Shaken and stirred: muscle structure and metabolism
Department of Ecology, Evolution and Marine Biology, University of California, Santa Barbara, California 93106-9610, USA
e-mail: suarez{at}lifesci.ucsb.edu
Accepted 13 March 2003
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Summary |
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Key words: muscle structure, metabolism, intracellular, myofibril, diffusion, glycolysis, channelling, kinetics, regulation, creatine kinase
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Introduction |
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In cardiac and locomotory muscles, the transition from rest to exercise is
accompanied by an increase in the rate of cellular ATP hydrolysis, brought
about by the activation of actomyosin ATPase and, to a variable extent,
Ca2+-ATPase and Na+-K+-ATPase. Bioenergetic
pathways are regulated such that ATP is synthesized at rates that match
hydrolysis rates. The stoichiometric matching of rates of synthesis and
hydrolysis allows the maintenance of contractile function. Bouts of exercise
may vary in both duration and intensity, and many species of animals possess
fiber types specialized in structure and biochemical properties to serve their
particular needs. Brief (e.g. 12 s) bouts of exercise may be
accompanied by the hydrolysis of relatively small amounts of ATP. Under these
circumstances, ATP concentration is maintained (over time, thus, the term
`temporal buffering') at the expense of creatine phosphate (CrP) in
vertebrates or arginine phosphate (or other `phosphagens') in the
invertebrates, via reactions catalyzed by creatine kinase (CK) or
other phosphagen kinases. High-intensity, `burst' exercise, sustainable for up
to several minutes in some species, involves the recruitment of muscles with
low oxidative but high glycolytic capacities. Under these conditions, ATP is
derived primarily from glycolysis, and the flux rate from glycogen to lactate
may increase up to several hundredfold higher than at rest. During prolonged,
steady-state exercise performed by hearts and aerobic locomotory muscles, the
energy requirements are met mainly by mitochondrial oxidative phosphorylation
(Suarez, 1996).
Muscle fibers appear to be crammed full of myofibrils, enzymes, mitochondria, nuclei and intracellular membranes. It is appropriate to begin this analysis by considering whether there are functional consequences to accommodating these components in various proportions.
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Intracellular space and muscle design |
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![]() | (1) |
At a given cell volume, fractional volumes of mitochondria and SR can only
increase at the expense of sarcomere volume. Thus, with increasing operating
frequency and the accompanying increases in capacities for Ca2+
cycling and oxidative phosphorylation, Pv would
be expected not to increase linearly with f, but instead to reach an
asymptote and to decline (Pennycuick and
Rezende, 1984). Theory suggests, therefore, that availability of
intracellular space should impose limits upon the enhancement of capacities
for Ca2+cycling and aerobic ATP synthesis. This is, in fact,
observed in cardiac and locomotory muscles, where mitochondrial volume
densities generally do not exceed about 45%
(Suarez, 1996
); higher values
are found in highly modified muscles that perform no mechanical work (e.g.
billfish heater organs; Block,
1991
).
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Molecules' eye views of sarcoplasm |
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A small molecule's perspective
In general, intracellular diffusion can be retarded by the (1) viscosity of
the fluid medium, (2) crowding and (3) binding of molecules to intracellular
structures (Verkman, 2002).
The viscosity of the sarcoplasm of skeletal muscle fibers is not very high,
and the resulting effect on the diffusion of high-energy phosphate compounds
is relatively modest. Using pulsed gradient 31P-NMR spectroscopy
and restricting measurements to short diffusion times, Hubley et al.
(1995
) determined that the
radial diffusion coefficients of ATP and CrP (DATP and
DCrP, respectively) are 30% and 34% less than in aqueous
solutions of similar ionic composition. DATP and
DCrP values approximately 50% lower than in water were
obtained by Yoshizaki et al.
(1990
), values consistent with
slightly higher estimates of sarcoplasmic viscosity (approximately 2.3 times
that of water; Arrio-Dupont et al.,
1996
). The intracellular diffusion of low-molecular mass
metabolites in skeletal muscles, studied using pulsed gradient
31P-NMR spectroscopy, is both time- and orientation-dependent.
