Maintaining muscle mass during extended disuse: aestivating frogs as a model species
Physiological Ecology Laboratory, Department of Zoology and Entomology, The University of Queensland, Brisbane, QLD 4072, Australia
* Author for correspondence (e-mail: cfranklin{at}zen.uq.edu.au )
Accepted 13 May 2002
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Summary |
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Key words: skeletal muscle, disuse, inactivity, atrophy, dormancy, aestivation, reactive oxygen species
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Introduction |
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The effect of muscle disuse or inactivity, characterised by a reduction in
muscle fibre cross-sectional area and a concomitant loss of muscle strength,
appears to be common to the vast majority of vertebrates studied. Research on
muscle wasting associated with disuse has focused extensively on mammals,
especially studies in which limbs have been artificially immobilised for
extended periods with a splint, pin or cast
(Booth, 1982;
Musacchia et al., 1988
;
Nordstrom et al., 1995
;
Soares et al., 1993
). A
significant amount of the data on muscle disuse atrophy comes from human
studies in which muscle wasting occurs as a result of limb immobilisation
(stemming from bone fractures), extended bed rest or as a consequence of
micro-gravity effects during prolonged space travel
(Fitts et al., 2000
). Apart
from these studies, most investigations have used laboratory-reared mammals
(namely mice, rats, guinea pigs, cats and dogs) to look at muscle disuse
atrophy (Bebout et al., 1993
;
Boyes and Johnston, 1979
;
Maier et al., 1976
;
Nordstrom et al., 1995
;
Soares et al., 1993
). These
animals reflect the fact that, historically, muscle disuse has been biased
towards biomedicine.
In more recent years, a number of comparative physiological studies have
investigated muscle structure and function in animals that undergo natural
periods of muscle disuse, such as are imposed during dormancy
(Harlow et al., 2001;
Tinker et al., 1998
;
Wickler et al., 1991
).
Examples include hibernating mammals and frogs
(Harlow et al., 2001
;
St-Pierre et al., 2000
), and,
from our laboratory, investigations on muscle morphology and locomotor
performance in aestivating (burrowing) frogs
(Hudson and Franklin,
2002
).
This paper aims to provide an overview of muscle disuse in vertebrates, describing the defining characteristics of muscle atrophy and discussing possible causative factors. Equal emphasis is given to experimentally induced and naturally occurring inactivity. In describing the cues and processes that underlie muscle disuse atrophy, the role played by reactive oxygen species (ROS) is emphasised. In particular, we highlight the work we are currently conducting on burrowing frogs, which can remain immobile for longer than 9 months yet still maintain muscle mass and function. In taking this comparative approach, we expose some trends and patterns that we believe provide a valuable insight into possible mechanisms that may regulate or inhibit muscle disuse atrophy.
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Muscle disuse atrophy: characterisation |
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On a gross level, there is a reduction in muscle fibre cross-sectional
area. Other structural changes include sarcomere dissolution and endothelial
degradation (Oki et al., 1995;
Tyml et al., 1990
). In
addition, there is a reduction in the number of mitochondria
(Rifenberick et al., 1973
), an
increase in the amount of connective tissue
(Oki et al., 1995
) and
apoptotic myonuclear elimination (Smith et
al., 2000
). At the biochemical level, amounts of muscle protein,
-actin mRNA and cytochrome c mRNA are all reduced
(Babij and Booth, 1988
). Per
gram of muscle mass, there is a decreased utilisation of
ß-hydroxybutyrate, palmitate and glucose, and levels of high-energy
phosphates decline (Booth,
1977
), as do levels of oxidative enzymes such as citrate synthase
(Bebout et al., 1993
) and
malate dehydrogenase (Rifenberick et al.,
1973
). In addition, there is a reduction in levels of
phosphokinase (Carmeli et al.,
1993
).
The structural and morphological changes associated with muscle atrophy
ultimately impact upon the muscle function and locomotor performance of the
animal. Force production by muscle is related to muscle cross-sectional area,
so muscle fibre atrophy results in a reduction in maximal force production
(Witzmann et al., 1982) and
muscle power output. This, in turn, leads to an impairment of locomotor
performance. Some of the structural changes associated with prolonged muscle
disuse are pathological, and lengthy recovery periods are often required
before full muscle and locomotor performance is reestablished. For example,
Booth and Seider (1979
) found
that, in the rat, 3 months of immobilisation required 4 months of recovery
before muscle performance returned to control levels.
