In recent years, long distance runners have seen significant improvements in training techniques, general nutritional approaches, and gear—particularly footwear. Nevertheless in races (especially at distances of 50 miles or more) most ultrarunners continue to confront the same old challenges: muscle cramps, fatigue, stomach distress, and blisters. Indeed the idea persists—both in the general public and amongst ultrarunners—that ultrarunning is all about suffering. This article is an attempt to dispel that myth by explaining how ultrarunners can avoid or minimize these challenges through an understanding of some relevant biochemistry. Certain approaches advocated here are not entirely new—what is new is an attempt to help ultrarunners grasp why these approaches work and the biochemical/performance consequences of ignoring them.

Aerobic Exercise—It’s All About the Mitochondria

Mitochondria are the intracellular powerhouses for most of our cells. They convert oxygen and fat or carbohydrate into ATP and specialized ion gradients. They play crucial roles in nerve and aerobic muscle cells, which continually require large amounts of ATP for function (see Appendix A: The Biochemistry of Muscle Contraction and Appendix B: The Biochemistry of Nerve Signaling.) In fact, an increase in the number and size of muscle mitochondria is one of the primary results of aerobic exercise training [McArdle WD, Katch FI and Katch VL (1996) Exercise Physiology: Energy, Nutrition and Performance (4th ed.). Philadelphia: Lea and Febiger; O’Toole ML and Douglas PS (1995) Applied physiology of triathlon. Sports Medicine 19:251-267, Tanaka H (1994) Effects of cross-training. Sports Medicine 18: 350-339]. The process of converting carbohydrate or fat and oxygen into ATP is a biochemical oxidation/reduction cycle that can be repeated reliably again and again as long as there are adequate supplies of everything needed for this process. It is fundamentally an oxidative process, so if something is not present in sufficient amount, the mitochondria may undergo oxidative damage, and any significant oxidative damage typically leads to mitochondrial destruction.

So what are the main things that mitochondria need for this process? Mitochondria can themselves produce or assemble most of the necessary proteins. They rely, however, on external sources of fat, carbohydrate, and certain electrolytes, as well as a pool of quinone molecules that mediate a critical step in the oxidation/reduction process. It follows that insufficient carbohydrate or carbohydrate and fat energy, insufficient electrolytes (for the mitochondria or their parent cells), or an inadequate quinone pool are the three things most likely to lead to mitochondrial oxidative damage and destruction.

You may at this point be thinking: “So what’s the big deal if I kill off a few of my mitochondria? My body can make more.” You are correct; your body will make more. The problem is that your event will be over before your body accomplishes that. Actually, you probably already know this if you have ever run a 50 or 100 mile race and developed muscle soreness during the race. Muscle soreness is one indication of mitochondrial destruction. Has that muscle soreness ever gone away before the end of the race? You spent weeks or months building up your mitochondria through training. Why destroy some of that halfway through an event?

In fact, there is an interplay between damage to mitochondria and damage to parent muscle and nerve cells. On the one hand, a lot of things can go wrong in muscle and nerve cells, and most of them can be repaired as long as the mitochondria in those cells are healthy. However, electrolyte imbalances make nerve and muscle cells inefficient, thereby stressing the capabilities of their mitochondria. As mitochondria begin to fail, they leak significant amounts of calcium into the cytoplasm, they no longer support the generation of proper action potentials in nerve and muscle cells, and they fail to protect their parent cells against oxidative damage. When enough mitochondria in a cell are damaged, the parent cell itself is programmed for destruction.

Mitochondrial destruction causes decreased performance. Directly or indirectly it leads to muscle cramps, and ultimately to mind-numbing fatigue. Conditions that produce mitochondrial destruction in muscle cells also cause mitochondrial destruction in the other cells of our body. So we don’t just develop cramps and muscle fatigue, we also lose the ability to think clearly. It follows that one of the most important things we can do as endurance athletes is to avoid carbohydrate, electrolyte, and quinone depletion.

Aerobic Exercise—Keep Those Carbohydrates Coming

The human body burns about 100 calories per mile while running. A typical runner stores enough glycogen for perhaps three hours at race pace. This is why many runners can last for an entire marathon—maybe even a 50K—with little or no additional carbohydrate besides a pre-race meal of 300-600 calories. The body can obtain some of its energy from fat metabolism, but the rate of fat metabolism is too slow to sustain race pace for most runners. For longer distances, therefore, a runner has two choices: slow down, or consume carbohydrate during the event.

