Vol. 90, Issue 1, 345-357, January 2001
HIGHLIGHTED TOPICS
Plasticity in Skeletal, Cardiac, and Smooth Muscle
Invited Review: Effects of different activity and inactivity
paradigms on myosin heavy chain gene expression in striated
muscle
Kenneth M.
Baldwin and
Fadia
Haddad
Department of Physiology and Biophysics, University of California,
Irvine, California 92697
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ABSTRACT |
The
goal of this mini-review is to summarize findings concerning the role
that different models of muscular activity and inactivity play in
altering gene expression of the myosin heavy chain (MHC) family of
motor proteins in mammalian cardiac and skeletal muscle. This was done
in the context of examining parallel findings concerning the role that
thyroid hormone (T3, 3,5,3'-triiodothyronine) plays in MHC
expression. Findings show that both cardiac and skeletal muscles of
experimental animals are initially undifferentiated at birth and then
undergo a marked level of growth and differentiation in attaining the
adult MHC phenotype in a T3/activity level-dependent fashion. Cardiac MHC expression in small mammals is highly sensitive to
thyroid deficiency, diabetes, energy deprivation, and hypertension; each of these interventions induces upregulation of the 
-MHC isoform, which functions to economize circulatory function in the face
of altered energy demand. In skeletal muscle, hyperthyroidism, as well
as interventions that unload or reduce the weight-bearing activity of
the muscle, causes slow to fast MHC conversions. Fast to slow
conversions, however, are seen under hypothyroidism or when the muscles
either become chronically overloaded or subjected to intermittent
loading as occurs during resistance training and endurance exercise.
The regulation of MHC gene expression by T3 or mechanical
stimuli appears to be strongly regulated by transcriptional events,
based on recent findings on transgenic models and animals transfected
with promoter-reporter constructs. However, the mechanisms by which
T3 and mechanical stimuli exert their control on
transcriptional processes appear to be different. Additional findings
show that individual skeletal muscle fibers have the genetic machinery
to express simultaneously all of the adult MHCs, e.g., slow type I and
fast IIa, IIx, and IIb, in unique combinations under certain experimental conditions. This degree of heterogeneity among the individual fibers would ensure a large functional diversity in performing complex movement patterns. Future studies must now focus on
1) the signaling pathways and the underlying mechanisms governing the transcriptional/translational machinery that control this
marked degree of plasticity and 2) the morphological
organization and functional implications of the muscle fiber's
capacity to express such a diversity of motor proteins.
muscle plasticity; neonatal development; functional overload; spaceflight; spinal injury; endurance exercise; thyroid state; gene
transcription
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INTRODUCTION |
MYOSIN IS THE MOST ABUNDANT protein expressed in
striated muscle cells, comprising ~25% of the total protein pool.
The native myosin protein exists as a complex molecule, composed of two
heavy chains (MHCs) and two pairs of light chains. [Although it is
recognized that the light chains serve important modulatory roles
during muscle contraction, they will not be a focus of this review.] This native protein serves as both a structural and regulatory protein
(enzyme) in that 1) it forms the backbone of the sarcomeric structure designated as the contractile apparatus and 2)
through its interaction with another sarcomeric protein, actin, it
functions as a "motor" and transduces, via its ATPase activity,
chemical energy (e.g., ATP) into the mechanical manifestation of force generation and/or sarcomere shortening and hence the muscle's production of mechanical work and power. From both a biological and
functional perspective, an important feature concerning muscle structural/functional properties is the existence of the MHC gene family of motor proteins in which specific genes encode MHC protein isoforms. These isoforms have distinctly different ATPase (and shortening velocity) properties, thereby impacting the intrinsic functional properties of the individual myofibers in which they are
expressed, which provide the molecular basis of a muscle
fiber's functional diversity (94).
