Transcription
Welcome back for part two of our online sport nutrition lecture series. Today's topic is fuel sources for muscle and exercise metabolism. Now, the goals of this lecture are to provide a brief overview of the basic structure of skeletal muscle, the pathways via which skeletal muscle is able to use fuels and generate ex energy during exercise, and some of the key factors that will regulate which of these fuels are being selected during exercise.
Let's take a moment to revisit the basic structure of skeletal muscle. Now, skeletal muscle cells are long, striated, or striped in appearance, have multiple nuclei, and are commonly referred to as myofibers. Now, each myofiber is made up of smaller units which are known as myofibrils, which contain the actual contractile elements. And what we can see here depicted is a sarcomere, and the sarcomere is actually the smallest unit of the contractile element. And if we take a look at the basic structure of a sarcomere, we'll see that what we have first are these thin filaments or these thinner proteins known as actin. So actin is our thin filament, and they're anchored within the sarcomere into these two terminal ends known as Z lines. Now, beneath each thin filament or between the thin filaments, what we see are a thicker protein, and that thicker protein is myosin. So actin and myosin are going to interact here in order to pull these Z lines towards each other, shortening the muscle and producing force. And the way in which that happens is that the heads, so these little protrusions on the myosin are the myosin heads; what they do is they attach to these active sites. So you can kind of see how these two things were sort of made for each other to fit together. And when these myosin heads bind to the active sites on actin, that's what's going to cause these filaments to slide, the thin filaments to slide, and pull these Z lines closer together to each other and ultimately produce force.
Now, in order for this process to occur and continue occurring, we need to have a source of energy to fuel it. And we know that the only source of energy that can be used directly for muscle contraction or any other energy-requiring processes in the cell is adenosine triphosphate. And this adenosine triphosphate provides energy when it is hydrolyzed, um, and it is hydrolyzed, and that um hydrolysis reaction is catalyzed by an enzyme known as myosin ATPase. Now, as the name suggests, if we take a look down here, the myosin ATPase enzymes are actually found within the heads of the myosin molecules themselves. And so, along with water, which is necessary for ATP to undergo hydrolysis, these myosin ATPase enzymes catalyze this reaction and release free energy, which can then be used to fuel the contractile process; about seven calories worth of energy per every mole of ATP that is broken down is provided. So, at the end of this hydrolysis, what we end up with is a molecule of adenosine diphosphate. So the energy is released because these phosphate bonds break off and leave us now with one or two, in most cases, phosphate groups, and in a molecule of adenosine diphosphate; we're also left with some hydrogen and inorganic phosphate that are produced as a byproduct of that enter of that reaction.
Now, we store some adenosine triphosphate in skeletal muscle, about four to five millimoles per kilogram of muscle. Now, that number might not mean anything to you, but what should mean something to you is that we only have enough of this ATP on board in order to fuel a few seconds of intense exercise. So, if we think about what would happen if we completely depleted our stored ATP, it would be fatal to all of our cells. And for that reason, we have to have ways to re-synthesize ATP from ADP at about the same rate at which we're breaking the ATP down, and that rate is going to change depending upon a lot of different factors, one of the main factors being how intense those muscle contractions are occurring and the amount of work that those muscles need to do to perform the given task. So let's review the three ways or pathways by which ATP can be resynthesized. Now, you'll remember that we have two anaerobic pathways or pathways that do not require any oxygen that we can use to re-synthesize ATP, and those are phospho-creatine hydrolysis and glycolysis. Additionally, we are also able to regenerate ATP aerobically or in the presence of oxygen via a process known as oxidative phosphorylation, and we're going to go over some of the details of each one of these pathways and now they might relate to sport nutrition.
