin monitors whole-body energy levels to coordinate energy expenditure, fat oxidation and overall metabolism. As fat stores increase, adipocytes release more leptin into the circulation, which crosses the blood-brain barrier and communicates with leptin receptors in the hypothalamus.

This is a signal that you're all "fueled up," which triggers the hypothalamus to send signals to the brain and the rest of the body to decrease appetite and increase metabolic rate. Likewise, when calorie intake decreases, fat cells produce less leptin. This tells the hypothalamus that fuel levels are low, triggering increased appetite and decreased energy expenditure. Leptin action isn't just confined to just the hypothalamus, however. There are leptin receptors all over the rest of the body, allowing leptin to globally coordinate appetite, metabolism, and energy expenditure.

As fat stores increasingly expand, more and more leptin is produced and released into the bloodstream. Eventually, when leptin levels are high enough for long enough, you develop leptin resistance. Leptin binds the leptin receptors, but no downstream messages are sent. The fuel gauge is broken, and any fat-burning effects are lost. In spite of the extra body fat mass, the brain never gets the "fueled up" signal. As a result, you lose a degree of appetite control.

Certain people are more or less susceptible to this. The most fortunate of us become only slightly less insulin sensitive in response to prolonged bulking diets and may develop some degree of leptin resistance. Those of us who have far-less resilient metabolisms with a pre-existing tendency to easily put on body fat have a much harder time; appetite control is broken, leading to continued fat gain.

This in turn causes more leptin resistance in the start of a vicious feed-forward cycle, bringing us to the final stage, where shit hits the fan, and you develop a full-on case of anabolic resistance.

Step 3: ER Stress – The Root Cause of Anabolic Resistance

ER stands for endoplasmic reticulum, which is located in the cytosol of all cells. The ER integrates metabolic signals to control glucose, lipid, and protein metabolism (14). It's also a major site for protein synthesis, where resident ribosomes make new proteins that are released into the ER lumen for folding and processing.

After being folded and processed in the ER, proteins are moved to the Golgi apparatus for further sorting, packaging, and distribution. Think of the ER as a protein factory: mRNAs produced in the nucleus are sent to ribosomes where they're decoded and translated into new proteins. These freshly produced proteins are then sent to the inside of the ER, into the lumen, where they're further processed and folded into their active conformations.

If the ER is the protein factory of your cells, then the Golgi apparatus is Fed-Ex. Proteins are sorted, packaged, and delivered from here to different parts of the cell. Together, the ER and Golgi apparatus carry out the processing, transport, and delivery of all new proteins. When demand for protein synthesis exceeds a cell's ability to process, package, and ship new proteins out to their cellular destinations, the ER becomes stressed.


ER Stress In Adipose Tissue

Fat cells aren't just passive storage containers for body fat. They also function as endocrine organs, secreting a number of different proteins to control metabolism, including leptin, adiponectin, and other peptide hormones (15). The larger a fat cell becomes, the more leptin it secretes, making the ER very important for fat cells.

It's the job of the ER/Golgi apparatus to produce and process all that leptin. The system becomes overwhelmed when proteins are produced faster than they can be processed, resulting in ER stress. This triggers the "unfolded protein response" (UPR), which reduces protein synthesis and increases ER protein folding capacity in an attempt to reduce the back-log of unprocessed proteins.

The problem is that this comes at a cost. UPR also triggers an inflammatory response that can create a vicious cycle of inflammation and oxidative stress. This "metabolic inflammation" is both a cause and an effect of ER stress. Nutrient excess causes an increased demand for protein synthesis in fat cells, both for the production of peptide hormones such as leptin, and for proteins needed for triglyceride production and fat storage.

When nutrient overload ramps up protein synthesis past ER's ability to process/fold all these proteins, the UPR is triggered. All that protein synthesis is an energetically expensive process. Insulin-resistant fat cells can't take up enough glucose to meet the energy demands of protein synthesis. This triggers more ER stress. The result is a vicious cycle between inflammation, oxidative stress, insulin resistance, and leptin resistance.


ER Stress In Muscle Tissue

Anabolic Resistance

When nutrient overload triggers the ER stress response in fat cells, fatty acid uptake slows down. This causes some spillover into muscle tissue. Insulin-resistant muscle tissue is ill-equipped to burn this fat for energy, so it gets stored as intramuscular triglyceride instead. This "ectopic" fat storage decreases insulin sensitivity in muscle tissue (3, 16, 17) and also causes muscle ER stress (18), which is the root cause of anabolic resistance.

When the ER stress response is triggered in muscle tissue, you're in a state of anabolic resistance. Muscle becomes less responsive to all the triggers for protein synthesis. Leucine uptake, mechanical loading, and even anabolic hormones become less effective at activating the protein synthesis machinery. You can see how all this comes together in the figure below:

To summarize, although a calorie surplus is required to grow, nutrient overload is a cause of anabolic resistance. Getting too fat is counterproductive, because the fatter you get, the more insulin resistant you become. Insulin resistance is both a cause and an effect of leptin resistance, because it causes fat gain. When you're in an insulin- and leptin- resistant state, you're more susceptible to ER stress, the root-cause of anabolic resistance.


Tips to Avoid Anabolic Resistance

1) Don't get too fat. The takeaway here is pretty straightforward: Keep body fat within a certain range at all times.

The ideal range is different for different people, depending on insulin sensitivity and other individual factors. If you exceed this range, you'll know it. More of the weight you put on will be fat, gains will slow down, the pump you get during training will be reduced, and you just won't have that same degree of muscle fullness. It's obviously best to avoid this in the first place by eating smart.

2) Fix it. To get better, pushing the limits is something we need to do. For this reason, it's not uncommon to find yourself in a situation where you pushed it a bit too hard for too long with the calories, arriving at the point of diminishing returns. All is not lost.

The only way to move forward in this situation, however, is to go slightly backwards. Reduce calories to below maintenance levels for a few weeks and decrease carb intake. Add a little cardio if necessary.

When over-bulked, chronic, low-grade inflammation induced by nutrient overload may be a very real issue. Supplements like cyanidin 3-glucoside, curcumin, and fish oil are indispensible here to limit inflammation and promote insulin sensitivity.

Increased intake of food-based antioxidants or supplements like Superfood that are loaded with potent natural antioxidants may also help throw a wrench in nutrient-overload induced oxidative stress. Continue the inflammation/oxidative stress-management and dieting phase until your body fat is back to an acceptable range.

You'll then have cleared up any anabolic resistance and will be metabolically primed to continue packing on quality muscle. It's not a coincidence that those who alter periods of increased calorie intake with dieting phases have physiques that just seem to evolve over time, whereas the typical "permabulker" is busy evolving a spare tire.


References

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09/23/13