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Factors influencing muscle disuse atrophy |
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A variety of extrinsic and intrinsic factors influence the extent of muscle atrophy during immobilisation/inactivity. Apart from the duration of inactivity, muscle disuse atrophy is influenced by muscle position (whether the limb/muscle is immobilised in a stretched or contracted position), muscle fibre type, age and species.
Muscle length
Muscle length has been shown to have a significant influence on muscle
atrophy in mammals. Muscles immobilised in the shortened position suffer
significantly greater atrophy than muscles fixed in a stretched position
(Tabary et al., 1972). McComas
(1996
) found that the length
of muscle at fixation is critical for sarcomere reabsorption. In the cat,
immobilisation of the soleus muscle in the shortened position resulted in
40
% fewer sarcomeres in series than control (active) muscle, whilst in
the lengthened position sarcomere number increased by 20 % compared with
active muscle (Tabary et al.,
1972
).
Muscle fibre type
Within an organism, muscle atrophy is greater in slow oxidative (SO) than
in fast oxidative glycolytic (FOG) muscle fibres
(Booth and Kelso, 1973;
Booth and Giannetta, 1973
;
Maier et al., 1976
; Booth,
1977
,
1982
;
McComas, 1996
;
Musacchia et al., 1988
;
Witzmann et al., 1982
). In the
rat (Rattus rattus), the soleus muscle is composed of both SO and FOG
muscle fibre types. Immobilisation of the hindlimb of the rat resulted in a
preferential atrophy of SO muscle fibres over FOG muscle fibres, which
culminated functionally in an increased contraction speed of the soleus.
Age
The age of the animal has been reported to influence the rate of muscle
atrophy resulting from limb immobilisation, and it appears that muscle wasting
decreases with age (Carmeli et al.,
1993). In rats immobilised for 4 weeks, 4- to 5-month-old animals
showed 49-64% atrophy of the soleus muscle, whereas 20- to 21-month-old
animals suffered only 27-38 % muscle atrophy
(Ansved, 1995
).
Species differences
There are conspicuous differences among species in the rate of muscle
wasting following limb immobilisation. Soares et al.
(1993) found that, after 4
days of hindlimb immobilisation, the mouse Mus musculus showed 15 %
atrophy of the gastrocnemius muscle. Boyes and Johnston
(1979
) reported that after 3
weeks of immobilisation of the hindlimbs of the rat (Wistar strain) there was
50 % wasting of the vastus intermedius muscle; in the guinea pig, 4 weeks of
hindlimb immobilisation incurred 43 % wasting of the gastrocnemius muscle
(Maier et al., 1976
).
Meanwhile, Bebout et al. (1993
)
discovered that 3 weeks of hindlimb immobilisation of the gastrocnemius of the
guinea pig led to 31 % atrophy. In humans, 4 weeks of knee immobilisation
caused 21 % atrophy of the quadriceps muscle
(Veldhuizen et al., 1993
).
It is clear that comparisons of muscle disuse atrophy data from different
species are confounded because studies have used different periods of disuse
and indeed different immobilisation methods and different muscles. However, if
these differences in immobilisation technique are disregarded and the data
normalised to 12 days, there is a significantly greater rate of muscle atrophy
in the smaller mammals (Table
1). When normalised to an immobilisation period of 12 days, the
rate of muscle atrophy ranges from only 9 % in humans
(Veldhuizen et al., 1993), to
17 % in dogs (Bebout et al.,
1993
), 18 % in guinea pigs
(Maier et al., 1976
), 28 % in
rats (Boyes and Johnston,
1979
) and 45 % in mice (Soares
et al., 1993
) (see Table
1).