Now, at the start of exercise, that stored ATP in skeletal muscle is going to be broken down pretty rapidly, and as a result, we're going to have an accumulation of ADP forming in the sarcoplasm. So what we want to do is be able to regenerate ATP from that ADP, and one of the ways that we do that and one of the simplest ways that we do that is through this high-energy phosphate known as phosphocreatine. And phosphocreatine is present in the sarcoplasm at nearly three times the concentration at which ATP is stored in the muscle, and this is a good thing because that phosphocreatine, the way that it functions is that it donates this phosphate group to the ADP to form ATP. Another important part of this reaction is that these hydrogen ions that are formed from the breakdown of stored ATP and may also accumulate for other reasons, such as the dissociation of lactic acid, which we will get into later in the presentation, but the phospho-creatine hydrolysis reaction requires hydrogen. So when this reaction occurs, it buffers off some of the hydrogen ions that are formed from the breakdown of ATP and other pathways, and that's important because muscles like to function within a pretty tight physiological pH, and hydrogen ions as they accumulate will drop that pH and contribute to early fatigue of those muscle fibers. The primary advantage of this metabolic pathway is that it occurs rather instantaneously and at an extremely rapid rate; that's due to the simplicity of the reaction; all that needs to happen is this very simple donation of a phosphate from phosphocreatine to ADP, and boom, there you have a re-synthesized ATP. And because this can be completed in a relatively short period of time and at a rapid rate, the energy is transferred at a rapid rate, and it allows for rather high power outputs to come from those muscle fibers when using this pathway.
Now, the disadvantage—if we take a look at the chart on our right, which gives a breakdown of our two anaerobic systems, our phosphagen or phosphocreatine system and our glycolytic system or the breakdown of carbohydrate via glycolysis—we can see that in terms of the power that is gained from each millimole of ATP per kilogram of muscle that is broken down from the phosphagen system is almost twice or actually more than twice that of what we get when we break down carbohydrate via glycolysis. But if we then also look at the capacity of the phosphagen system relative to the glycolytic system or the amount of energy that we have available to run these two pathways and resynthesize ATP via these two pathways, we see that there is much less energy available in the phosphagen system compared to the glycolytic system. And this is why, after only a few seconds of maximal force generation, the rate of PCR hydrolysis will begin to decline very rapidly. Of course, once this decline occurs, we have the capacity to continue resynthesizing ATP anaerobically through the glycolytic breakdown of carbohydrate.
Now, I want to point out that you don't need to know all of these detailed steps in the glycolytic pathway for our course; this was sufficiently tested in your exercise physiology course. It is important, however, for our purposes to review the important overall outcomes of this process. First, we'll see that in order to activate these molecules, glucose and glycogen, we're going to have to invest some energy, or it's going to cost us some ATP in order to get these molecules into an active form. Now, in the case of glucose, this costs two ATP per every molecule of glucose that undergoes this activation. However, in the case of glycogen, because of the activity of the enzyme glycogen phosphorylase and its ability to use inorganic phosphate, we're able to save one of these ATP. So, compared to a molecule of glucose in this energy investment phase, a molecule of glycogen will cost one less ATP. Now, once this occurs, each of these six-carbon molecules, whether we're talking about glycogen or glucose, they're now in the form of these six-carbon active molecules, and once they're fully activated and the energy investment phase is over, they can then be split into two three-carbon molecules. Now, each of these three-carbon molecules are ultimately converted into a molecule of pyruvate during the process of substrate-level phosphorylation. So, for every one six-carbon molecule that gets split into two three-carbon molecules, we're going to end up with two pyruvate, and for every one of those pyruvate that are formed during substrate-level phosphorylation, we generate two ATP. So if we've got two pyruvate and two ATP generated per pyruvate, we'll see that in the case of either glucose or glycogen, this process is going to generate a total of four ATP. Now, the net from a molecule of glucose is going to be two ATP per molecule, and I'll remind you that this is because in the energy investment phase, the activation of glucose cost us two ATP, as where we will yield three ATP per molecule of glycogen—again, still the same four ATP being generated here from each of these three-carbon molecules that gets converted into pyruvate, but remember we saved an ATP in the activation phase, so our yield is going to be one ATP larger, so three ATP per molecule of glycogen.
