Conclusion
An increased resistance to fatigue enhances endurance performance. Systematic use of intense, high-quality training spikes the amount and duration of neural output, and this boosts resistance to fatigue. Explosive training, extended training at goal race pace, shortened recovery times within interval workouts, and sessions that optimize muscle oxidative capacity and lactate-threshold velocity are all prove fatigue fighters.
Part VII
Molecular Biological Changes in Running
Chapter 30
Training Effects at the Molecular Level
Gaining an understanding of the ways in which workouts turn on genes inside muscle cells and thus produce biochemical and structural adaptations might seem to be an esoteric and overly scientific pursuit to many runners and coaches, but such understanding is actually critical. Approaching training from the molecular perspective takes the guesswork out of running and helps identify the workouts that have the most potent impact on running capacity. The bottom line is that coaches and runners should always be trying to turn on an optimal cascade of biochemical reactions via training. This is not possible without an understanding of what goes on inside muscles at the molecular level.
Effects of Training on Genes
Running training induces an array of significant molecular responses inside muscle cells. Each workout causes a multitude of genes inside muscle cell nuclei to be read, known as transcription. This action initiates an outburst of messenger RNA (mRNA) within muscle fibers; mRNA codes for proteins that will become new, adaptive structures and enzymes inside muscle cells. This activity peaks 3 to 12 hours after a training session is over. Levels of mRNA do not usually return to normal until 24 hours after the end of a training session, indicating that adaptation to the workout is continuing during that time.1, 2
Each molecule of mRNA that appears after a workout has been transcribed from a segment of DNA (i.e., a gene) and has a chemical blueprint for a specific protein. A molecule of mRNA carries its gene-derived information to a site of protein synthesis within a muscle cell called a ribosome. At the ribosome, the individual mRNA molecule is translated into a chain of amino acids—a protein. The protein may be structural in nature, increasing the basic strength of the muscle cell in which it is found. It may also act as an enzyme, enhancing the activity of a specific metabolic process inside the muscle. For example, the protein might be a key enzyme called phosphofructokinase, the concentration of which can place an upper limit on the breakdown of carbohydrate for energy during very intense running.
The process just described is the most basic way a workout enables endurance runners to improve their running capacity. A training session produces mechanical and chemical signals inside muscle fibers that cause hundreds of different genes to be read. The reading produces mRNA that is then translated into protein, and the protein functions in ways that can enhance endurance performance. In one sense, when runners train, they are hoping to turn on and transcribe the most advantageous genes so that the best proteins for performance can be produced. Long-term adaptation to training is caused by the additive effects of each workout, leading to alterations in the concentrations of performance-related proteins and new steady-state levels of proteins that promote endurance and speed.3
Signals Leading to Adaptation
Molecular biologists have identified a number of different signals that can lead to transcription, protein synthesis, and thus adaptation at the molecular level. The mechanical stretching muscle cells undergo during running is a signaling message. In fact, this mechanical elongation is sometimes referred to as a primary messenger. Molecular biologists know that one specific effect of mechanical stretching is the activation of a chemical called insulin-like growth factor, which is actively involved in muscle growth and repair.4 The nature of the mechanical stress appears to be very important. For example, axial mechanical stretch, which tugs on a muscle cell in a lengthwise direction, produces completely different molecular, intramuscular responses than transverse mechanical stress, which applies force perpendicular to the long axes of muscle fibers.5 The use of both kinds of mechanical stretching during training probably produces more complete strengthening of muscle cells.
Calcium
Calcium is a chemical primary messenger that can elicit a cascade of adaptive molecular events. When a neuron stimulates a muscle cell to contract, an internal network of tubular structures within the fiber (i.e., the sarcoplasmic reticulum, or SR) releases calcium ions (Ca2+) into the general subcellular fluid space. The freeing of calcium evokes shortening of the muscle cell. When the fiber relaxes and relengthens, the Ca2+ is drawn back into the SR.
Among fairly inexperienced runners, prolonged running at moderate intensity of about 60 to 70 percent of O2max enhances the calcium reuptake capacity of the SR, probably by increasing the number of active calcium pumps in the walls of the SR. This appears to be a highly adaptive response since it increases the amount of Ca2+ available for sustained muscle contractions. Repeated exercise sessions cause the release and reuptake of calcium to become more regular, which enhances resistance to fatigue.6
High-intensity running workouts, conducted at intensities above O2max for example, produce a different calcium response. They can promote a short-term, 20 to 50 percent decrease in calcium ion reuptake and thus release, perhaps by shutting down the calcium pumps in some way. This drop-off in calcium transport ability can require at least 60 minutes to correct,7 which helps explain the extreme muscle fatigue that can occur in response to high-intensity running.
