It's a common runner's complaint. Just when you've built up enough strength and endurance
to make running fun, those niggling aches and pains won't go away. Every time your
foot hits the ground, a force equal to about twice your weight shoots through your
body, eventually chipping away at bones, cartilage, muscles, tendons, ligaments, and
joints. For those lucky souls who can take the pounding, the main limitation to running
performance stems from muscle fatigue. Now, Randall Johnson and colleagues report
that a protein found in skeletal muscle profoundly influences muscle endurance.
Running, like any sustained skeletal muscle activity, consumes large quantities of
adenosine triphosphate (ATP), a molecule that fuels many essential cell processes.
A number of metabolic pathways supply muscle tissue with the ATP needed to power muscle
contraction and sustain ongoing exercise. Which pathway predominates depends on factors
like speed, duration, and type of activity, as well as on the availability of oxygen,
which fluctuates during activity. (For more on muscle cell type and endurance, see
the synopsis titled “Gene Targeting Turns Mice Into Long-Distance Runners.”)
Say you start a half-hour run with a sprint. Within a few seconds, your body uses
up the oxygen in its muscles and has to switch to anaerobic pathways, which metabolize
sugars and fats to regenerate ATP. Aerobic pathways operate inside mitochondria, the
cell's major power generators. Anaerobic pathways like glycolysis function in the
cytoplasm.
Hypoxia (the physiological state that occurs when oxygen levels drop below normal
levels) governs how ATP is recycled and which energy-producing substrates (for example,
glucose or fatty acids) are used; it also generates metabolic by-products, like lactic
acid, during strenuous exercise. (Runners know the “lactic acid burn” associated with
reduced blood pH.) Glycolysis—the primary source of anaerobic energy in animals—uses
glucose, stored as glycogen in muscle cells, to produce ATP. When blood oxygen levels
drop, the gene transcription factor hypoxia-inducible factor 1α (HIF-1α) triggers
the glycolytic pathway.
To understand how HIF-1α regulates skeletal muscle function, Johnson's team generated
mice that couldn't express HIF-1α in skeletal muscle. Normal and mutant mice went
through exercise routines that included swimming and running on treadmills. After
exercise, the normal mice had increased levels of gene transcripts and enzymes involved
in glucose transport and metabolism. In the mutant mice, expression of these glycolysis-associated
genes and enzymes was significantly lower. The mutants' ATP levels, however, were
normal. Without the molecular machinery to engage anaerobic metabolism, their muscles
switched to aerobic pathways. The presence of enzymes that respond to reduced ATP
levels by increasing mitochondrial ATP production, combined with low levels of lactic
acid, confirmed the switch.
During endurance tests, the mutants could swim and run uphill (on treadmills tilted
upward) longer than the normal mice, but when it came to running downhill, the normal
mice prevailed. Downhill running, it turns out, favors glycolytic metabolism; uphill
running and swimming favor oxidative pathways, which the mutants were predisposed
toward. But their inappropriate use of this pathway came at a cost. By the final day
of a four-day exercise routine, the mutants' run time was significantly shorter and
their muscles were clearly damaged.
The mutants displayed a number of the trademark muscle defects seen in human patients
with glycolytic processing disorders. These patients often have reduced lactate levels
and elevated levels of mitochondrial enzymes, which apparently can cause a second
wind and enhance endurance. This inappropriate use of oxidative pathways—which compensates
for the inability to trigger glycolysis—may account for the exercise-induced muscle
damage associated with these diseases.
These results demonstrate that losing the molecular wherewithal to engage hypoxia
response pathways has serious consequences for muscle function during exercise; it
can give increased endurance, but at a high price. The mouse model presented here
will help researchers explore how muscles normally function in response to low oxygen
and how metabolic deficiencies cause debilitating muscle disease.