At least nine MHC isoforms have been identified in mammalian striated
muscles (defined herein as heart and skeletal muscle), and they have
been designated as 1) embryonic, 2) neonatal,
3) cardiac alpha (
), 4) cardiac beta () or
slow type I (as expressed in skeletal muscle), 5) fast type
IIa, 6) fast type IIx/IId, 7) fast type IIb,
8) extraocular, and 9) mandibular or masticatory (m-MHC)
(94). The embryonic and neonatal isoforms are expressed predominantly in developing skeletal muscles and can be detected in the
adult muscle in regenerating fibers (30) as well as in specialized adult muscles such as the masseter and extraocular muscles
(94). The - and -MHCs are expressed chiefly in
cardiac muscle. -MHC has been detected in certain adult muscles such as the masseter (94). -MHC (type I) expression is not
only confined to cardiac muscle but also is found in embryonic skeletal muscle and is the major isoform expressed in adult slow-twitch skeletal
muscle (67, 94). In addition to type I MHC, adult skeletal
muscles express various proportions of type IIa, IIx, and IIb MHC
isoforms. The extraocular MHC isoform is confined chiefly to the eye
and laryngeal muscles, whereas the m-MHC is expressed in the mandibular
muscles of carnivores (94).
Although it has been long appreciated that the protein expression of
these MHC genes is highly plastic in that it can be modulated by a
variety of factors, including (but not limited to) fetal/embryonic developmental programs (3, 27, 28, 71, 76), innervation and associated neuronal firing patterns (85, 94), hormonal factors (17), and mechanical activity/inactivity factors
(17, 105), the goal of this mini-review is to focus more
specifically on the findings to date concerning the role that
mechanical activity and inactivity paradigms play in altering MHC
expression in both cardiac and limb skeletal muscle of neonatal and
adult animal models (including, where feasible, human studies). This
will be done in the context of certain hormonal factors such as
thyroxin, which has been shown to act either independently of or
synergistically with mechanical activity in regulating MHC gene
expression. We fully recognize that diaphragm skeletal muscle responds
to mechanical intervention and thyroid hormone in a fashion typical of
limb skeletal muscle (21, 61, 78, 98, 99); however, this important topic was not covered due to space limitations. Also, several
excellent reviews have been reported, the collection of which provide
greater depth and breadth on the topic of MHC gene regulation than what
can be provided in this mini-review (17, 41, 46, 47, 85, 93, 103,
105, 114).
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MHC PLASTICITY IN CARDIAC MUSCLE |
Developmental impact.
In both humans and small animals, during the fetal developmental period
of the heart, -MHC is the principal isoform initially expressed in
the ventricles (66); -MHC, however, is the principal isoform expressed in atria of small and large neonatal and adult animals (66). However, in rodents shortly after birth,
when thyroid hormone (T3, 3,5,3'-triiodothyronine) titers
begin to increase progressively, expression of the -MHC becomes
rapidly decreased and is replaced by the -MHC such that, by ~3 wk
of age, the -MHC is exclusively expressed in the ventricles of small mammals (but not in large mammals such as humans). As the rodent heart
continues to mature to adulthood, the -MHC becomes reexpressed, accounting for ~10-15% of the total MHC pool. This regulation of the -MHC is thought to be due to an increase in the mechanical stress gradient that occurs across the wall of the myocardium as the
chamber enlarges during maturation to adulthood (103, 120). In humans, throughout the growth and development phase of
the heart, it appears that the -MHC remains as the dominant isoform
that is expressed in the ventricles under normal conditions, although
there have been reports that low levels of -MHC can be detected
(79). This residual pool of -MHC appears to be absent
in patients under hemodynamic overload, suggesting there is some degree
of cardiac MHC plasticity in the human heart. This is further
illustrated by the increased expression of -MHC in the atria of
human hearts under pressure overload (13, 93).
MHC plasticity in the adult rodent heart.