The exact nature of the gene expression and protein synthesis that occur in response to intensity-dependent signals is not yet known, but changes in calcium ion concentrations are believed to represent strong primary messages that produce an array of secondary molecular events and thus create a number of different adaptive pathways for muscle cells.6 It is clear that the amount and duration of calcium ion flux, and thus the strength of the calcium signal, are determined by the duration, frequency, and intensity of running. The exact way in which these factors interact is not yet understood. Future research will likely examine the ways in which intensity and duration of training influence calcium flux in both experienced and novice runners.
ATP and AMP
Adenosine triphosphate (ATP) is the energy currency of all cells in a runner’s body, providing instantly available energy for muscle contractions and an array of other important activities. The relative ratio of ATP and a closely related compound, adenosine monophosphate (AMP), is an important signaling mechanism.8 Strenuous or prolonged running tends to increase the ratio of AMP to ATP inside muscle fibers. This upswing activates a compound called AMP-activated protein kinase (AMPK), which is a potent second messenger, or additional signal.8 Activation of AMPK can create a variety of performance-enhancing effects, including improvements in glucose uptake by muscle cells9 and upgrades in the rate of fatty acid oxidation.10 Both of these changes make more energy available to muscle cells and thus can prolong endurance and the ability to sustain a desired intensity of effort.
Scientific investigations reveal that faster running speeds and advanced power outputs during cycling invoke heightened AMPK activation when compared with less intense levels of exertion.11 Long-term aerobic training decreases the acute AMPK response associated with workouts, but this is true only when exercise is conducted at the same pretraining work rate.12 This is important to note because the pretraining work rate becomes a smaller percentage of maximal work rate as fitness advances over time.
As long as workout intensity is adequately high, AMPK activation will be significantly enhanced: For example, interval training at 90 percent of O2max can increase AMPK activity in well-trained athletes.12 AMPK activation is also dramatically increased after high-intensity sprint-cycling efforts of short duration.13 These effects should also be present after similar levels of effort during running. The underlying mechanism is that high levels of effort depress intramuscular ATP concentrations, thus
increasing the ratio between AMP and ATP and activating AMPK. The AMP-ATP signaling mechanism suggests that the maintenance of a high average intensity of training is paramount for endurance runners.
Impact of Molecular Adaptations
Many of the molecular adaptations associated with long-term endurance training are well understood. If a previously sedentary individual begins to run three or four times a week, performance-related intramuscular protein content can increase dramatically within a few weeks as appropriate genes are repeatedly transcribed and used to create new proteins. For example, research has shown that endurance training can increase mitochondrial protein content in leg muscles by as much as 100 percent after 6 weeks of workouts, producing a major advance in the leg-muscles’ ability to use oxygen and supply the energy (ATP) necessary for sustained running.14
Mitochondria are the main subcellular structures in muscle fibers that determine aerobic capacity and resistance to fatigue.15 A single mitochondrion has about 615 different proteins. Mitochondria carry out the process of oxidative phosphorylation, a series of reactions dependent on oxygen that use the energy found in carbohydrate and fat to synthesize ATP. Without well-developed mitochondria, an endurance runner will lack the ability at the molecular level to run fast over long distances. Increases in mitochondrial protein content are usually associated with improvements in endurance and maximal aerobic capacity, or O2max.15
The protein content of muscle cells is quite dynamic, and the half-life of mitochondrial protein can be as short as 1 week.16 In other words, just half of the mitochondrial protein created on a specific day will be present in the mitochondria 1 week later, and only 25 percent of the original protein will still exist after 2 weeks. This helps explain why a sudden cessation of training can lead to a fairly rapid loss of aerobic capacity. Without the appropriate signals associated with training, the expression of genes related to mitochondrial development and endurance-running capability grinds to a quick halt.
The genes coding for a chemical called PGC-1alpha are crucial for mitochondrial biogenesis, which is an increase in mitochondrial protein content, enzyme activity, and overall density. PGC-1alpha appears to boost mitochondrial biogenesis by co-activating multiple mitochondrial transcription factors. These factors are compounds that cause the reading of numerous genes related to mitochondrial-protein synthesis.17 Thus, PGC-1alpha is like a master regulator of mitochondrial biogenesis. Studies in which mice were given supplemental genetic material coding for PGC-1alpha showed that such mice significantly improved endurance capacities compared with rodents with normal levels of PGC-1alpha.18
PGC-1alpha is also the co-activator of an important compound called PPAR that can enhance fatty acid oxidation, increase mitochondrial DNA content, and convert muscle fibers from fast-twitch to slow-twitch.19 Slow-twitch muscle cells have higher oxidative capacities and greater resistance to fatigue during submaximal running. One study found that mice that produced unusually large amounts of PPAR improved running performance by as much as 90 percent.19 So, a key goal of training is to optimize the production of PGC-1alpha and thus PPAR. While such effects are well understood, a persistent problem remains: The study of the molecular biology of running has not progressed far enough to know which training sessions and programs produce optimal concentrations of PGC-1alpha and PPAR and thus a maximal rate of mitochondrial biogenesis. This will likely be a subject for future research.
