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So what are these mitochondria that take care
of our needs for aerobic respiration? They
are a bacterium sized organelle with its own
genetic material found within the cytoplasm of
our cells. The endosymbiotic theory states
that mitochondria were likely at one point an
independent aerobic bacterium which found a home
within a larger eukaryotic cell (Alberts et al.,
2002). This partnership was then favored
by natural selection and resulted in a
proliferation of larger organisms which required
and could utilize the metabolic power of aerobic
respiration. This symbiotic relationship
has evolved to such an extent and economized so
much that some of the mitochondrial genetic
material has been transferred to our nuclear
genome, and the function of both genomes have
become greatly interdependent (Virbasius, 1994).
As an aside, we inherit our mitochondria and our
mitochondrial DNA from our mothers due to their
residence in the cytoplasm.
Mitochondria
have two membranes; an outer membrane and an
inner membrane. The inner membrane is
folded extensively into structures called
cristae, which create a large surface area for
the chemistry responsible for aerobic
respiration. This chemistry occurs on both
sides of, and within the inner mitochondrial
membrane. ATP is eventually produced on
the inner surface of this membrane and is then
sent outside of the mitochondria to fuel the
cell’s energy demands.
Endurance
exercise is a strong stimulus for the
proliferation of mitochondrial enzymes.
The increase in mitochondrial density is
associated with an increase in the duration one
can perform endurance exercise and the ability
to spare total body glycogen stores (Fittz et
al., 1975). Generally, more lipids are
used to generate ATP as a result of the
increased mitochondrial density in response to
exercise. A large body of research
suggests that the enhancement of mitochondrial
density in skeletal muscle is a key component in
the development of performance in endurance
sport. In a general sense, building more
mitochondria allows an athlete to function
closer to their potential.
How does one ramp up mitochondrial density?
First, let’s take a quick look at what tells
mitochondria to up-regulate. Recent
research has begun to identify the signaling
that initiates the chains of enzymatic reactions
which turn on the combination of nuclear and
mitochondrial genes responsible for
mitochondrial biogenesis. It appears that
at least two significant signals exist, and that
potentially these signals work together.
Cytosolic calcium concentrations are one of
these signals.
Research suggests that simply an increase in the
concentration of calcium within the cells of
skeletal muscle, something which happens with
each muscle contraction, is capable of inducing
mitochondrial protein synthesis. This
increase in calcium is suggested to activate an
enzyme called calcium-calmodulin kinase (CAMK)
which then plays a role in the expression of
mitochondrial biogenesis associated proteins
such as PGC-1, NRF-1, NRF-2, and mtTFA (Ojuka et
al., 2003). However, it appears that not
all of the proteins necessary for mitochondrial
biogenesis are activated by calcium signaling
alone (Devin, 2004).
The other apparently essential and dominant
signal necessary to incur mitochondrial
biogenesis appears to be a reduction in cellular
concentrations of high energy phosphates such as
ATP and phosphocreatine. Decreases in the
concentrations of these molecules are generally
associated with the inability of aerobic
respiration to maintain them during high
intensity exercise. Research in this area
suggests that a reduction in the cellular
concentrations of these high energy phosphates
activates an enzyme called 5’-AMP activated
protein kinase (AMPK), which is closely related
to CAMK. Activation of this enzyme
apparently plays a critical role in
mitochondrial biogenesis (Winder et al., 2000;
Zong et al., 2002). Interestingly, this
enzyme also plays a role in the genetic
expression of vascular endothelial growth factor
(Ouchi et al., 2005), a key component in the
induction of angiogenesis or the development of
the new blood vessels needed to supply
mitochondria with oxygen. The current
knowledge regarding the genetic signaling
necessary for overall mitochondrial
up-regulation suggests that it may be necessary
for mitochondrial uncoupling to occur, or when
ATP consumption outpaces ATP production during
intense exercise (Devin, 2004).
Research has also been done which investigated
mitochondrial enzyme concentration responses to
different exercise stimuli. It has been
demonstrated that in all muscle fiber types,
exercise durations longer than about sixty
minutes at controlled intensities, do not result
in significant, additional mitochondrial enzyme
densities (Dudley et al., 1982). This
research perhaps also supports the notion that
calcium signaling has a limited role in the
induction of mitochondrial biogenesis given the
rapidly diminishing returns when muscle
contractions are continued. Dudley et al.
also demonstrated that very high exercise
intensities (approaching and exceeding VO2max)
performed as intervals with cumulative durations
of less than thirty minutes per day increased
mitochondrial enzymes similarly to longer
durations at lower intensities in both slow
twitch and fast twitch muscle. This result
suggests that mitochondrial density adaptations
can be achieved in a reasonably duration
independent manner (Dudley et al., 1982).
