Mitochondrial
DNA and Maximum Oxygen Consumption Matthew B Brearley, Shi Zhou School
of Exercise Science and Sport Management, Southern Cross University, Lismore,
NSW 2480, Australia. Email: matt.brearley=AT=nt.gov.au Sportscience
5(2), sportsci.org/jour/0102/mbb.htm, 2001 (1775 words) Reviewed by Ronald JA Trent, Department of
Molecular & Clinical Genetics, University of Sydney, Sydney, NSW 2006,
Australia Mitochondrial
DNA contains genes for 13 mitochondrial proteins involved in oxygen
consumption. Variation in the DNA sequence of these genes could therefore
contribute to the differences in endurance performance between individuals.
Recent studies have provided conflicting data on the relationship between
mitochondrial DNA and an important factor influencing endurance performance,
maximum oxygen consumption. The conflict may arise from poorly controlled
maternal ethnicity or population differences between studies. Reprint pdf · Reprint doc
KEYWORDS:
displacement loop, gene, mtDNA, polymorphism, VO2max |
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Most of the energy for endurance exercise
comes from oxidation of fuel. The maximal capacity of an individual to
consume oxygen is therefore one of the important factors limiting endurance
performance. The effect of training on maximum oxygen consumption (VO2max)
has been a major focus of researchers, but increased attention is now turning
to the effect of genes. The early researchers addressing the contribution of
inheritance to aerobic performance suggested that individual differences in
VO2max were determined primarily by genetic factors (Klissouras, 1971).
Subsequent investigations have demonstrated a substantial but lesser effect
of heritability on VO2max of sedentary individuals (Bouchard et al., 1998)
and on the response of VO2max to training (Bouchard et al., 1999). Current
estimates of heritability span the range of 20 to 50%. Additionally, a
maternal influence for VO2max has been observed (Lesage et al., 1985). This
field of research forms the foundation for molecular investigations that aim
to identify genetic markers associated with the heritability of aerobic
performance--in essence, relating genotype to phenotype. Such investigations
are in their infancy, and no clear relationships have been established
between specific genetic markers and elite performance, as noted by Hagberg
et al. (2001) in a recent review. It is well known that different individuals
have different DNA sequences. Collectively, DNA sequence differences
occurring in more than 1% of the population are termed polymorphisms, or
morphs. Morphs may account for some of the differences in performance
capacity between individuals (phenotypic variance), including VO2max.
Research in this area has focused on mitochondrial DNA sequences, genes for
creatine kinase, and genes for angiotensin converting enzyme (see Hagberg et
al., 2001, for review). Mitochondrial DNA is of particular interest, because
it contains the genes for several enzymes involved in oxygen consumption, and
it is inherited only from the mother. Investigations of the relationship
between mitochondrial DNA and VO2max are the focus of this article. Aerobic
energy production involves the metabolic pathway for oxidative
phosphorylation, particularly the electron transport chain in mitochondria.
Mitochondrial DNA contains genes for 13 proteins of the electron transport
chain as well as 22 transfer RNAs and two ribosomal RNAs required for their
intra-mitochondrial synthesis (Shadel and Clayton, 1997). Theoretically,
variations within these genes and/or their associated regulatory regions
could affect the passage of electrons and
hydrogen ions through the electron transport chain to oxygen, thereby
altering the capacity for energy production. The first report to address the association
between mitochondrial DNA sequences and aerobic performance was by Dionne et
al. (1991). Through a 20-week endurance-training program, the authors
assessed the relationship of baseline VO2max and its response to training
with mitochondrial DNA morphs detected by 22 restriction enzymes. The subjects were 46 North Americans who
were sedentary at the time of the study. Of the variants identified, those
subjects harboring a morph in the gene encoding Subunit 5 of NADH dehydrogenase
demonstrated a significantly lower training response for VO2max. Additional
morphs located in the gene for Subunit 5 of NADH dehydrogenase, a transfer
RNA gene for threonine, and one morph in the regulatory region of
mitochondrial DNA known as the displacement loop (D-loop), demonstrated
significant relationships to the training responses of VO2max. Subsequently,
Rivera and colleagues (1997) measured the frequency of each of the three
morphs identified within the NADH dehydrogenase gene and of one morph of the
D-loop in 125 elite endurance athletes and in 65 sedentary controls. They found
no significant difference in the frequency of these morphs between the two
groups. However, the interpretation of such results may be limited by the
ancestral origin of the subjects. The elite group included Caucasian
endurance athletes from three continents, whereas the control group consisted
of Caucasian Americans and Canadians. The ancestral data from Dionne et al.