Most of us understand that we need to eat predominantly complex (low glycemic) carbohydrates in everyday life. High (or even moderate) intensity exercise is an exception to this rule. The process of digestion actually requires significant energy in its own right. Under exercise stress, the rate and quality of digestion therefore decline considerably. To increase the likelihood that nutrients will actually reach the bloodstream rapidly (and reduce the amount of energy expended for digestion itself), we need to consume predominantly simple (high glycemic) carbohydrates. There are additional considerations. A typical 150 lb. runner can only take up (transport from the digestive tract to the bloodstream) 300-500 calories per hour during exercise, and optimal carbohydrate and water uptake from the stomach occurs when the stomach contains 60-100 grams of carbohydrate per quart of liquid (300-450 calories per quart) [Am J Physiol Endocrinol Metab. 2002 Sep;283(3):E573-7. Plasma glucose kinetics during prolonged exercise in trained humans when fed carbohydrate. Angus DJ, Febbraio MA, Hargreaves M.; Sports Med. 2000 Jun;29(6):407-24. Oxidation of carbohydrate feedings during prolonged exercise: current thoughts, guidelines and directions for future research. Jeukendrup AE, Jentjens R.]. Above 110 grams/quart, uptake decreases rapidly, and gastrointestinal distress is highly likely [Eur J Appl Physiol. 2003 Jan;88(4-5):431-7. Epub 2002 Nov 19. Metabolic profile of 4 h cycling in the field with varying amounts of carbohydrate supply. Meyer T, Gabriel HH, Auracher M, Scharhag J, Kindermann W.]. (The optimum of 60-100 grams of carbohydrate per quart of water applies to runners of all sizes, but the total needs for calories and water scale with body size. Runners lighter or heavier than 150 lb. should scale their intake of carbohydrate and water down or up but maintain the appropriate ratio of carbohydrate to water.)

The highest levels of carbohydrate uptake appear to only occur only when multiple sugars (e.g. glucose, fructose) are consumed that can be metabolized through different biochemical pathways [Adopo E et al (Appl Physiol 1994 Mar;76(3):1014-9)]. Thus honey (a roughly equal mixture of glucose and fructose), sucrose (which is digested to equal parts glucose and fructose in the upper GI tract), and even high fructose corn syrup (typically 55% fructose and 45% glucose) are useful carbohydrate sources for endurance running. Fructose leaves the stomach more slowly than glucose and is metabolized (in both liver and skeletal muscle) mostly through biochemical pathways that are insensitive to insulin and glucagon. Therefore under exertional stress, consumption of fructose in addition to glucose has the extra benefit that it levels out some of the blood sugar swings that can occur with glucose or dextran (glucose polymer) alone. Maltodextran (a simple starch) is sometimes used with or as an alternative to glucose because it has very little sweet taste but is metabolized nearly as quickly (and through the same pathway) as glucose.

A little arithmetic shows that ultrarunning competition actually takes place at or near the limits of human aerobic energy metabolism. Top average paces in longer ultra races are in the range 5 to 6 miles per hour, which translates into a need for 500 to 600 calories per hour. Fat metabolism can be estimated to provide as much as 200 to 300 calories per hour (the higher number probably only for women). Thus a top competitor needs to be able to consume something like 300 to 400 calories of carbohydrate per hour. This is near the limit of what a human can take up. A winning ultrarunner must either have greater biomechanical efficiency (therefore requiring slightly fewer calories), or be able to take up and use calories at maximum rate, or both! It is possible that the very fastest ultrarunners may have a genetic predisposition for a higher fat metabolism rate, which allows them to sustain faster paces without having to consume more carbohydrate.

One convenient way to consume carbohydrate while running is in the form of a sports drink. These are formulated to provide electrolytes and carbohydrate at optimal concentrations for uptake from the stomach. However, different athletes will have different electrolyte needs, so it is important to choose a sports drink that contains an electrolyte mix appropriate for you. Sports drinks also differ widely in the type of carbohydrates they provide, and quite a few contain no fructose, so choose wisely. Sports drinks free the athlete of the need to separately monitor carbohydrate, electrolyte, and water intake during an event. At the same time, the fixed carbohydrate/electrolyte/water ratio in a sports drink is a potential drawback. Carbohydrate needs do not tend to vary much under different race conditions, but electrolyte and hydration needs can vary a lot. You may therefore need to have different sports drink formulations for different temperatures and stages of an event.