Kinsey et al. (1999
) found
that in fast-twitch glycolytic (white) fibers, DCrP values
for radial diffusion declined over time, whereas values for axial diffusion
were only slightly affected. In slow-twitch oxidative (red) fibers,
DCrP values for both radial and, to a lesser degree, axial
diffusion declined with time. It was inferred from these results that,
although CrP diffusion is not impeded by myofilaments, the SR and mitochondria
act as physical barriers to its diffusion. The low mitochondrial volume
density of white fibers result in the SR being the only significant barrier
(to radial diffusion), while the presence of significant volume densities of
both SR and mitochondria in red fibers result in the time-dependent decline of
both radial and axial DCrP values. Nevertheless, these
DCrP values declined by only 50% and are still 23
orders of magnitude greater than cytoplasmic diffusion coefficients
(Dcyt) of macromolecules.
A large molecule's perspective
The diffusion of macromolecules in muscles has been studied using a variety
of techniques, including measurement of the rate of glycolytic enzyme leakage
from mechanically skinned fibers (Maughan
and Lord, 1988; Maughan and
Wegner, 1989
), as well as microinjection of myoglobin (Mb) into
muscle fibers and micro-spectrophotometry to measure time-dependent changes in
Mb absorbance (Papadopoulos et al.,
1995
). Alternatively, cytoplasmic diffusion coefficients
(Dcyt) of inert, fluorescently labeled macromolecules or
proteins of various molecular masses have been estimated. In one such study
(Arrio-Dupont et al., 1996
),
fluorescein isothiocyanate-labeled dextrans of various molecular masses were
microinjected into cultured myotubes, and Dcyt values
estimated by a photobleaching technique. Diffusion coefficients in aqueous
medium (Dw) were estimated in parallel experiments. As in
the case of ATP and CrP, Dcyt values for dextrans are
consistently lower than Dw. Dextrans in aqueous solution,
however, assume random-coil conformations and do not behave as compact
spheres, and their hydrodynamic radii are higher than those of globular
proteins of equal molecular mass. Taking this into account, relative diffusion
coefficients (Dcyt/Dw), plotted
against hydrodynamic radii Rh, decline with increasing
Rh. These results compare favourably with predictions of
model calculations that take into account both the crowding effect of soluble
proteins in the fluid medium and screening effect of myofilaments
(Arrio-Dupont et al.,
1996
).
In contrast with dextrans, globular proteins behave more like rigid spheres
in solution. Using the same model system and experimental approach,
Arrio-Dupont et al. (2000)
estimated Dcyt values of proteins of a wide range of
molecular mass. As with the dextrans,
Dcyt/Dw values decline with increasing
Rh. However, protein diffusivities decline more rapidly
than those of dextrans. The proteins used were selected partly because they
were assumed not to participate in specific binding interactions. However, if
similar-sized proteins formed complexes with other globular proteins, their
Dcyt/Dw values would be much lower.
Protein complexes of molecular mass approximately 500 kDa, or higher, are
virtually immobile in the sarcoplasm
(Arrio-Dupont et al., 2000
).
Fig. 2 presents
Dcyt values versus molecular masses of several
globular proteins obtained using cultured myotubes
(Arrio-Dupont et al., 2000
) and
from adult, skinned fibers (Maughan and
Lord, 1988
; Maughan and
Wegner, 1989
). The latter authors obtained their estimates by
measuring the rates of leakage of glycolytic enzymes from skinned fibers.
Dcyt values obtained by this approach are generally lower
than those measured using fluorescently labeled proteins injected into
cultured myotubes (Fig. 2).
Although this might be due to structural differences between the cells, as
suggested by Arrio-Dupont et al.
(2000
), it is difficult to
exclude methodological differences (e.g. enzymes may somehow be more greatly
inhibited from diffusing out of, rather than within, muscle
fibers). Specific binding interactions (e.g. formation of complexes with other
globular proteins, binding to fibrous sarcoplasmic proteins or proteins on the
outer mitochondrial membrane) may have also occurred in the adult muscle
fibers.
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Enzymes and metabolism in sarcoplasmic space |
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Consider a sequence of two enzyme-catalyzed reactions occurring by
MichaelisMenten kinetics, as:
![]() | (2) |
![]() | (3) |
A simple thought experiment
If metabolic enzymes were all `soluble' but diffuse at rates 23
orders of magnitude more slowly than their substrates and products, they can
be imagined, for the sake of argument, to be uniformly distributed in
three-dimensional space and to move in slow motion relative to their more
rapidly diffusing substrates and products. As enzyme E1 converts S
to P, let us suppose that a gradient is formed in which [P] is highest
proximal to E1 and its concentration declines with distance
d (Fig. 3).
