Metabolic Integration, cont.

Last time we looked at the availability of fuel and tissue fuel usage in a typical male human. Today I want to continue by looking at fuel usage in stavation.

For humans the brain uses about 20% of resting energy, regardless of whether its user is "vegging out" or studying like crazy. In the fed state the brain uses about 4 g/hr of glucose while the anaerobic tissues (e.g. red blood cells) use about 1.5 g/hr. This is a particular problem because the brain is quite restricted in what fuels it can use, while the anaerobic tissues are restricted to glucose alone.

Now we can look at what occurs in fasting. In Table 3, below, is some data on the varying concentrations of key fuels and insulin, the major metabolic regulatory hormone. Notice that glucose concentrations fall for a few days, but then stabilize at about 3.5 mM. Given that an average liver has about 100 g of glycogen, and that glucose usage in the fed state is about 9-10 g/hr an average man would run out of glucose in only ten hours if some other fuel source did not become available after feeding. In fact liver glycogen lasts for about 24 hours. So what's going on?

Looking at fasting from 24 hours to 24 days or so, we see

• After 24 hours the liver glycogen is depleted, so glucose is supplied by a high level of gluconeogenesis from lactate (from anaerobic tissues, about 39g of glucose/day, resting), glycerol (from fats in adipose, about 19g of glucose/day, resting), and amino acids (from muscle, about 60g of glucose/day after one day, resting). Since the brain needs about 100g of glucose equivalents/d and it only has the glucose from amino acids and glycerol available, the remainder must come from ketone bodies. Other tissues, such as muscle can use fatty acids and ketone bodies, and in fact "prefer" these fuels.
• As the fast progresses the brain shifts more to ketone bodies. Thus the brain uses only 16g of glucose/day after several weeks, with ketone bodies providing the remaining energy. This is critical, as a continued high use of gluconeogenesis from muscle amino acids would quickly deplete muscle to less than 50% of its initial mass and mammals generally cannot survive at less than 50% of normal muscle mass (muscle has about enough protein to provide 17 days of glucose, assuming 50 g/day).

So how are these changes initiated and controlled?

Glucose/Fatty acid control cycle (muscle): During carbohydrate stress (liver glycogen stores are depleted, so serum [glucose] falls) the utilization of glucose by muscle falls as fatty acids are metabolized.

• Low [glucose] causes a drop in insulin, which normally inhibits fatty acid release from adipose.
• Free fatty acids are released from the adipose tissue.
• Free fatty acids are used in peripheral tissues and:
  • The acetyl-CoA/CoA-SH ratio rises as fatty acids are broken down, activating Pyruvate DH Kinase, which in turn phosphorylates Pyr DH Complex to the inactive form.
  • Fatty acid and Ketone body oxidation in the mitochondria results in an increase in [citrate], which is transported to the cytosol by the Pyruvate-Malate Cycle.
  • Citrate potentiates the effects of ATP on PFK, reducing its activity, in turn causing a consequent increase in [G-6-P].
  • The high [G-6-P] in turn inhibits Hexokinase, blocking further glucose use by the muscle.

Glucose/Ketone body/Fatty acid control cycle (peripheral tissues, i.e. brain, kidney, intestine): When at rest the non-muscle peripheral tissues generally consume more glucose than muscle. So how do they respond to carbohydrate stress?

• Ketone bodies control glucose utilization in a manner similar to fatty acids:
  • PFK activity is decreased by increased [citrate].
  • The resultant increase in [G-6-P] inhibits Hexokinase, blocking further use of glucose.
  • The metabolism of Ketone bodies results in a rise in the acetyl-CoA/CoA-SH ratio, activating Pyruvate DH Kinase, which in turn phosphorylates Pyr DH Complex to the inactive form.
• A high concentration of 3-hydroxybutyrate effects blood fatty acid concentrations in a number of ways:
  • It reduces the rate of adipose tissue lipolysis
  • It increases the sensitivity of adipose tissue to insulin, which decreases lipolysis (appears to be quantitatively most important.
  • It stimulates insulin secretion by the pancreas.

Metabolism in Exercise

Heavy exercise may also result in carbohydrate stress. There are two extreme situations:

• Short duration, high power (remember, power = energy/time) output exercise, such as sprinting.
• Long duration, relatively low power output exercise, such as marathon running.