A more flexible approach is to consume carbohydrate gel. Two to three gels (30 grams carbohydrate or 110 calories per gel) consumed with 24-32 ounces of water over the course of an hour works effectively. You can vary the amount of water you drink, depending on temperature. You can and should also use electrolyte supplements. Make sure to consume enough water, and do not try to mix gels with sports drink unless you are absolutely certain you know what you are doing. Consuming more than 110 grams of carbohydrate per quart of fluid or more than 100 grams of carbohydrate per hour (for a 150 pound runner) greatly increases the chances your stomach may shut down. It can take more than an hour and a half for your stomach to recover. During that time you will be traveling slower, and/or starving your mitochondria of carbohydrate and electrolytes—a situation from which they will not recover during your event.

Some ultrarunners believe it is better to consume “real food” than simple carbohydrate (gel or sport drink). Certainly ultrarunners DO need some amount of protein (or at least certain amino acids) in addition to carbohydrate. It is also likely true that some runners can settle an upset stomach with food that contains soluble fiber and protein. It is important to understand, however, that soluble fiber works mainly by slowing the rate of digestion. Under such conditions, ultrarunners are probably reduced to traveling at a pace that is limited by their rate of fat metabolism. So some real food is probably a good thing; just don’t overdo it, or you are likely to feel better and better because you are traveling slower and slower.

Finally, some of you may be in a position to estimate your maximal contribution to pace from fat burning alone. If you have ever done a long race in which you had to slow down late in the race because of the inability to consume food, that pace is a good measure of your maximum speed when metabolizing fat. If you want to race at a faster pace, you need to consume 0.67 calories (about 0.2 g) of carbohydrate per hour per pound of body weight for each mile per hour that you want to go faster.

Aerobic Exercise—Maintain Electrolyte Balance

Most distance runners know about the need to maintain electrolytes. There are four main electrolytes of importance to endurance athletes—sodium, potassium, calcium, and magnesium. Sodium tends to receive the most attention. It is the primary electrolyte in sweat and is therefore the electrolyte most likely to be depleted during warm temperatures or from heavy exertion over the course of a few hours. Potassium, calcium, and magnesium play important roles in mitochondria and are extremely important for muscle and nerve function during aerobic exercise. Like sodium, these can also be depleted in sweat and in the kidneys, but it typically takes longer. A runner suffering from muscle cramps at distances less than 40 miles probably has a sodium deficiency. Whereas a runner suffering from cramps after 40 miles (or especially in cool temperatures) may well be deficient in potassium, calcium, and/or magnesium.

Do not fall into the trap of believing that all runners have identical electrolyte needs. Humans may have overwhelming genetic similarity, but we all still differ in significant (and obvious) ways. Some of our most pronounced individual differences show up in ion transport systems and in the relative balance of Type I versus Type II muscle. Different muscle types utilize oxidative metabolism to different extents and are optimized to contract with different levels of force and for different durations. These different conditions require different amounts of the various electrolytes. Thus different runners show significant variation in their need for and response to different electrolytes. Because of this variation, it is extremely important to experiment with different electrolytes and their amounts and ratios during training.

Aerobic Exercise—Supplement with CoQ10 to Prevent Fatigue

Coenzyme Q10 (CoQ10 ) is a non-essential quinone vitamin found primarily in mitochondrial membranes. It plays a necessary role in mitochondrial energy conversion [Littarru, Gian Paolo, et al. Clinical aspects of coenzyme Q: Improvement of cellular bioenergetics or antioxidant protection? In Handbook of Antioxidants, eds. Enrique Cadenas and Lester Packer, NY, Marcel Dekker, Inc., 1996, pp. 203-39; Vanfraechem, J.H.P. and Folkers, K. Coenzyme Q10 and physical performance. In Biomedical and Clinical Aspects of Coenzyme Q, Vol. 3, eds. Folkers, K. and Yamamura, Y., Amsterdam, Elsevier, 1981, pp. 235-41]. It is considered non-essential because the body can synthesize it. However, levels of naturally produced CoQ10 drop about 10% every decade after age 20. CoQ10 is one of the most effective anti-oxidants in the human body. It is re-used (regenerated) under normal mitochondrial energy conversion, but is destroyed under oxidative stress conditions. CoQ10 depletion is the most likely cause of mitochondrial destruction besides carbohydrate and electrolyte deficiency. The mitochondrial membrane can store large quantities of CoQ10 . This improves the efficiency and fidelity of energy conversion. More importantly it serves as a CoQ10 reservoir, thereby permitting CoQ10 to be preloaded and stored for extended aerobic exercise.