Now, in order for this chain of reactions to continue, the pyruvate that is formed in glycolysis, it needs to be removed for this to move forward and to continue re-synthesizing ATP via this pathway, and this removal of pyruvate occurs in one of two distinct ways. Now, the first way that it can be removed is that it can be reduced to lactate. Now, this happens at a high rate when oxygen availability is limited, uh, and it happens when the rate of pyruvate formation is extremely high. So the example would be during high-intensity exercise; the formation of pyruvate is occurring at a rate that exceeds our ability to remove it; therefore, a quick way to get rid of some of it is to reduce it to lactate. Now, one of the other things you'll notice is that during this reduction from pyruvate to lactate, we're going to actually accumulate some hydrogen ions, and we've discussed what the relationship is between the accumulation of those hydrogen ions and the onset of muscular fatigue. Now, the other option is for pyruvate to be converted into acetyl coenzyme A, and this process occurs in the mitochondria and involves the oxidation of these pyruvates to acetyl CoA, where they can then undergo further oxidative phosphorylation and be used to generate a higher yield of ATP compared to the glycolytic breakdown of carbohydrate. Now, this generally occurs when there is plenty of oxygen available to the muscle; an example would be during low-intensity exercise where we have some time and oxygen available to us for these pyruvate to be converted into acetyl CoA and move into the mitochondria to undergo subsequent oxidation.
Here in the mitochondria is where carbohydrate and fat metabolism intersect, as both of these fuels can be oxidized in the mitochondria via the tricarboxylic acid or Krebs cycle and the electron transport chain for full oxidative phosphorylation. Now, both the pyruvate that is formed in glycolysis from the breakdown of carbohydrate as well as two-carbon chunks of our fatty acid chains that undergo beta oxidation are able to be converted into acetyl coenzyme A. Now, the purpose of these acetyl-CoA are, through the tribar tricarboxylic acid cycle, primarily the purpose is to generate hydrogen-carrying coenzymes. So we see two different forms that are generated via the tricarboxylic acid or Krebs cycle, NADH and FADH, and those are the primary reasons that we undergo the Krebs cycle. There's also a small amount of ATP that's generated during this process as well as some carbon dioxide that ultimately is going to have to be expelled, but the primary purpose is to generate these hydrogen-carrying coenzymes so that they can transport these hydrogens and their associated electrons to the electron transport chain. Now, once these coenzymes are oxidized and lose their electrons here inside the mitochondrial matrix, the remaining protons or positively charged hydrogen ions are going to move across the inner mitochondrial membrane into this inner membrane space, and this is where oxygen comes into play in that it accepts the final remaining electron from the electron transport chain. So it's our final um acceptor in this chain. Now, once this water is formed, the remaining hydrogen protons, which begin to build up on in the inner membrane space, are then going to flow back into the mitochondrial matrix through this ATP synthase synthase protein complex, and it's this process that serves as the driving force for the oxidative formation of large yields of ATP. Specifically, when we're talking about carbohydrate, approximately 38 to 39 ATP molecules are re-synthesized from the complete oxidation of the molecule of either glucose or glycogen. Compare that to a 16-carbon fatty acid. Now, because this 16-carbon fatty acid is going to give us significantly more acetyl CoA than a molecule of glucose or glycogen, we're going to see a much higher ATP yield compared to that molecule of carbohydrate. An example—now this depends upon the length of the carbon chain of the fatty acid—but for a 16-carbon fatty acid, which is a pretty typical chain length, you'll get 131 ATP molecules compared to 38 or 39 molecules of ATP when breaking down carbohydrate.