As described above, the adult heart of small animals such as rodents
and mice chiefly expresses the -MHC throughout the adult state. This
MHC pattern can change toward increased -MHC expression under
several pathophysiological conditions, including 1) chronic pressure overload (induced hypertension) (53, 68, 77, 80), 2) hypothyroidism or thyroid deficiency (TD) (17, 36,
52), 3) diabetes (33, 35, 54),
4) chronic energy (caloric) deprivation (55,
100), and 5) chronic endurance-type running
(42, 69, 70). In the models of hypertension, caloric
restriction, and exercise, the heart can increase expression of the
-MHC approximately two- to fourfold above control levels. -MHC
expression, however, can become exclusively expressed with TD and
diabetes (56). Of the five interventions, TD appears to be
the most potent. T3 has been shown to exert its biological
action via binding to its nuclear receptors, the thyroid hormone
receptors (31, 91). The thyroid hormone receptors are
ligand-dependent transcription factors that modulate transcriptional
activity via interaction with specific DNA recognition sequences known
as thyroid-responsive elements (TREs) located in the promoter region of
the target genes (14, 39, 45). Several TREs are thought to
be strategically located in the promoter region of the both the -
and -MHC genes (38, 51, 60, 72, 89). T3
regulates - and -MHC gene transcription in an antithetical
fashion, increasing the expression of -MHC while simultaneously
decreasing that of -MHC (89, 119). Interestingly, there
is some evidence to suggest that the interventions of diabetes and
chronic energy deprivation may mediate their effects either directly or
indirectly through the actions of T3 (56,
100). However, the mechanism(s) of overload-induced upregulation
of -MHC gene transcription appears to be more complex and involves a
different set of trans-acting factors and
cis-regulatory elements in the -MHC promoter.
In the case of endurance exercise, both neonatal and adult rats
extensively conditioned by endurance running respond with modest
upregulation of the -MHC, which is offset by concomitant decreases
in the relative expression of the -MHC type (42, 69,
70). However, the factors causing this transformation remain
poorly understood. Interestingly, in sympathectomized neonatal rats
undergoing endurance training, the transformation of - to -MHC is
augmented relative to the training of normal control animals
(70). This observation provides some evidence that
subcellular events that are associated with the downregulation of
sympathetic nervous system activity (a common adaptive response to
endurance training) may favor greater expression of -MHC. Although
the mechanism underlying this type of adaptation in MHC gene expression is not known, it is possible that sympathectomy could lengthen the
calcium signaling transients in the myocardial cell to activate the
calcineurin-nuclear factor of activated T cells pathway.
Activation of this pathway has been proposed to be involved in the
transcriptional activation of genes that define a slow phenotype in
striated muscle (25, 82). Clearly, more research is needed
on this matter.
In the context of the remodeling of the MHC motor proteins that occurs
in the rodent heart, it is thought that the physiological impact of the
interventions that induce upregulation of the -MHC gene in the heart
of small animals is an increased economy of force production (cross
bridge and calcium cycling) in the face of the increased mechanical
stress, which the heart must endure when either opposing the
hypertensive state or accommodating the volume overload associated with
endurance exercise (4, 103). On the other hand, during
diabetes, TD, and energy deprivation conditions, the strong bias toward
greater expression of the -MHC has been correlated with an intrinsic
cardiac functional state characterized by a low intrinsic contractility
state, heart rate, and cardiac output, that is, conditions consistent
with the animal's conservation of substrate energy utilization, both
globally and in the heart. Consequently, the heart of small
animals can be remodeled both biochemically and functionally in
accordance with the demand for chronic level of energy placed on either
the heart itself or the organism in general. As discussed above, there
is evidence that the same functional adaptations can occur in the cardiovascular system of humans, and these alterations appear to be
associated with some degree of plasticity involving the MHC isoforms
(81, 93).
