Myoglobin: an essential hemoprotein in striated muscle
1 Department of Physiology, University of Texas Southwestern Medical Center,
Dallas, TX 75390, USA
2 Department of Internal Medicine, University of Texas Southwestern Medical
Center, Dallas, TX 75390, USA
3 Department of Molecular Biology, University of Texas Southwestern Medical
Center, Dallas, TX 75390, USA
* Author for correspondence (e-mail: george.ordway{at}utsouthwestern.edu)
Accepted 30 June 2004
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Summary |
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Key words: myoglobin, hemoprotein, skeletal muscle, cardiac, myocyte, function, regulation, gene targeting
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Introduction |
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Structural elegance |
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The structure of myoglobin was first delineated by John Kendrew and
colleagues over 40 years ago (Kendrew et al.,
1958,
1960
;
Kendrew, 1963
). Subsequent
work has shown that the myoglobin backbone is a polypeptide chain that
consists of eight
-helices assigned the letters AH
(Fig. 3A). Myoglobin binds
oxygen by its heme residue, a porphyrin ring:iron ion complex. The polypeptide
chain is folded and cradles the heme prosthetic group, positioning it between
two histidine residues, His64 and His93. The iron ion interacts with six
ligands, four of which are provided by the nitrogen atoms of the four pyroles
and share a common plane (Fig.
3B). The imidazole side chain of His93 provides the fifth ligand,
stabilizing the heme group and slightly displacing the iron ion away from the
plane of the heme. The sixth ligand position, unoccupied in deoxymyoglobin,
serves as the binding site for O2, as well as for other potential
ligands such as CO or NO. When O2 binds, the iron ion is partially
pulled back toward the porphyrin plane. Although this displacement is of
little consequence in the function of monomeric myoglobin, it provides the
basis for the conformational changes that underlie the allosteric properties
of tetrameric hemoglobin. In addition, studies using X-ray diffraction and
xenon-binding techniques have identified four highly conserved internal
cavities within the myoglobin molecule that may serve to concentrate and
orient molecules for binding to the heme residue
(Frauenfelder et al.,
2001
).
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Functional roles |
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PO2 buffering
Related to its role as a tissue reservoir of O2, myoglobin has
been proposed to also serve as a buffer of intracellular
PO2 in a number of species including the human,
rodent and bovine models. Similar to the role of creatine phosphokinase, which
functions to buffer ATP concentrations when muscle activity increases,
myoglobin functions to buffer O2 concentrations under similar
conditions (Hochachka, 1999;
Meyer et al., 1984
). As a
result, the intracellular concentration of O2 remains relatively
constant and homogeneous despite dramatic activity-induced increases in
O2 flux from capillary to mitochondria. Myoglobin saturation has
been shown to decrease rapidly at the onset of muscle activity and reach its
nadir (3060%) at approximately half-maximal levels of work
(Richardson et al., 1995
). As
work increased to maximal effort, however, myoglobin saturation remained
relatively constant, indicating that O2 concentration was likewise
relatively constant (Richardson et al.,
1995
). By contrast, Molé et al.
(1999
) showed that, although
myoglobin saturation was approximately 48% at peak muscle O2
consumption, the degree of desaturation increased linearly as a function of
muscle work output. Irrespective of this difference, these studies indicate
that myoglobin may provide a source of readily available O2 at the
onset of exercise and increase the PO2 gradient
from capillary to muscle cell even at low levels of activity, suggesting that
myoglobin has a role that is intermediate between two other functions,
O2 storage and facilitated O2 diffusion.
Facilitated O2 diffusion
A third role purported for myoglobin is facilitated or myoglobin-mediated
O2 diffusion. As indicated, myoglobin desaturates rapidly at the
onset of muscle activity, increasing the PO2
gradient from capillary blood to cytoplasm. Furthermore, it has been proposed
that desaturated myoglobin close to the cell membrane then binds O2
and diffuses to the mitochondria, providing a parallel path that supplements
simple diffusion of dissolved O2 (Wittenberg,
1959,
1970
). Compelling theoretical
and experimental evidence has been presented for
(Conley and Jones, 1996
;
Merx et al., 2001
;
Murray, 1971
;
Salathe and Chen, 1993
) and
against (Jürgens et al.,
1994
; Papadopoulos et al.,
2001
) this purported role for myoglobin, so its contribution to
overall O2 flux in exercising muscle remains equivocal.
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Genetic regulation and expression patterns |
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It's nice to have but is it necessary? |
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Following birth, the myoglobin knockout mice showed no apparent phenotype
other than depigmentation of the heart and soleus muscles
(Fig. 5B;
Garry et al., 1998;
Gödecke et al., 1999
).
They grew normally, were able to perform exhaustive treadmill exercise and
responded normally to a hypoxic challenge
(Garry et al., 1998
). In
addition, skeletal muscles and hearts isolated from the knockout mice were
equal to those from their wild-type counterparts in studies of contractile
function in the presence or absence of O2
(Garry et al., 1998
;
Gödecke et al., 1999
).
Although there were no apparent disruptions of sarcomere structure or
mitochondrial content, a number of cardiac adaptations were seen that favored
improved O2 delivery in the absence of myoglobin
(Gödecke et al., 1999
).
These included increases in capillarity, coronary flow and hematocrit.
Subsequent studies have confirmed these cardiac adaptations and shown that
they occur in skeletal muscle as well
(Grange et al., 2001
;
Meeson et al., 2001
). In
addition, myoglobin-deficient mice demonstrate increased expression of a
number of hypoxia-inducible genes (hypoxia-inducible factors 1 and 2, vascular
endothelial growth factor, nitric oxide synthase, etc.) that may provide the
molecular basis for the cellular adaptations observed in the muscles of these
knockout animals (Grange et al.,
2001
; Meeson et al.,
2001
). Studies are in progress to determine whether previously
undescribed tissue hemoproteins may further compensate and preserve
contractility in the absence of myoglobin.
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Emerging functional roles |
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Future studies will be necessary to further define the functional role(s)
for myoglobin in oxidative skeletal muscle. For example, important questions
regarding myoglobin biology that remain unanswered include: what are the
genetic factors that regulate myoglobin expression in response to an acute or
chronic hypoxic stimulus; is the transcriptional regulation of myoglobin a
hypoxia inducible factor (HIF-1)-dependent mechanism; does the
induction of myoglobin expression in response to hypoxia require muscle
activity (i.e. swimming, running, etc.)? Moreover, the recent identification
of additional tissue hemoglobinsneuroglobin and
cytoglobinsuggests a physiological model in skeletal muscle that is
increasingly complex and fluid regarding the role of tissue hemoglobins and
muscle biology.
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Nice to have and necessary |
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Acknowledgments |
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References |
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