CoQ10 supplementation is recommended for all adults over 50 and for anyone taking a statin drug to treat elevated cholesterol. It appears to be highly beneficial for anyone exercising (even hiking or backpacking) at altitude. It is likely to be beneficial for any endurance athlete over 40. In my experience, supplementation with 50 to 100 mg of CoQ10 per day for seven to ten days prior to an ultra race eliminates the fatigue often experienced at distances near or greater than 50 miles. It also substantially decreases muscle soreness and cramping during and after an event. These benefits presumably result because fewer mitochondria are destroyed due to quinone depletion and because the anti-oxidant effects of CoQ10 mitigate much of the oxidative stress associated with endurance exercise.

Other Related Distance Running Issues

Although muscle cramps and fatigue are very common problems encountered by ultrarunners, there are several other related problems that can often be dealt with successfully through biochemical approaches. These problems include gastrointestinal distress and blisters.

Distance Running—Prevent Upper GI Distress with H2 Blockers

A common problem among distance runners is upper GI distress. This manifests in different ways: bloating, belching, heartburn, or vomiting. Not everyone experiences the same symptoms or all these symptoms. In more severe cases, the stomach empties very slowly (gastroparesis), and nutrients and water fail to enter the bloodstream. If this goes on for more than an hour or two, mitochondria start dying because of carbohydrate and/or electrolyte depletion. In a race this typically leads to severe fatigue and/or a seriously slowed pace. Consuming more than 100 grams of carbohydrate per quart of water or more than 100 grams per hour (for a 150 pound runner) is a frequent cause of upper GI distress. Upper GI distress is sometimes also attributed to sodium deficiency/depletion—especially in warm temperatures or during high exertional output.

There are presumably other causes of upper GI distress, because many runners encounter the problem even in cool weather and when consuming only 60 grams of carbohydrate per quart of water. Stress—either everyday emotional stress or race day stress—is one very likely cause. Drugs that block H2 receptors in the stomach, such as famotidine (Pepsid), cimetidine (Tagamet), or ranitidine (Zantac), offer a promising way to prevent this problem. Upper GI distress is often interpreted as gastroparesis (failure of the stomach to empty). Many people regard H2 blockers as a treatment for heartburn or gastroesophageal reflux (GER), so it may initially seem counterintuitive that H2 blockers should be beneficial. However, H2 receptors are histamine receptors, and in the stomach, histamine is a by-product of stress (physical or mental). It is therefore logical that H2 blockers should prevent upper GI distress by interfering with the response to stress in the stomach.

Long distance runners who occasionally experience upper GI distress may want to experiment with famotidine as a prophylactic (10 to 20 mg before a race, and again at 12 hour intervals for longer races). It is available over the counter, has relatively few side effects, and is generally well-tolerated. There are some reports that proton pump inhibitors (PPIs) may also work to prevent upper GI distress. In fact PPIs have been shown to reduce gastrointestinal bleeding in ultrarunners [Thalmann, M., Sodeck, G. H., Kavouras, S., Matalas, A., Skenderi, K., Yiannakouris, N. et al. (2006) “Proton pump inhibition prevents gastrointestinal bleeding in ultra-marathon runners: A randomized, double blinded, placebo controlled study. British Journal of Sports Medicine, 40(4), 359-362]. These drugs are another treatment for GER, and so they may also be blocking the stress response in the stomach. PPIs require a longer course of treatment, and have undesirable side effects when taken over prolonged time. An H2 blocker like famotidine is probably a better choice unless a runner frequently suffers GER when not running.

Distance Running—Avoid Overhydration and Blisters

It may come as a surprise to learn that many blisters experienced by trained runners really result from overhydration, or in some cases, electrolyte imbalance. Think about it. Your body does its best to keep optimal electrolyte concentrations in your muscles. If your water intake is too high, your body attempts to deal with the problem by shunting excess water into the spaces between your cells. Gravity makes this effect more pronounced in your extremities—hence “sausage fingers”, swollen feet, and ultimately blisters.