E2 is some distance from E1 and catalyzes the formation
of P to Q at a rate based on its kinetic properties and on the local [P]. This
also leads to a gradient, with [Q] being highest in the vicinity of
E2. E2 serves as a sink for P and, therefore,
contributes to maintaining the gradient in [P]. If E1 and
E2 were closer to each other, E2 could operate at a
higher fractional velocity. The extreme case of this would be seen if the two
enzymes formed the complex E1E2, as in a tight
channel where d=0. On the other hand, increasing d between
the two enzymes could cause [P] to become more limiting to the reaction
catalyzed by E2. If substrates and products occur at low (micro- or
nanomolar) concentrations, or if enzyme kcat values are
high, or if E1 and E2 were immobilized far from each
other, the gradient in [P] may not be large enough to drive diffusion from
E1 to E2 at sufficiently high rates to keep the reaction
catalyzed by E2 from becoming diffusion-limited.
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Evaluating what might make intuitive sense in quantitative terms is not so
easy. For example, it took fairly elaborate calculations before Fell
(1980) arrived at the
conclusion that, despite the inhomogeneous distribution of adenylate cyclase
and phosphodiesterase, intracellular concentration gradients in cyclic AMP
should tend to be modest. A more general outcome of this approach is that
metabolite diffusion rates over typical inter-enzyme distances are much faster
than rates of enzyme turnover in vivo, and so metabolite
concentration gradients over typical inter-enzyme distances would be expected
to be negligible (Fell, 1991
).
Conducting calculations based on reactiondiffusion theory, Westerhoff
and Welch (1992
) arrived at
the conclusion that the activity of the glycolytic enzymes in yeast cells
would not be expected to be diffusion limited, given the concentrations of
glycolytic enzymes, their kcat values, cell dimensions and
glycolytic flux rates. However, diffusion may become limiting to catalysis
when pathway enzymes operate at high rates, when diffusion distances are large
(because cells are large and/or because enzyme concentrations are low), or
when product/substrate concentrations are low
(Welch and Easterby,
1994
).
A number of familiar reactions in muscle energy metabolism are now examined within this framework.
Creatine kinase and ATP turnover in aerobic muscles
In muscles that sustain high operating frequencies for extended durations,
mitochondrial oxidative phosphorylation is responsible for most of the
resynthesis of the ATP hydrolyzed by cellular ATPases. Because of the
distances separating mitochondrial ATP synthase and actomyosin ATPase
activities, as well as the rates at which ATP turnover occurs, it is
here where we encounter one of the exceptions to the generalization that
intracellular metabolite gradients are insignificant to metabolism. During
exercise, there is a need for high rates of diffusive flux of ADP from
myofibrils, where actomyosin ATPase catalyses the hydrolysis of ATP to ADP +
Pi, to mitochondria, where ATP is resynthesized. ADP is both a
substrate and a regulator of mitochondrial ATP synthesis. The free,
cytoplasmic ADP concentration in muscles is so low that, at high rates of ATP
turnover, it has been calculated (Jacobus,
1985) that the intracellular gradient in [ADP] could not be large
enough to account for the required flux from myofibrils to mitochondria. It
has been found that in vertebrate skeletal and cardiac muscles, about half of
the CK occurs in the sarcoplasm and the other half occurs, as specific
isoforms, bound to mitochondria and myofibrils. The problem of ADP-diffusion
limitation of oxidative phosphorylation is solved through the diffusion of
creatine from myofibrils to mitochondria, where, via the
mitochondrial CK reaction, creatine accepts a phosphate group from ATP and
diffuses back to the myofibrils as CrP. At the myofibrils, ATP is hydrolyzed
by actomyosin ATPase and the ADP produced is rephosphorylated at the expense
of CrP in a reaction catalyzed by myofibrillar CK. The essence of this cycle,
called a `shuttle' by some, was described by Meyer et al.
(1984
) and is the subject of
the paper by Dzeja (2003).
A full account of the role of CK in energy transport in muscles is beyond
the intended scope of this paper; however, a number of features of the process
are relevant to the issues raised here. In their insightful analysis, Meyer et
al. (1984) argued that the
transport functions of creatine and CrP are simply consequences of the
near-equilibrium nature of the CK reaction. A decade later, McFarland et al.