The overall higher mitochondrial densities
associated with the higher intensities outlines
the potential need for mitochondrial uncoupling
and the AMPK signaling, at least beyond the
completely untrained state. It is
interesting to note that Dudley et al. also
discussed in the cited research that a limiting
factor in the slow twitch muscle fiber
respiratory capacity development measured at the
extremely high intensities tested was likely the
mode of exercise and not the intensity of the
exercise. The test subjects were running
at very high speeds which required extreme
muscle contraction velocities which may have
been beyond the ability of the slow twitch
fibers to produce sufficient tension.
Therefore, the slow twitch fibers may not have
been overloaded enough to fully adapt (Dudley et
al., 1982). On a bicycle, muscle
contraction speeds are essentially a non-factor
due to the use of gears. Interestingly,
research has also shown that extremely short but
intense exercise bouts (~ 30 second all out
sprints) can increase the respiratory capacity
of whole muscle and overall endurance
performance (Burgomaster et al., 2005).
So what does this all mean in terms of practical
application to the development of cycling
training programs? First of all, it means
that rides over an hour in duration will not
necessarily improve mitochondrial density and
the respiratory capacity of skeletal muscle.
These generally lower intensity rides, which are
often suggested to be an essential part of
building one’s aerobic engine, are not
inevitably more productive than an hour long
ride at the same intensity. Intuitively,
this does make some sense. If one can
already meet the rate of ATP demand with aerobic
respiration, as suggested by already having the
ability to sustain such intensities for that
long or longer, there is not likely to be much,
if any, effective stimulus for mitochondrial
development. Additionally, intensities
approaching or exceeding VO2max, or in cycling
power terms above approximately 95% of one’s 20
minute maximal power (20MP), appear to be
required in order to elicit the largest
concentrations of total mitochondrial enzymes.
This is likely a combined result of additional
motor-unit recruitment with increasing intensity
and mitochondrial uncoupling in the
progressively oxygen limited environment found
when closing in on the limits of oxygen
delivery. Aerobic metabolism of a variety
of organic molecules is not up to the job of
energy production, and more mitochondria are
needed to fill the demands.
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In general, it appears that in order to push
mitochondrial densities to their maximum when
building one’s aerobic engine, it would be wise
to regularly include intensities which approach
VO2max or harder, or about 20MP or harder, on a
regular basis within an overall training
program. Perhaps, this can reasonably be
broken down into 2-3, one or so hour rides per
week with 20MP+ intervals as long as possible
for a given intensity, accumulating 10-30
minutes per day. If time and weather
permits, this can be augmented by 1-2 rides per
week of event specific training. This
generalization obviously does not require a
large time investment, but it does require that
one train intensely. Long, easy rides or
larger volumes of moderate intensity (ie. tempo
training) do not appear to be required for
maximal mitochondrial adaptation. These
types of training have a limited ability to
induce the metabolic stresses required to elicit
additional mitochondrial and vascular
development with perhaps the exception of a very
short period if beginning from a completely
untrained state
In particular, long, exclusively easy rides do
not appear to effectively promote mitochondrial
development and/or bolster the size of one’s
aerobic engine. The process of building a
bigger aerobic engine appears to be skewed
towards an accumulation of high intensity
training over time. Eventually though, it is
largely the ability to deliver oxygen to our
mitochondria which limits the rate at which our
mitochondria can generate ATP from the variety
of organic molecules that can be oxidized.
Without adequate oxygen, the chemical reactions
involved in aerobic respiration are impaired.
The primary reason our aerobic engines can only
be so big is because our cardiac output and our
blood’s oxygen carrying capacity can only be so
good!
Once one gets beyond engine size, there are
other factors which can influence performance.
One cannot expect to have reached their
performance potential in extremely long
endurance events on a diet of exclusively one
hour rides with high intensity intervals.
The targeting of an event’s expected, more
specific demands, such as a combination of the
total work and the distribution of that work, is
likely to be of benefit. In at least the
weeks leading up to target events, an additional
1-2 rides per week can augment the 20MP+
training discussed above. It may be that
these days are combined with the 20MP+ work.
For example, if one is targeting an event
expected to require 4000kj’s, it would be wise
to include some training in preparation for the
event which approximates those demands, even if
such training is not likely to be helpful in
building a larger aerobic engine.