Now, the caveat to that is because this process of beta oxidation as well as the process of running all of the acetyl CoA that are created from the process of beta oxidation through the Krebs cycle and carrying all of those hydrogens over to the electron transport chain, this process takes much longer than it does to oxidize a molecule of carbohydrate. We can see this concept clearly reflected if we take a look at the table depicted here. Now, this table is showing us two different properties of each of our metabolic pathways here, and the first is the maximal rate, and we already looked at this with in relation to PCR breakdown and glycolysis, our anaerobic methods. But if we look at the maximal rates at which ATP can be resynthesized from these fuels and we look at our two primary oxidative pathways, the first thing that we'll notice is that carbohydrate oxidation is able to re-synthesize ATP at a much higher and much faster rate than the oxidation of fat. Now, related to that, we'll also see that if we look at the time delay or the amount of time it takes for each of these pathways to reach their maximal rates, it takes significantly longer for fat oxidation rates to peak than it does for the oxidation of a fuel-like glycogen to peak. So if that's the case—if the oxidation of carbohydrate both resynthesizes ATP at a higher rate and takes significantly less time to reach that peak rate compared to fat—then why do we not exclusively rely on the oxidation of carbohydrates during exercise? The answer to that question lies in the amount of energy that we have stored and therefore available to us in these different forms. If we look at all three forms of our stored carbohydrate, our two sources of glycogen and our blood glucose, and we add them together, we have about 2,000 or so calories available to us in the form of stored carbohydrate. Now, compare that to how much fat we have available to us for energy or how much energy we have available to us from fat, and I want you to notice that this is based on a person who has about 15% body fat, so a relatively lean individual; we have 93,000 calories worth of energy approximately available to us in this particular form. Now, if we translate that over to time exercising, so this would be these numbers are reflective of the amount of time that these stored fuels could be used um to provide energy for running at a pace that would be close to marathon running pace in a trained runner, we only have enough carbohydrate on board to fuel about 100 minutes worth of that exercise, as where we have almost 5,000 minutes worth of energy at that intensity available to us in the form of fat.
When we begin to look at which types of fuels and which energy pathways a muscle fiber prefers to use, we first have to consider what type of muscle fiber it is, and we know that human muscle fibers are commonly divided into three specific phenotypes, and those are displayed in the table to your right. And our primary three types of muscle fibers found in human beings are: first, type one, and these are considered our oxidative fibers; we also have type 2a fibers, which can work either oxidatively or glycolytically, as well as our type 2x fibers, which prefer to work glycolytically. Now, what we have listed here are a host of biochemical properties of muscle fibers and fiber types that are indicative of either their oxidative or glycolytic capacity. So let's take a look by comparing our two bookends here, our type 1 or our slow oxidative fibers and our type 2x or our fast glycolytic fibers. All of the numbers for each of these biochemical properties are in reference to that of a type 1 fiber, which is why the value of all of our type 1 fibers for all of these biochemical variables is set at 1.0. So let's look at the type 1 fiber compared to the type 2x fiber. Now, when we think about the function of type 1 fibers, again they're highly oxidative, and as a result of their oxidative capacity, they're pretty specialized for repeated contractions over time, but they generally produce force at a pretty slow rate, so those contractions aren't very powerful because of the slower rate of oxidative metabolism. Now, these fibers prefer to work oxidatively mainly because, compared to type 2x fibers, they have numerous mitochondria and capillaries, so they have a high capacity to receive and process oxygen compared to that of a fast glycolytic fiber. They also have a much higher rate of activity of specifically aerobic enzymes such as citrate synthase and succinate dehydrogenase, which are two enzymes that are key in regulating the rate of the Krebs cycle. So our type 1 fibers have considerably more or considerably higher activity of these aerobic enzymes compared to our type 2x fibers. Additionally, they store a greater amount of intramuscular triglycerides compared to our type 2x fibers. Now, remember that triglycerides are a stored form and source of fatty acids, which can only be broken down via oxidative pathways. So a type 1 fiber is going to have a higher concentration of these intramuscular triglycerides compared to a type 2x fiber.
Now let's go in reverse here now and compare our type 2x fiber to our type 1 fiber. Now, type 2x fibers, in contrast, are highly anaerobic, and as a result, they're able to cycle through ATP at a higher rate. However, because of the limited capacity of our anaerobic energy systems, they're able to do so for shorter periods of time. So they're specialized for producing powerful contractions, but they're not able to sustain these for very long periods of time. And if we look at the biochemical properties, first we'll see that the myosin ATPase activity of type 2x fibers, so the isoform of this myosin ATPase enzyme that's found on the myosin heads of type 2x fibers, cycles through ATP at more than twice the rate of a type 1 fiber. The next thing that we'll notice is that these fibers have significantly more glycogen and significantly more phosphocreatine stored, so they have more raw material for anaerobic energy production compared to our type 1 fibers. And related to that, in terms of glycolysis, we'll see that these fibers also have higher activity of key glycolytic enzymes such as phosphorylase and phosphofructokinase; therefore, they're able to catalyze glycolytic reactions at a much higher rate compared to our type 1 slow-twitch oxidative fibers.