|
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Muscle disuse in dormant animals |
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Studies on muscle structure and function in dormant organisms have focused
primarily on hibernating mammals. This work has consistently shown less of an
atrophic response than would be predicted from laboratory models (compare
Tables 1 and
2). For example, the ground
squirrel Spermophilus lateralis exhibited only a 15-20 % decrease in
gastrocnemius fibre cross-sectional area after 6 months of hibernation
(Steffen et al., 1991), and
the brown bear Ursus americanus displayed no muscle atrophy after 4
months of dormancy (Tinker et al.,
1998
). Even though some muscle atrophy occurred in the case of
S. lateralis over 6 months, it was no more severe than that following
just 1 or 2 weeks of artificial limb immobilisation in a rat
(Musacchia et al., 1988
).
|
Vyskocil and Gutmann (1977)
investigated the effect of hibernation on the latency period, rate of tension
development, contraction time and half-relaxation time in the golden hamster
Mesocricetus auratus. After 3 months of inactivity and muscle disuse,
they found no change in muscle performance, which indicated that the
functional capacity of actin, myosin, the sarcoplasmic reticulum and the
myofibrillar organelles were all maintained through hibernation. This is in
stark contrast to the findings for artificially immobilised muscles after a
few weeks. For example, time to peak tension decreased by 30 % in the guinea
pig soleus after 4 weeks of limb immobilisation
(Maier et al., 1976
), and
isometric force development in the soleus muscle decreased by 34 % in the rat
after 3 weeks of hindlimb suspension
(Anderson et al., 1999
).
Moreover, hibernation has little effect on muscle function in the black bear
Ursus americanus. After 130 days of hibernation, U.
americanus was found to lose only 23 % of its hindlimb strength
(Harlow et al., 2001
) in
comparison with a predicted 90% loss for humans.
Other vertebrate classes show even more impressive periods of prolonged
inactivity. Several species of arid-zone Australian frogs, such as the
green-striped burrowing frog Cyclorana alboguttata, survive the
lengthy droughts by digging an underground chamber, forming a waterproof
cocoon of shed skin and mucus, and conserving energy in a process called
aestivation (Flanigan et al.,
1993; Withers,
1993
). In this capacity, these frogs are inactive and immobile in
their burrows often for months and possibly years. However, when the summer
rains finally come, a selective advantage is conferred on those frogs capable
of compressing their feeding and breeding into a narrow time frame of only a
few weeks when water is plentiful. During this short period of opportunity,
locomotor performance, which varies with muscle performance, is at an absolute
premium.
We have found that the chronic disuse associated with 3 and 9 months of
aestivation had no effect on muscle mass, in vitro force production
and swimming performance in C. alboguttata
(Hudson and Franklin, 2002; N.
J. Hudson and C. E. Franklin, in preparation). The absence of atrophic changes
is consistent with the patterns found during periods of disuse in hibernating
mammals discussed above, and it is clear that the response of skeletal muscle
to disuse during dormancy is quantitatively different from that found in
artificial immobilisation studies.
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Muscle disuse atrophy: etiology |
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The ultimate causation of atrophy is the muscle disuse per se, and
it is important to note that, in quantifying the actual disuse stimulus, both
the period of inactivity (i.e. duration) and the relative reduction in the
activity of the muscle at the onset of immobilisation are significant. Thus,
within a species, the duration of inactivity has been shown to be positively
correlated with the degree of muscle atrophy, although the actual rate of
atrophy decreases with time (Booth,
1977). In addition, wasting is greater in muscles used
regularly/intensively prior to immobilization than in muscles that are used
only intermittently. In frequently used muscles, the disuse stimulus is
greater as there is a larger difference between use and disuse
(Musacchia et al., 1988
;
McComas, 1996
).
Proximately, there are two key processes that govern the extent of muscle atrophy: (i) the magnitude of the regulated decline in the rate of protein synthesis and (ii) the level of oxidative damage and subsequent unregulated protein degradation.
Decline in rates of protein synthesis
The exact signal transduction pathways that translate changes in
contractile activity into regulated declines in rates of protein synthesis
have not been elucidated (Rennie,
2001), although several changes operating at different levels of
organisation have been described. For example, among the first changes during
muscle atrophy is an impairment of sarcolemmal ion transport, which can lead
to changes in rates of protein turnover and degradation
(Reznick et al., 1995
). Within
muscle fibres, the number of lysosomes and autophagic vacuoles containing
proteolytic enzymes increases, which attack the myofibres
(Reznick et al., 1995
).