First, if we look at athletes (human or animal) at these two extremes, there are significant difference in muscle types, thus for humans,

• Sprinters have >70% fast twitch (Type II) muscle fibers. Fast twitch muscle is characterized by having:
  • a poor blood supply (operates anaerobically at high power, so blood not needed to bring oxygen)
  • few mitochondria and low concentrations of "aerobic" enzymes (e.g. Krebs' TCA cycle enzymes)
  • little myoglobin
  • high levels of glycolytic enzymes and Creatine phosphokinase
  • fast conduction nerves
  • a rapid rate of contraction.
• Marathon runners have >70% slow twitch (Type I) muscle fibers. Slow twitch muscle is characterized by having:
  • a good blood supply (operates aerobically, so needs lots of oxygen)
  • high levels of myoglobin
  • lots of mitochondria
  • slow conduction nerves
  • slow contracting fibers.

Let's look at the performance of world class runners as a function of distance (time). If we look at the figure below it appears that there are three processes (as shown by the three different best fit lines), indicating three different metabolic regimes corresponding to:

1. The initial 20 seconds.
2. The time from 20 to 200 seconds.
3. Times exceeding 200 seconds.

Redrawn from R.W. McGilvery (1979) Biochemistry: A Functional Approach. W. B. Saunders Company, Philadelphia: p 704

• 0 - 20 s: In the initial time the runner is operating fast twitch muscle anaerobically, using two different energy sources:
  1. Initially the energy in muscle can be provided by ATP stores and the Phosphocreatine-ATP buffering system. For a trained athlete muscle phosphocreatine stores go from about 17 mmol/g to 4 mmol/g, at which point they are essentially exhausted. As it turns out this gives about 4 seconds of energy for maximum power output. During this time Ca²⁺ released in the muscle will activate the glycogen cascade at the level of Phosphorylase kinase, and glycolysis will be activated by controls on PFK.
  2. For up to 20 seconds anaerobic glycolysis will then provide the additional energy required past the available ATP/P-creatine supply. If we look at the glycogen supply in fast twitch muscle there is enough to give about 80 seconds at this high power level. So why do we run out of steam at 20 seconds? Essentially fatigue is a result in this case due to changing pH, as [H⁺] increases, fatigue ensues. This is pretty much independent of [lactate], though [lactate] increases are generally the cause of the decreasing pH. A variety of processes appear sensitive to low pH - Ca²⁺ diminishes, the contractile process is negatively effected, and PFK is inhibited.
• 20 - 200 s: For slightly more sustained exercise the athlete must pace herself to maximize power production over the longer period. Thus for up to around 200 seconds, glycogen is still the major fuel, but now there is a significant aerobic contribution and blood glucose will also be expected to contribute. Under these conditions we expect power contributions from both types of muscle fiber. The second leg of our plot shows the gradual transition from fully anaerobic to aerobic metabolism as the power output decreases.
• 200 - 8000 s (3 - 133 min): Prolonged exercise requires a sustained aerobic pace. Thus marathon runners use essentially no anaerobic metabolism. As seen in the table below, muscle glycogen use is gradual and continues over the entire exercise period. Note also that liver glycogen contributes via the provision of blood glucose. Note also that over the study period of four hours fatty acid utilization increases up to about 60% of total energy use. When the carbohydrate stores are finally exhausted, exhaustion ensues as well, we need carbohydrate to sustain a high power output - fatty acids are not sufficient. (Why? Note P/O ratios and and the amount of oxygen needed for given power output.) The relative contributions of carbohydrate are reflected in the slope of the curve. In order to optimize power vs. time the athlete must adjust her pace so as not to run out of glycogen before the exercise period ends.

Fuel Utilization in Prolonged Exercise   Fuel O2 utilization   Fuel Concentrations in Blood (mM)   Blood-delivered Fuels Exercise Time (min) Muscle Glycogen Glucose Fatty Acid Glucose Lactate Fatty Acid Glycerol 0       4.5 1.1 0.66 0.04 40 36% 27% 37% 4.6 1.3 0.78 0.19 90 22% 41% 37%         180 14% 36% 50% 3.5 1.4 1.57 0.39 240 8% 30% 62% 3.1 1.8 1.83 0.48 Data from E. A. Newsholme & A. R. Leach (1983) Biochemistry for the Medical Sciences, John Wiley, NY. pp 370-372.

"Carbohydrate Stress" and Injury

Pathway Diagrams

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Last modified 25 February 2009