So what about these type 2a fibers that are sort of in between that of a type 1 and a type 2x fiber? And that description in between is a really good way to to think about how these fibers function and the biochemistry of these fibers. If we, for example, look at the myosin ATPase activity of a type 2a fiber, it is very similar to that of a type 2x fiber and is more than two times the rate of the myosin ATPase activity of our type 1 oxidative fibers. Additionally, we see that the oxidative capacity—so if we take a look at the capillary and mitochondrial density as well as the activity of aerobic enzymes such as citrate synthase and succinate dehydrogenase and the content of intramuscular triglycerides—we'll see that they are closer to that of type 1 fibers than our type 2x fibers are. So, for these reasons, type 2a fibers are sort of a jack of all trades, master of none metabolically, and they're able to help provide energy and generate force both aerobically and anaerobically.
Now, there are many factors that dictate the selection of fuel during exercise, and we'll discuss many of them in this course, but the ones that I want to start with, which are the primary factors that will dictate um how these fuels...
Are selected and their contribution to overall energy production and ATP re-synthesis is the duration at which the exercise is performed, or how long the exercise is performed. And so what we're looking at here is a study where they had individuals exercise at a fixed intensity; so in this case, it was about 60% of VO2 max, and they had them exercise at this intensity for up to two hours.
What you're looking at here is, again, this would be the overall rate of ATP resynthesis, so the total demands needed to perform at each one of these intensities. And then what each one of these bar graphs is made up of, or each one of these bars on the graph is made up of, are these stacks which are representative of the relative contribution of glycogen, or muscle glycogen, fat, and plasma glucose.
If we look at what happens early on in exercise, because of the high rate at which carbohydrate and glycogen are able to resynthesize ATP in the early phases, the majority of ATP is being resynthesized from the breakdown of carbohydrates, specifically from the breakdown of muscle glycogen. However, as we progressively go on, um, to longer and longer durations, although we know that the overall rate of fat oxidation supplies ATP at a slower speed—again, remember we have much more stored energy available in the form of fat than we do carbohydrate—so as we progressively move through this two-hour session, what was established was that as exercise duration increased, the contribution of fat to the overall ATP resynthesis and energy demand significantly increased with every subsequent phase. By the end, at two hours, fat was providing more than 60 percent of the energy needed to meet the demands of this work.
Now, again, what's causing this to happen? Well, the main factor driving this is that as exercise duration increased, well, the availability of muscle glycogen and carbohydrate also begins to decrease. And once that reaches a low enough level, well, then fat is going to need to be the predominant fuel source contributing to these work demands in order to make up the deficit that we're no longer getting from this muscle glycogen as we begin to deplete it. But of course, remember that this was at 60 percent of VO2 max. One of the things that's going to affect how rapidly these changes in fuel selection occur over the course of time is also going to be largely affected by the intensity at which the exercise is being performed.
Now, in contrast to the relationship between exercise duration and fuel selection, we'll now take a look at the effect of exercise intensity on how these fuels are selected. So in this particular example, this is a study that looked at the effects of exercising at 25%, 65%, and 85% of VO2 max on the relative contributions to the overall energy expenditure needed to perform at these intensities of glycogen, our fat stores, our triglycerides, and plasma fatty acids, as well as plasma glucose. And what we will see as intensity increases is that to generate ATP at a fast enough rate to sustain higher intensities of exercise, there's an increased reliance on carbohydrate.
So if we look at the contribution of muscle glycogen to each one of these particular, um, work rates, we'll see that that once we get up to around 85 percent of VO2 max, the majority of energy, or the predominant fuel, is going to come from the breakdown of muscle glycogen. And this is again due to the fact that in order to perform at these higher intensities, well, we need to be able to generate ATP fast enough in order to meet the high rate of ATP breakdown and turnover that is occurring. We simply don't have the time to wait for our fat oxidation pathways to provide that energy.
Now, ultimately, both exercise duration and intensity are also going to have the greatest impact on what causes us to fatigue. And functionally, when we're referring to fatigue, we're talking about the inability to maintain a given, or anticipated, or expected force or power output. So let's take a look at what causes fatigue during short-duration, high-intensity exercise. And if we look at a bout of all-out maximal effort exercise, we will clearly see that in just 30 seconds—not a lot of time—that the power output compared to the maximum observed value during those 30 seconds will fall by about 40 to 60 percent. So a lot of, um, a lot of power output being lost in a very short period of time when we're working as hard as we can.