Increases in intracellular levels of Ca2+ in muscle fibres help to
stimulate this autophagic response (Soares
et al., 1993
). Calpains, Ca2+-activated cysteine
proteins, also play a key role in the disassembly of sarcomeric proteins.
Furthermore, loss of Ca2+ homeostasis is thought to impair
mitochondrial respiratory function (Soares
et al., 1993
).
Overall, there is a sharp decline in the rate of protein synthesis, and
concentrations of myogenic regulatory factor transcripts are reduced during
disuse (Loughna and Brownson,
1996). Muscle atrophy is associated with reduced rates of
transcription (Gunderson and Merlie,
1994
) and a progressive loss of muscle protein.
Oxidative damage
Reactive oxygen species (ROS), which leak out of mitochondrial membranes
during aerobic respiration, have a significant degenerative effect on muscle
fibres, degrading (stochastically) muscle proteins and lipids (Kondo et al.,
1991,
1993
,
1994
). Examples of ROS include
superoxide, hydrogen peroxide and hydroxyl radicals. All aerobically respiring
tissues are exposed to ROS during routine functioning; however, oxidative
stress occurs only when the rate of formation of ROS exceeds the rate of
removal. Thus, an accumulation of oxidative damage occurs as a result of
either a decline in anti-oxidant defences or a loss of repair function (i.e.
the rate of de novo protein synthesis)
(Ames et al., 1993
).
Skeletal muscle is particularly susceptible to oxidative damage. Muscle
generally has a large aerobic scope, which means it has to deal with a
fluctuating supply of oxidants. It also has surprisingly low levels of
antioxidants (Avellini et al.,
1999), which compromises defence. Finally, during immobilisation,
the negative protein balance that leads to muscle atrophy is primarily a
result of a decline in the rate of protein synthesis (which compromises
repair) and not an increase in the rate of regulated protein degradation
(Tucker et al., 1981
).
Moreover, it has been established that, as the damage progresses, the muscle
fibres release bound transition metals such as myoglobin iron, which catalyse
some of these oxidative processes and further accelerate atrophy
(Kondo et al., 1993
).
It follows that, because ROS represent a fixed proportion of the oxygen
processed (Avellini et al.,
1999; Adelman et al.,
1988
), their production must correlate with both the density of
mitochondria and the aerobic activity of the muscle. This stochastic
relationship is important in understanding the differences in the extent of
muscle wasting that occur between muscle fibre types and the differences
observed in muscle disuse atrophy among species.
Slow-twitch fibres (such as typically found in postural muscles) have
repeatedly been shown to suffer a more severe disuse response than fast-twitch
fibres in experimental systems, although the underlying cause for this
disparity is unclear. We believe that this difference can be attributed to the
combined effects of the relative size of the disuse stimulus and the extent of
oxidative damage between fast- and slow-twitch fibres. As fast-twitch fibres
are recruited only intermittently compared with slow-twitch fibres, the
relative size of the initial disuse stimulus following immobilisation is
proportionately smaller, and this elicits a correspondingly smaller atrophic
response. In addition, because ROS are produced during aerobic respiration and
leak out from mitochondrial membranes, fast-twitch fibres, with their
dependence on anaerobic pathways for energy production and low density of
mitochondria, are less afflicted. Consistent with this hypothesis is the
finding that, under normal circumstances (i.e. not during immobilisation),
slow-twitch fibres suffer more oxidative damage as measured by the production
of protein carbonyl (Sen et al.,
1997).
With respect to understanding difference in the rates and extent of muscle disuse atrophy among species, we have found that the severity of muscle atrophy is highly correlated with mass-specific metabolic rate (Fig. 1). Mice, which have comparatively higher mass-specific metabolic rates, are subject to accelerated atrophy, whilst animals with lower mass-specific metabolic rates such as humans are intrinsically spared. Thus, organisms with lower mass-specific metabolic rates experience a less dramatic atrophy than their high-metabolic-rate counterparts. We believe there are two reasons for this.