The next time you are out there training, think
about your mitochondria sucking up that oxygen
and powering your body. They are your
friends…diligently providing the matrix a
portion of the enzymes responsible for the
chemical reactions which power your muscles.
It would also be a good idea to think about how
to efficiently get more of them when trying to
build your aerobic engine as big as it can be.
Generally, you have to go hard to make them
grow! The bigger the engine, the faster one can
go! Train hard, rest hard, train hard
again, and have fun along the way!
References
Alberts, Bruce, Alexander Johnson, Julian Lewis,
Martin Raff, Keith Roberts, and Peter Walter.
(2002). Molecular Biology of the Cell (4th ed.).
New York: Garland Science.
Burgomaster, Kirsten A., Scott C. Hughes, George
J.F. Heigenhauser, Suzanne N. Bradwell, and
Martin J. Gibala. Six Sessions of Sprint
Interval Training Increases Muscle Oxidative
Potential and Cycle Endurance Capacity in
Humans.
J Appl Physiol. Jun; 98 (6): 1985-90.
Devin, Anne and Michael Rigoulet. (2004).
Regulation of Mitochondrial Biogenesis in
Eukaryotic Cells. Toxicology Mechanisms and
Methods. 14: 271-279.
Dudley, G. A., W.M.
Abraham, and R. L.
Terjung. (1982). Influence of exercise
intensity and duration on biochemical
adaptations in skeletal muscle.
J Appl Physiol. Oct; 53 (4):844-50.
Fitts, R. H., F. W. Booth, W. W. Winder, and J.
O. Holloszy. (1975). Skeletal Muscle Respiratory
Capacity, Endurance, and Glycogen Utilization.
Am J Physiol. 1975 Apr; 228 (4): 1029-33.
Gastin, Paul B. (2001). Energy system
interaction and relative contribution during
maximal exercise.
Sports Med. 2001;31(10):725-41.
Ojuka, Edward O., Terry E. Jones, Dong-Ho Han,
May Chen, and John O. Holloszy. (2003). Raising
Ca2+ in L6 myotubes mimics effects of exercise
on mitochondrial biogenesis in muscle.
FASEB J. Apr; 17(6):675-81.
Ouchi, Noriyuki, Rie Shibata, and Kenneth Walsh.
(2005). AMP-activated protein kinase signaling
stimulates VEGF expression and angiogenesis in
skeletal muscle. Circulation Research. 96:
338-346.
Virbasius, Joseph and Richard Scarpulla. (1994)
Activation of the human mitochondrial
transcription factor A gene by nuclear
respiratory factors: a potential regulatory link
between nuclear and mitochondrial gene
expression in organelle biogenesis.
Proc Natl Acad Sci U S A. 1994 Feb 15;
91(4):1309-13.
Winder, W. W., B. F. Holmes, D. S. Rubink, E. B.
Jensen, M. Chen, and J. O. Holloszy. (2000).
Activation of AMP-activated protein kinase
increases mitochondrial enzymes in skeletal
muscle. J Appl Physiol. Jun; 88 (6):
2219-26.
Zong, Haihong, Jian Ming Ren, Lawrence H. Young,
Marc Pypaert, James Mu, Morris J. Birnbaum, and
Gerald I. Shulman. (2002). AMP kinase is
required for mitochondrial biogenesis in
skeletal muscle in response to chronic energy
deprivation. Proc Natl Acad Sci U S A. December
10; 99(25): 15983–15987.
About our Contributor:
Kirk Willett, is a twenty-year+ participant
in the sport of cycling who has competed in 17
different countries on 5 different continents.
Originally from Pullman, Washington, his racing
career has ranged from his roots as a Pacific
Northwest junior and amateur competitor to time
with the U.S. National Team and then on to
professional competition as a member of the
Mercury Cycling Team including events such as
the Tour of Switzerland. He was also a
director with the Mercury Cycling Team and then
directed the Prime Alliance professional team
full-time from 2001 through 2003. He has
also been a coach and advisor to members of both
the Mercury and Prime Alliance professional
teams in addition to other Pacific Northwest
athletes.
Kirk is currently a medical student attending
Oregon Health Sciences University building on his exercise
science education from Washington State
University. He resides in Portland, Oregon
with his wife Tina and two sons. He is a
strong advocate for clean, ethical sport and
encourages all athletes to take the same pledge
he did as a young amateur: “I will never
participate in doping no matter what I stand to
gain.
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