Runners who regularly experience blisters (even while training) should carefully examine whether they have sufficient potassium in their regular diet or whether they may be routinely overhydrating. There are indications that regular soaking of feet in brewed black tea can help avoid blisters because the tannic acid in tea dries and toughens the skin and outermost tissues. Runners who commonly experience blisters only on race day should consider whether they may be overhydrating in the days immediately leading up to races. Runners who only occasionally experience sausage fingers, swollen feet, or blisters can use these symptoms as a signal to decrease fluid intake and/or possibly increase potassium intake at the time. This will improve muscle performance, as well as help avoid hyponatremia.

Endurance Athletes—Get Enough Vitamins and Minerals

Endurance athletes need elevated quantities of most vitamins and minerals. Vitamins and minerals should ideally come from diet. (Your mom DID tell you to eat your fruits and vegetables, didn’t she?) You should also be taking a daily performance multivitamin as insurance. Table 1 lists recommended vitamin and mineral supplement levels for most athletes.

A few of these deserve special mention:

Both male and female athletes of all ages need 1200 mg of calcium per day. Athletes consuming less than this amount are at increased risk for stress fractures. Women should probably supplement with 1200 mg calcium because women seem to be less effective than men at getting calcium from regular diet. Also consumption of more than 1200 mg/day does not seem to pose any health risk for women. Excessive calcium correlates with increased risk for prostate cancer in men. Men should therefore estimate their total dietary calcium intake from dairy products, multivitamin, etc., and then supplement with as much calcium as necessary to achieve 1200 mg/day when training. Both male and female athletes need to make sure they get sufficient Vitamin D, since Vitamin D is essential for incorporating calcium into bone.

Large quantities of zinc are lost in perspiration. Therefore both male and female adult athletes of all ages need 40 mg of zinc per day. This level is particularly helpful in maintaining appropriate amounts of testosterone needed for optimal male athletic performance.

Vitamin C is critical for muscle repair and for ligament and tendon flexibility. Recent increases in achilles tendon ruptures amongst runners is probably at least partially due to insufficient Vitamin C in runner diets. Vitamin C has largely been debunked as an immune supplement in the average population, but a number of studies have demonstrated it is beneficial to the immune systems of athletes. In addition, Vitamin C aids in incorporation of iron and calcium, and the antioxidant effects of Vitamin C may also be protective.

Running appears to deplete iron in the human body. There is not a big enough effect to justify supplementation in most men, but vegetarian and female athletes should make sure they consume 18 mg iron per day.

Endurance exercise imposes additional oxidative stress on the human body. Endurance athletes should therefore try to consume large quantities of fruits and vegetables that contain antioxidants. They should also make sure to get adequate amounts of vitamins A, C, E, and (as noted earlier) CoQ10. Large quantities of Niacin interfere with fat metabolism. Endurance athletes should avoid quantities greater than 25 mg per day.

Conclusion

The strategies outlined here are no substitute for proper training and everyday nutrition. But if you are a runner who occasionally suffers from muscle cramps, severe fatigue, blisters, or stomach upset, one or more of these strategies might just keep you upright and running efficiently in your next event!

Appendix A: The Biochemistry of Muscle Contraction

Our skeletal muscles are bundles of long, parallel muscle cells. Each muscle cell contains a repeating network of thin filaments of actin protein and thick filaments of myosin protein oriented along the length of the cell. These thin and thick filaments overlap and can slide partially past each other. The myosin proteins in the thick filaments have the capability to bind to and move along adjacent actin fibers, consuming cellular ATP as they pull their way along the actin thin fibers [Webb, MR, and Trentham, DR. Chemical mechanism of myosin-catalyzed ATP hydrolysis. In: Peachy, L.D., Adrian, R.H., and Geiger, S.R., ed. Handbook of Physiology. Bethesda, MD: American Physiological Society.1983;237-255]. The binding of myosin to actin is regulated by tropomyosin and troponin proteins that are associated with actin thin filaments. Under relaxed or elongated conditions, the tropomyosin prevents myosin binding, and the thick filaments therefore slide freely along the thin filaments.