(1994
) used a spin-transfer
NMR method to measure forward and reverse CK flux rates in soleus, a
slow-twitch, oxidative muscle. It was found that over a tenfold range of ATP
turnover rates, forward and reverse flux rates remain equal and the behaviour
of CK in vivo is reconcilable with the kinetic properties of the
enzyme in vitro. These results have been interpreted as providing
further support for the near-equilibrium model for the `spatial buffering'
role of CK and the idea that solution biochemistry provides a sufficient
explanation for high-energy phosphate transport in muscles. Evidence for
channeling of ATP between the adenine nucleotide translocase and mitochondrial
CK (Moreadith and Jacobus,
1982
; Wallimann,
1996
), between myofibrillar CPK and actomyosin ATPase
(Arrio-Dupont, 1988
), the
apparent inaccessibility of a fraction of the creatine/creatine phosphate pool
to CK (Hochachka and Mossey,
1998
; Trump et al.,
2001
) and, most recently, detection of compartmentalized
displacement from equilibrium of mitochondrial and myofibrillar CPKs in hearts
(Joubert et al., 2002
), have
led others (e.g. Wallimann,
1996
) to question the near-equilibrium explanation of Meyer et al.
(1984
). To some extent, it
seems possible to reconcile these datasets and views by recognizing that
soleus muscles possess much lower mitochondrial volume densities than hearts.
The data obtained by McFarland et al.
(1994
) are therefore
consistent with Meyer et al.
(1984
), given what is
observable using 31P-NMR in this system. In hearts with greater
mitochondrial volume density, CK net fluxes occurring in opposite directions
are observable at the mitochondria and the myofibrils, where compartmentalized
or channeled reactions occur, while equal and reversible fluxes are also
observed in the cytosol (Joubert et al.,
2002
). Thus, intracellular high energy transport in highly aerobic
muscles is made possible by channeled reactions in compartments, as well as a
near-equilibrium reaction in solution (Fig.
4).
|
Glycolytic enzymes, their substrates and products
If, for the sake of argument, a uniform distribution of glycolytic enzymes
is assumed to occur in muscles, their concentrations would range from
approximately 30 to >1000 µmol l-1
(Srivastava and Bernhard,
1986; Albe et al.,
1990
; Betts and Srivastava,
1991
). When enzyme concentrations are compared with their
substrate and product concentrations, we find that in some cases, [S] and [P]
occur in the millimolar range, exceeding [E] by 23 orders of magnitude.
For example, phosphoglucoisomerase occurs at a concentration of approximately
33 µmol l-1 (Albe et al.,
1990
), while its substrates, G6P and F6P (glucose 6-phosphate and
fructose 6-phosphate, respectively), are held close to equilibrium at
millimolar concentrations (e.g. Kashiwaya
et al., 1994
; Staples and
Suarez, 1997
) in the reaction, G6P
F6P. Although there is
evidence of hexokinase binding to porin on the surfaces of mitochondria
(Adams et al., 1991
;
de Cerqueira Cesar and Wilson,
1998
; Wilson,
2003
) and PFK binding to actin
(Liou and Anderson, 1980
;
Roberts and Somero, 1987
),
hexose phosphate flux from hexokinase, through phosphoglucose isomerase (PGI),
to PFK does not appear to occur via a channeled mechanism
(Srivastava and Bernhard,
1986
). Thus, the net flux rate at PGI, v, is equal to the
steady-state rate of glycolysis and represents the difference between forward
and reverse flux rates. Given the kinetic properties of the enzyme, v
is defined by the Haldane equation
(Haldane, 1930
;
Veech et al., 1969
) as:
![]() | (4) |
In contrast, the steady-state concentrations of pathway substrates and
products of a number of reactions further downstream in glycolysis [e.g.
aldolase (ALD), triosephosphate isomerase (TPI), glycerol 3-phosphate
dehydrogenase (G3PDH), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and
phosphoglycerate kinase (PGK)] occur in the micromolar range
(Veech et al., 1969;
Connett, 1985
;
Kashiwaya et al., 1994
). Under
these conditions, a large fraction of pathway intermediates may be bound to
enzyme active sites (Veech et al.,
1969
; Connett,
1985
) and, at high flux rates, the enzymes could be
diffusion-limited if they were uniformly distributed within the sarcoplasmic
space. In work to be described in greater detail and, no doubt, updated by
Sullivan (2003), Wojtas et al.
