I am finally back from a very busy semester.  I taught physiology classes at Mills College and UC Berkeley this semester, so I have been interested in new topics in human physiology.  This week’s paper by Schippers et al. came out recently in Current Biology and describes adaptations that mice must make in order to live at high altitude.  They compared the metabolism of mice that live at 4000m above sea level in the Andes where the oxygen content of air is about 13%, to mice at sea level, which contains 21% oxygen.  We all know from experience that we need oxygen to survive and it’s harder to exercise at high altitudes, but why do our bodies actually need oxygen?

Oxygen in cellular respiration
Most all physiology can be explained by the following equation, which describes the process of cellular respiration:
Glucose + 6 Oxygen (O2) –> 6 Carbon dioxide (CO2) + 6 Water (H2O) + 34 ATP
Glucose is a simple carbohydrate (sugar) that we use as a direct energy source.  Glucose, which is 6 carbons long, gets broken down step by step in a series of chemical reactions.  At each step, a little bit of energy is released by the reaction and that is stored in carrier molecules.  These carriers then donate the energy in the form of electrons, which is then harnessed to make another molecule called ATP.  ATP is cellular energy.  The chemical bonds in ATP store high energy and can be used to drive other cellular reactions, like pumping ions, or the process that causes muscle contraction.  Without ATP we die. 
But what does oxygen have to do with this?  Well, the electrons that are donated by the carrier molecules must hop from protein to protein in what is known as the “electron transport chain”.  The final electron acceptor is oxygen (O2), which forms water with that extra electron.  That’s it.  That’s why we breathe, that’s why our heart pumps blood— our tissues need energy (ATP) to perform cellular tasks and in order to get energy from glucose, we need oxygen to accept the final electron.  Carbon dioxide is produced as a byproduct and is removed from the body during exhalation.
Glycolysis is anaerobic respiration and does not use oxygen. Note that oxygen is used as the last step of the electron transport chain to make the majority of the ATP. (www.phschool.com/science/biology_place/biocoach/cellresp)
I should also mention here that the more our tissues are active and working, the more ATP they need and the more O2 needs to get to the cells.  When we exercise our muscles are very active, so that’s why the heart rate and breathing rate increase; our body needs to intake more oxygen and distribute it faster to our muscles.
You can see that oxygen plays a critical role in our cells, so the mice at high altitudes are going to have a harder time getting their cellular energy.  How do they manage to run around when there is so little oxygen?
Energy sources
As I mentioned above, we can make ATP directly from glucose (a carbohydrate).  We can also make ATP by using fats as an energy source.  There are two differences between these two energy sources:
1) When we use fats as an energy source, it always requires oxygen.  Glucose, on the other hand, can make a limited amount of ATP without oxygen, which is called anaerobic respiration.  This is useful during short vigorous activity, but we cannot make enough ATP by anaerobic respiration for sustained exercise.
2) For a given amount of oxygen, more ATP is produced from carbohydrates, like glucose, than from fats.  However, the amount of ATP created from a single fat molecule is greater than from a glucose molecule.  In other words, if you have plenty of oxygen, you should be burning fats.  But once oxygen becomes limiting, either because you’re working so hard, or because you’re at a high altitude, then carbohydrates should be used.
Given this information, the authors hypothesized that the mice at high altitudes will burn more carbohydrates than mice at sea level.  They have a limited amount of oxygen in the air, so they need to use it in the most efficient way to produce the energy they need.
High altitude mice burn more carbohydrates, but fatigue sooner
The authors did all their tests in the same experimental conditions, with the same amount of oxygen in the air for both sets of mice.  Under normal oxygen conditions and when there was low oxygen content, the high altitude mice burned more carbohydrates than the other mice during moderate exercise.  At rest, they also burned more carbohydrates under low oxygen conditions.  The authors found that the activity of enzymes associated with breaking down carbohydrates were greater in the high altitude mice, specifically in the heart muscles.  The heart has to work harder at high altitude to get enough oxygen to the tissues, so it makes sense that these muscles, in particular, would be burning carbohydrates preferentially. 
The high altitude mice, therefore, have adapted to the low oxygen environment by having more active enzymes to break down carbohydrates rather than fats.  One problem with that, though, is that the carbohydrate storage is less extensive than fat storage.  The researchers found that high altitude mice fatigued more quickly than the sea level mice, which burned more fats.  They suggest that the fast fatigue is a result of using up all the carbohydrate stores.  These mice, though, don’t travel long distances and just need short bursts of speed to escape predators.
I really like how so many physiological processes can be explained through understanding cellular respiration.  It’s so logical that animals at high altitude need to use oxygen more efficiently, so they use carbohydrates more for energy.  It’s simple.

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