Muscle contraction is initiated when all the cells in the bundle (simultaneously) receive a signal from their motor nerve in the form of an action potential (see Appendix B: The Biochemistry of Nerve Signaling.) The action potential is a transient electrical polarization of the cell membrane that is propagated to a region of the cell membrane where there is a special connection (T tubule) to the sarcoplasmic reticulum. The sarcoplasmic reticulum is an organelle in the interior of the muscle cell that sequesters (accumulates) calcium ions. When the sarcoplasmic reticulum is stimulated by the action potential, it releases large amounts of calcium ions into the cytoplasm. This spike of cytoplasmic calcium ions causes a conformational change in the troponin and tropomyosin proteins that are associated with actin thin filaments. As a result of this conformational change, the myosin in thick filaments can bind to actin and use cellular ATP to pull its way (ratchet fashion) along its nearby actin thin filament, thereby contracting the length of the muscle cell.

As soon as the sarcoplasmic reticulum has released its calcium contents, and the action potential has dissipated, the sarcoplasmic reticulum begins pumping calcium ions back into its interior from the cytoplasm. It consumes ATP for this pumping process—although not anywhere near as much ATP as is used by myosin for muscle cell contraction. By the time the muscle cell has completed its contraction, the cytoplasmic calcium concentration has dropped to normal levels, and troponin and tropomyosin have converted back to their normal conformation. This prevents binding of thick filaments to thin filaments and allows the muscle cell to relax back to its normal length (i.e., to elongate).

Muscle cells require large amounts of ATP. Mitochondria are cellular organelles, which specialize in the production of ATP under aerobic conditions. Ideally, muscle cells have large quantities of carbohydrate, typically in the form of glycogen. As needed, glycogen is converted into three-carbon sugars in the cytoplasm by way of the citric acid cycle, which produces small amounts of ATP. The three-carbon sugars are then consumed by the mitochondria to produce much larger quantities of ATP. Since, the muscle cell uses so much ATP for each contraction cycle, it stores some of the ATP energy in its cytoplasm in the form of creatine phosphate, which can be easily and quickly converted back into ATP.

There are several different types and classifications of skeletal muscle cells that are specialized for different muscular activity. Type I (slow twitch) muscle cells make up the classical aerobic red muscle that carries out high-endurance, slower and lower-force contraction. These are the primary muscle cells used for distance running, distance cycling, hiking, etc., and they contain large amounts of oxygenated myoglobin (which produces the red color of aerobic muscle), large stores of glycogen, and large numbers of mitochondria. Type II (fast twitch) muscle cells come in several variations, but all carry out faster and more forceful contraction than Type I muscle cells. Type II muscle cells have a larger cross section than Type I muscle cells and contain considerably less myoglobin, considerably fewer mitochondria, and considerably more creatine phosphate. These are the muscle cells used for sprinting and lifting big weights, but distance runners need some Type II muscle for running up shorter hills, etc. The prototypic Type II muscle is white and is called fatigable. There are also intermediate fatigable and fatigue resistant Type II muscle cells that, respectively, have more Type I character than fatigable Type II cells. Although we each have some individual genetic predisposition to produce more or less Type I or Type II muscle, individual muscle cells can actually interconvert between types over time, depending on whether we do a lot of resistance training or aerobic exercise with a particular muscle.

Quite a variety of things can go wrong—some easily repairable, some not. Muscle cells, like nerve cells, require appropriate amounts of potassium and sodium ions to produce action potentials (see Appendix B: The Biochemistry of Nerve Signalling].) Muscle cells also require significant quantities of calcium ions. If quantities of any of these ions get too far out of balance, the cell may generate action potentials or calcium signal spikes that have the wrong magnitude, duration, or propagation. This typically causes the cell to waste ATP in various ways. When muscle cells use up their carbohydrate reserves, their mitochondria cannot produce enough ATP, and contraction does not occur. The muscle cell is said to be fatigued. A worse situation occurs if ATP runs out during a muscle contraction or if too much calcium is released into the cytoplasm from failing mitochondria. Under these conditions the muscle cell becomes locked in a contracted state. This leads to muscle soreness and tightness. If enough muscle cells reach this state simultaneously, a muscle cramp occurs. Muscle cell carbohydrate reserves can be replenished via the bloodstream (assuming the liver has carbohydrate reserves to transfer into the blood). However, if an aerobic (high oxidative) muscle cell (Type I or Type II fatigue resistant muscle) goes too long without sufficient carbohydrate (tens of minutes), some mitochondria begin to undergo oxidative damage. Cells contain many mitochondria, but producing new mitochondria requires hours to days. If enough mitochondria are damaged, the cell itself begins to experience oxidative damage and becomes programmed for cell death. Synthesis of new muscle cells takes days.