Now, if we start to think about what causes this decline in power output, the decline is mostly related to the decline in the rate of phosphocreatine hydrolysis. So if we look at the rate of phosphocreatine hydrolysis during a maximal isometric contraction in a human skeletal muscle over the course of a 30-second bout, well, what we'll see is that after just a few seconds, the rate of PCR hydrolysis starts to significantly decline as we continue on at this maximal intensity. So in order to continue performing after a few seconds of high-intensity exercise, we're going to need a marked increase in the contribution of our other anaerobic energy systems. So we're going to have to ramp up the rate of glycolysis if we're going to attempt to maintain this high rate of ATP re-synthesis for longer than 30 seconds. And so when we perform at high intensities for durations that last approximately one to five minutes, at this point, as we can see here, our rate of PCR hydrolysis bottomed out long ago, and in order to continue to do this, we're going to have to start to break down more carbohydrate glycolytically, which is beneficial in helping to maintain a high rate of ATP resynthesis. But if we remember back to our metabolic pathways, we know that once that rate of pyruvate starts to [Music] reach a significantly increased rate of production, well, then more of that pyruvate is going to be converted to lactate. And the problem there is not necessarily the lactate, but the hydrogen ions that dissociate from the formation of this lactic acid. We know that those hydrogen ions, again, are going to drop the physiological pH of the muscle and impair its ability to function.
Now, this is coupled with the fact that we now, at this point, because we used up all of our phosphocreatine before this point, we're not getting the hydrogen buffering, um, effects of PCR hydrolysis. So ultimately, the combination of our increased reliance on glycolysis and the reduction in the rate of PCR hydrolysis is going to lead to a greater accumulation of these hydrogen ions and a more significant drop in pH and impairment in muscle function.
Now let's compare that to what causes fatigue during more prolonged bouts of exercise, or exercise at lower, um, or more moderate intensities that can be sustained for longer periods of time. We might also hear this referred to as endurance exercise. And if we take a look at this particular study in which they had trained endurance athletes exercise at various percentages of their VO2 max and looked at their overall time to fatigue, one of the things that, um, we will notice is that if we take a look at the concentration of muscle glycogen across each one of these bouts of performance, we can see that first of all, at a marathon-like pace, which would be somewhat around somewhere around 75 percent of VO2 max in a in a well-trained runner, that the muscle glycogen stores are able to fuel exercise for about 90 minutes before they become entirely depleted. However, once these muscle glycogen stores are depleted, well, in order for exercise to continue, what happens is ultimately we begin to increase the oxidation of blood glucose once muscle glycogen has been depleted. And where that blood glucose is coming from—because remember we need to maintain blood glucose in order to provide fuel for the brain and central nervous system—is coming from the breakdown of liver glycogen. So this will enable us to continue exercise as muscle glycogen stores become more depleted. But what ultimately will happen is we will exhaust both of our stores of muscle glycogen as well as our stores of liver glycogen. And at this point, we're going to have a compromise in terms of the rate of ATP production. So in order to continue, we're going to have to significantly slow down so that fat can provide the majority of the energy and can do so at a rate that is commensurate with its peak rate of oxidation. So at lower intensities—60 percent, 30 percent of VO2 max—we see that glycogen stores are doing a whole lot better because we're able to provide more of that energy via the oxidation of fatty acids. But at higher intensities for longer periods of time, or those that would be reflective of something like a marathon effort, we know that eventually we're going to deplete both our stores of muscle and liver glycogen. And ultimately, what will happen is we will start to significantly dip into our stores of blood glucose once these glycogen stores become depleted. And again, the problem with this is that the drop in blood glucose will limit the availability of the central nervous system's preferred source of fuel. So at this point, we will have a high likelihood of hypoglycemia and central nervous system fatigue. So what I want you to think about is what adaptations might occur as a result of exercise training that would help delay the onset of fatigue during these more prolonged bouts of exercise.