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First, low-metabolic-rate organisms are relatively quiescent, which means
that prior to immobilisation their muscles are less active. This exposes them
to a smaller disuse stimulus, which in turn elicits a smaller atrophic
response. Second, because the production of ROS represents a fixed proportion
of the total oxygen processed, the magnitude of the ROS insult must vary in
line with metabolic rate (Grundy and
Storey, 1998) so that an organism such as a human has tissues that
are subjected to a smaller ROS insult than comparable tissues in a mouse.
The effect of age on muscle disuse atrophy can also be explained using the above criteria. Older animals tend to become progressively more sedentary, and so the initial disuse stimulus must become less dramatic. Furthermore, as vertebrates grow and increase in size with age, there is a corresponding decrease in mass-specific metabolic rate, which would reduce the ROS insult inflicted upon their muscle.
Of all the patterns described above, the effect of muscle length is the only one that cannot adequately be explained by the impact of the disuse stimulus or oxidative damage. The factors influencing muscle atrophy during disuse are summarised in Fig. 2.
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Preservation of muscle structure in dormant animals |
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Winter dormancy is characterised by a marked decrease in metabolic rate in all animals concerned (Table 2). The production of ROS represents a fixed proportion of the total oxygen processed, so the reduction in mass-specific metabolic rate that occurs during dormancy automatically reduces the ROS insult and, thereby, limits the extent of oxidative damage. Consequently, the demands placed on both the muscular defence (antioxidants) and repair (de novo protein synthesis) systems are also alleviated and the rate of atrophy is reduced accordingly. In comparing the degree of muscle wasting across hibernators/over-winterers, bears showed the smallest response, ground squirrels were intermediate and hamsters atrophied the most. This is surprising given that the differences in their metabolic rates during dormancy are not that dramatic (Table 2).
However, if the pre-dormancy metabolic rates are compared, a pattern emerges that is consistent with the differences in the atrophic response. Thus, the hamster mass-specific metabolic rate during dormancy itself is only 66% greater than that of the bear. But, prior to dormancy, the mass-specific metabolic rate of the hamster is 468% greater than that of the bear (Table 2). Thus, part of the reason that the hamster suffers a much greater atrophy than a bear or ground squirrel may be related to the greater activity of its muscle before immobilisation, leading to a more pronounced disuse stimulus when the inactivity associated with dormancy begins.
Frogs (including our study animal, C. alboguttata) are
bradymetabolic organisms whose limb skeletal muscle is predominantly composed
of fast-twitch fibres (Sperry,
1981) used in brief anaerobic bursts as part of a sit-and-wait
strategy of prey capture or for escaping predators. Consequently, during
immobilisation/aestivation, they are subject to a relatively small disuse
stimulus and also a relatively small ROS insult. In addition, as in the
hibernators, the marked depression in metabolic rate that accompanies
aestivation (up to a 60% drop in metabolic rate) further reduces the ROS
insult, which must automatically act to preserve skeletal muscle structure
during aestivation. However, there is some evidence that more active
mechanisms may be in operation in aestivating frogs.
All tissues, including skeletal muscle, are protected against oxidative
damage by a range of scavenging antioxidants such as superoxide dismutase. The
experimental administration of antioxidants has been shown to decelerate
muscle atrophy by 15% in artificially immobilised rats
(Kondo et al., 1991). The
endogenous regulation of antioxidant levels therefore represents a potential
means of further reducing muscle wasting. Consistent with this hypothesis is
the finding that levels of antioxidants are upregulated during extended
periods of dormancy in amphibians. In the spadefoot toad Scaphiosus
couchii, skeletal muscle oxidative damage was found to be less severe
during aestivation than during arousal
(Grundy and Storey, 1998
). Of
the six antioxidants analysed, levels of two were elevated during aestivation,
whilst those of the other four matched control levels. Given that metabolic
rate drops by approximately 80% during aestivation, maintenance at control
levels can be interpreted as a functional upregulation. We believe that the
relative increase in antioxidant levels offers a means, in concert with a
depression of metabolic rate, of reducing muscle atrophy in aestivating
anurans by the amelioration of oxidative damage. The verification of this
hypothesis by assessing seasonal fluctuations in levels of skeletal muscle
antioxidants in other animals that undergo dormancy, such as hibernating
mammals, will be of considerable interest.
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Acknowledgments |
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