Appendix B: The Biochemistry of Nerve Signaling

Nerves consist of networks of neurons. Neurons are highly elongated single cells that are specialized to transmit signals in the form of electrical activity over long distances (as much as a meter) to one or more target cells. A typical neuron consists of a cell body, a number of dendrites that are offshoots of the cell body, and a typically longer axon region that extends from the cell body to the target cell(s). The cell body contains the nucleus, ribosomes, and most of the standard cell organelles besides mitochondria. The dendrites are long tubes that provide sites for stimuli from other cells. The axon transmits the nerve’s electrical signal over a long distance and usually makes branches to multiple target cells near its end (for example all the muscle cells in a muscle).

The junctions between stimulating cells and neuronal dendrites and between the neuronal axons and target cells are called synapses. There are many different types of synapses, but in most cases the originating cell releases some kind of neurotransmitter, such as acetylcholine. When a nerve cell is the stimulating cell, the neurotransmitter is released in response to the nerve cell’s electrical signal. After release, the neurotransmitter diffuses across the short space between cells at the synaptic junction. When the neurotransmitter arrives at the target cell membrane, it binds to a receptor on the target cell, which precipitates electrical activity in the target cell. The mechanism of neurotransmitter release typically involves some kind of membrane rearrangement that has very specific requirements for concentrations of sodium, calcium, and magnesium ions on the inside and outside of the neuronal cell membrane. For example, when magnesium ion is insufficient at the junction between a motor neuron and a muscle cell, the junction (and therefore the target muscle cell) is hyperexcitable.

The electrical signal propagated by a nerve cell is called an action potential. Membranes in all cells typically have some kind of normal polarization that results from differences in ion concentrations on the two sides of the membrane. This normal polarization gives rise to what is called a resting potential. In nerve cells, there is a resting potential of about -70 millivolts (outside negative). This resting potential results from the fact that nerve cells maintain a much higher concentration of potassium ion inside the cell than is found outside and a somewhat lower concentration of sodium ion inside the cell than is found outside. These concentration differences are maintained by special cell membrane proteins that consume ATP to pump sodium out and potassium in. Nerve cell membranes also contain large numbers of voltage-gated channels. These channels allow specific ions to flow across the membrane only when the membrane becomes sufficiently depolarized and then only for a very brief period of time. There are voltage-gated sodium channels and voltage-gated potassium channels. When a neurotransmitter binds at the dendritic synapse of a nerve cell, the binding briefly opens other pores that cause a transient depolarization of the membrane. This depolarization opens the voltage-gated channels in the vicinity of the synapse and generates a further depolarization. Because of the specificity of the channels for specific ions, the membrane potential actually reverses direction. This reversal in electrical potential is the action potential. The voltage gating of the channels, their unique timing, and the continued pumping of sodium and potassium ions by the ATP driven pump causes the action potential to be very short-lived but to travel rapidly down the length of the nerve cell.

Nerve cells require large amounts of ATP to drive their sodium/potassium ion pumps. This ATP is mostly produced by nerve cell mitochondria. Nerve cell axons have special structures called microtubules along which the mitochondria are spaced to ensure that ATP is readily available over the entire length of the axon. Nerve cell mitochondria also play an important role in sequestering calcium ions. This is critical in the vicinity of the terminal axon synapses.

Muscle cells have some of the same features as nerve cells. They receive their signal to contract from nerve cells, so they have an incoming synapse. They also propagate the signal to contract as an action potential, and therefore require ATP driven sodium/potassium ion pumps and voltage-gated ion channels.

A number of things can go wrong in nerve cells. Action potentials depends on the presence of appropriate sodium and potassium ion concentrations on the inside and outside of the nerve cell membrane. Shortages of either of these ions can interfere with proper development and propagation of action potentials or can cause the cell to waste unnecessary energy maintaining ion gradients. In addition, appropriate concentrations of calcium and magnesium ions are critical at nerve synapses. Inadequate carbohydrate stores, inadequate electrolytes, or inadequate quinone pools can lead to mitochondrial damage and destruction, just as in muscle cells. This rarely becomes serious enough to cause nerve cell destruction itself, but it can seriously harm action potential propagation whenever a critically spaced mitochondrion in the axon ceases to function.