(1997
) made transgenic
Drosophila with G3PDH lacking a C-terminal tripeptide required for
binding to Z-discs and M-lines. Failure of G3PDH to localize
also resulted in failure of GAPDH and ALD to colocalize at these sites and, as
a result, the flies could not fly. Although metabolic data are lacking, these
results have been interpreted as being consistent with the need for these
enzymes to be held in close proximity to each other. It is possible that,
given the low, near-equilibrium concentrations of substrates and products,
close proximity of active sites is required to overcome diffusion limitations
that may occur at the high metabolic rates
(Lehmann et al., 2000
)
required to sustain flight. Such an explanation may be intuitively appealing,
but it leaves open the question of what actual mechanisms are involved. The
enzymes may bind specifically to each other to form stable complexes or, they
may form weak, transient associations. If channeling does occur, it would be
interesting to know if it operates via a perfect or leaky mechanism.
Finally, given the observation that the Dcyt of some
metabolic enzymes changes with metabolic state
(Verkman, 2002
), it is
conceivable that the degree of channeling or the relative leakiness of
channeled reactions may change with transitions between rest and exercise.
Does convection help or hinder muscle metabolism?
Because many cell types are known to expend energy to promote cytoplasmic
streaming, (e.g. Sugi, 2003) it is tempting to assume that fluid convection is
a universally desirable phenomenon. When a muscle fiber shortens and lengthens
while maintaining constant volume, its cross-sectional area would be expected
to increase and then decline in cyclic fashion. While this occurs, the
distances between actin and myosin filaments would remain constant, but as
fiber cross-sectional area increases and declines, water molecules might
undergo cycles of radial displacement and replacement. The exact nature of
these water movements may be difficult to predict at the small spatial scales,
low Reynolds numbers, muscle strains and operating frequencies involved.
However, this raises the possibility that, in addition to their random,
diffusive walks through the sarcoplasm, enzyme molecules may be subjected to
convective movement. That convection may be unimportant in muscles might be
suggested by that lack of effect of muscle contractions on myoglobin diffusion
(Papadopoulos et al., 1995).
Nevertheless, given the idea that close proximity might be necessary between
enzymes operating at high rates and at low substrate concentrations, the
disruption of such associations by convective movement may provide another
explanation for why anchoring to intracellular sites, as well as to other
enzymes, may be required for flies to fly.
Interspecific variation is interesting and important
Muscles differ in structure, mechanical function and biochemical properties
within individuals and species, as well as across species. Such variation
provides the opportunity to explore the extent to which mechanisms,
established using only a few model systems and considered to be `fundamental,'
apply to other species over a range of lifestyles, body sizes, and metabolic
rates. It also provides an opportunity to test hypotheses concerning the true
adaptive significance of proposed mechanisms. Consider, for example, the
apparent absence of a mitochondrial form of arginine kinase in locust flight
muscles (Schneider et al.,
1989). If creatine and CrP have assumed such important roles in
energy transport in vertebrate muscles, why should arginine and arginine
phosphate not play such roles in insect flight muscles, considering their even
higher rates of aerobic ATP turnover? Could the mitochondrial volume densities
in insect flight muscles be so high that, despite high rates of ATP turnover,
diffusion distances are small enough to allow ADP to travel from the
myofibrils to serve as the mitochondrial phosphate acceptor, without causing
diffusional limitations? Alternatively, are arginine and arginine phosphate
involved in the spatial buffering of ATP concentrations by way of the
near-equilibrium mechanism proposed by Meyer et al.
(1984
)? Consider also
hexokinase binding to porin on mitochondrial surfaces and the channeling of
ATP from the adenine nucleotide translocase to this enzyme, a topic covered by
Wilson (2003
). It has been
proposed that this may serve as a mechanism by which glucose phosphorylation
is coordinated with mitochondrial oxidative phosphorylation in aerobic cells.
In contrast, Drosophila hexokinases do not contain the appropriate
hydrophobic sequences required for binding to porin
(Duvernell and Eanes, 2000
),
and preliminary experiments in my laboratory (J. Staples and R. K. Suarez,
unpublished observations) have failed to reveal evidence of hexokinase binding
to mitochondria in honeybee Apis mellifera flight muscles, a system
in which most of the carbon fueling mitochondrial oxidative metabolism must go
through the hexokinase reaction! These examples serve to illustrate how
conclusions derived from the results of experiments using more conventional
model systems can be further evaluated by application of the comparative
method. Far from being trivial exercises, such comparative studies provide a
means by which the fundamental nature of biochemically interesting phenomena
can be assessed.
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Reconciling the old and the new |
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Acknowledgments |
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