(1991) were less complete, as their subject population comprised French
Canadian and other subjects of unstated ethnicity. Furthermore, it is unclear
whether the ancestral origin reflects the maternal origin of subjects from
these investigations. Recent
Chinese studies (Chen et al., 2000; Ma et al., 2000) have involved subjects
with well-defined maternal ethnicity. The researchers focused on the D-loop,
which contains factors that modulate mitochondrial DNA replication and
transcription (Shadel and Clayton, 1997). In the study of Chen et al. (2000),
the morphs within the D-loop generated by four restriction enzymes (which
fragment the DNA reproducibly) were examined in a sample of 120 Chinese
subjects consisting of 67 elite endurance athletes, 33 general endurance
athletes, and 20 sedentary controls. There were nine morphs, and their
frequencies were significantly different between the three groups. Ma and
colleagues (2000) used the same enzymes and investigated the occurrence
frequencies of eight morphs in 27 junior female athletes. Carriers of three morphs
showed higher values of VO2max. These authors suggested that this apparent
association between mitochondrial DNA D-loop polymorphism and endurance
capacity needs confirmation. Chen et al. (2000) suggested that a better
relationship might exist between the mitochondrial DNA morphs and endurance
performance rather than VO2max. In light
of the findings from the Chinese cohort and the paucity of genetic data
available for Australian athletes, our laboratory has investigated the
relationship between mitochondrial DNA D-loop morphs (generated by the four
restriction enzymes) and VO2max of 40 well-trained Australian male endurance
cyclists (for methodology see Brearley et al., 2001). These cyclists were
selected by a questionnaire screening for European maternal ethnicity,
because European populations have very similar mitochondrial DNA sequences.
(Melton et al., 1994). There was no significant association between VO2max
and the D-loop morphs in this population of athletes. We also used three more
restriction enzymes to analyze genetic sequences within the D-loop, but we
found no new sequence variations. Our
findings are in agreement with the reports of Dionne et al. (1991) and Rivera
et al. (1998), who found no significant relationship between D-loop morphs and
either sedentary VO2max or elite endurance athlete
status.
The discrepancy between these findings and those of Chen et al. (2000)
and Ma et al. (2000) may be related to the ethnic differences between the
subjects, because the D-loop region is known to vary between populations
(Horai and Hayasaka, 1990). Also, in our study and that of Ma et al. (2000)
the small sample sizes do not allow firm conclusions about the presence or
absence of small effects. To date, only
7% of the D-loop region and 4% of the mitochondrial DNA genome have been
analysed in athletic populations. These investigations (Brearley et al. 2001;
Chen et al. 2000; Ma et al. 2000) have added new evidence, although
conflicting, to the hypothetical relationship between mitochondrial DNA sequence,
endurance performance, and VO2max. If the
relationship between mitochondrial DNA polymorphisms and aerobic performance
and/or responsiveness to training turns out to be substantial, the next
challenge will be to explain how this relationship ties in with factors
limiting VO2max. There is some evidence that VO2max in athletes is limited by
the ability to deliver oxygen to the muscles, rather than the ability of
muscles (and therefore mitochondria) to utilize oxygen (Bassett and Howley,
2000; Richardson et al., 1999). However, mitochondrial function could still
be closely related to the trainability of VO2max in previously sedentary
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Reviews of Biochemistry 66, 409-435 Edited and Webmastered by Will Hopkins. |