The same can be said for many other key adaptive molecular events within muscles. For example, it is known that endurance training boosts the subcellular production of GLUT4, a chemical that increases the rate at which glucose can be transported into muscle cells.20 In experimental work, rodents that produce large quantities of GLUT4 can exhibit dramatically improved running performances.21 However, the form of training that turns on the genetic code for GLUT4 to the greatest extent is not yet known.
The muscles are not the only sites that undergo molecular transformations in response to endurance training. When genes that code for a specific receptor in the heart are highly expressed as a result of training, the heart is capable of a greater total cardiac output, sending more blood and oxygen to the muscles during strenuous workouts and competitions.22 The best way to signal these genes via training is not yet known.
Conclusion
It is clear that a key goal for the molecular biology of running is to identify the ways in which the intensity, duration, and frequency of training produce unique signaling mechanisms and thus changes in gene expression and protein production within muscle cells and the heart. Such an understanding should upgrade the quality of training programs for runners.
Chapter 31
Training Favoring Molecular Enrichment
Molecular biologists who study running may eventually be able to tell runners exactly which genes are expressed in response to different kinds of running workouts, knowledge that will greatly enhance training productiveness. In the meantime, the current understanding of the molecular biology of running (outlined in chapter 30) can help runners and coaches answer key questions about running training.
Specifically, understanding sports molecular biology can assist runners and coaches with their use of strength training for running. Traditionally, strength training has been viewed as an activity that is too anaerobic for distance runners, but molecular research reveals that resistance training can be highly beneficial if conducted in the proper way. Furthermore, molecular research has much to say concerning the best possible frequency of training, the effects of glycogen depletion and repletion on overall fitness, and optimal adaptation to training as will be outlined in this chapter.
Molecular Changes of Strength Training
A historic debate in distance running concerns whether strength training provides significant benefits for the endurance runner. One can begin to resolve that question by thinking about how muscles respond to strength training versus endurance running at the molecular level. If such molecular adaptations are quite different, it is possible that strength training could interfere with the adaptive responses associated with endurance work by forcing muscles to use precious resources to create proteins and structures that do not help—and might even hinder—endurance performance.
Research reveals that when an individual begins to lift weights two or three times a week, the genes associated with the adaptive response to resistance training are expressed, proteins unique to strength-training adaptations are produced, and the overall changes are different from those associated with running training. Usually, muscle cells upgrade their diameter and overall volume in response to resistance training, and as a result, strength may improve rather dramatically. To put it simply, there is a greater amount of muscle tissue available to exert force, and thus strength increases. In contrast, endurance training usually does not produce muscle hypertrophy.
If an athlete only pushes weights around in the gym, however, and does not engage in any other form of training, the genes that become active during endurance training will not be well expressed unless the activities are carried out as part of an intense circuit workout; the athlete will struggle during any sustained activity carried out at a significant fraction of O2max in spite of the enhanced muscular strength. The runner’s muscles won’t respond well in a 10K race, for example, and he or she will finish the competition far behind individuals with considerably less sinuosity and strength. The problem is not that strength training hurts endurance performance; rather, it does not seem to produce—by itself—molecular adaptations that greatly enhance distance running.
The muscles take an entirely different trajectory when an individual avoids the gym and begins a program of regular endurance training, for example running for 45 to 60 minutes five times a week. In this case, the genes for endurance are expressed, the muscle fibers busy themselves with the process of synthesizing increased quantities of aerobic enzymes and higher densities of mitochondria, and muscle cells may signal surrounding capillaries to create bushy new networks o
f small blood vessels that envelop muscle fibers like tangled spiders’ webs. Any fast-twitch cells that are present in the muscles, the kinds of fibers that promote raw strength, undergo at least a partial metamorphosis making them much more like slow-twitch cells. After 8 weeks of this kind of training, moderate-intensity endurance exercise is easy, but a trip to the gym would most likely reveal a surprising lack of strength and coordination. The muscles would be far different—and significantly weaker—compared with the sizable sinews produced by a steady diet of strength training.
It is clear that two different adaptive directions are possible at the molecular level when training consists of resistance or endurance work. With resistance training, muscle cells create new proteins that increase the size of muscle fibers and whole muscles. With endurance training, muscle cells synthesize aerobic enzymes and structures that enhance stamina without increasing muscle bulk. Traditionally, many exercise physiologists and running coaches have said that these two possible adaptive directions are contradictory: If an athlete pushes muscles on a path toward strength, this will retard the development of greater endurance, and vice-versa. The basic idea is that muscles cannot simultaneously involve themselves with the processes of increasing size and augmenting aerobic characteristics. As a result of this kind of thinking, many endurance athletes avoid strength training altogether.
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