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MHC PLASTICITY IN LIMB SKELETAL MUSCLE |
Mammalian skeletal muscles can be generally classified into two
major groups, slow-twitch and fast-twitch, based on their intrinsic
contractile properties, which are, in part, determined by their MHC
expression profiles (85, 94). Slow muscles of mammals
predominantly express the slow type I MHC isoform with some varied
proportion of type IIa, the slowest of the fast MHCs (11, 40, 41,
88, 94, 105). This profile is exemplified in muscles such as the
soleus and vastus intermedius, which play a strong role in antigravity
function. Fast muscles of small mammals such as the
gastrocnemius-plantaris complex, the vastus, the extensor digitorum
longus, and the tibialis anterior predominantly express the two fast
isoforms, IIx and IIb, with variable proportions, depending on the
muscle, the region of the muscle, or the specific animal (11, 32,
40, 41). It is interesting to note that, although the IIb MHC
gene has been identified in the human genome (115, 116),
evidence for its expression at the protein level has not been reported
(84, 105). Thus, in human muscle, there appears to be only
two fast isoforms that are expressed (IIa and IIx) in addition to the
slow type I MHC. MHC analysis of human soleus muscle shows that this
muscle expresses an approximately equal mix of type I and IIa isoforms,
but the type IIx MHC is not expressed (58). In contrast,
human fast muscles such as the vastus lateralis express a mix of all
three types of MHC isoforms at variable proportions (58,
64), depending on the physical fitness and activity of the
subject. For example, in moderately active humans (e.g., not undergoing
rigorous endurance or resistance-type training exercise), the MHC
profile of the quadriceps (vastus) muscle is ~50% slow type I, 40%
type IIa, and 10% type IIx (5, 9, 62). On the other hand,
world-class marathon runners and ultra-endurance athletes have been
reported to have remarkably high type I fibers in their major muscle
groups (as much as 95%) (9, 86), whereas muscles of
sprinters and power weight lifters predominantly consist of the IIa/IIx
fibers (7, 9). Whether these extreme patterns of MHC gene
expression are due exclusively to genetics, specificity of training, or
some combination of factors is uncertain.
Polymorphism of MHC isoform expression in single myofibers.
Before examining how various forms of activity/inactivity induce
skeletal muscle transformations related to development as well as adult
muscle plasticity, it is important to point out that single fibers of
both developing and adult skeletal muscle exist as hybrids, i.e.,
fibers coexpressing more than one MHC isoform in various combinations
(37, 96, 109, 110). This is best illustrated by
single-fiber analyses of the plantaris muscle during development at 5-, 20-, and 40-day postpartum (37) (Fig.
1). This study (37) showed
that, at 5 days of age, the muscle contains a large population of
fibers that is polymorphic, with a predominance of fibers coexpressing
the embryonic and neonatal isoforms (~60%). The other 40% of the
fibers coexpressed various combinations of developmental and adult
isoforms consisting mainly of embryonic/neonatal/I- and
embryonic/neonatal/IIb-expressing fibers (37). By 20 days
of age, ~10% of the fibers expressed pure type IIb or type I
isoforms, and the rest of the fiber population coexpressed various
combinations of adult fast MHC isoforms with some low proportion of
neonatal MHC (37). By the adult state, i.e., 40 days of
age, only a small pool of fibers (~15%) expressed one MHC isoform (I
or IIb), whereas the rest of the population consisted of hybrid fibers
coexpressing adult fast MHC isoforms with ~35% coexpressing IIx and
IIb (37). This polymorphic nature of single fibers was
also demonstrated by Caiozzo et al. (18) in the adult
plantaris. Among the adult skeletal muscles, the soleus seems to
consist of the most homogeneous fiber-type population. In fact,
single-fiber analyses of adult rat soleus muscle revealed that over
70% of the total fibers express only type I MHC isoform, 5-10%
of the fibers express type IIa isoform, and the remaining are type
I/IIa hybrid fibers coexpressing type I and IIa MHC isoforms in
different relative proportions (15) (see Fig. 3). The
significance of MHC polymorphism in single myofibers is not clear;
perhaps, it could lead to a more efficient MHC transition in a muscle
under altered functional demands. Given the pattern of MHC expression in rodent muscles, it would appear that the phenotype remodeling resulting in the isoform shifts largely involves changes in MHC isoform
content among the many fibers that normally express a combination of
isoforms such as IIx/IIa and IIx/IIb and type I/IIa (15, 16, 18,
37). Therefore, this polymorphism could be a characteristic of
fibers with high adaptive potential, i.e., hybrid fibers are more
suitable to switch phenotype to meet new functional demands.
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Fig. 1.
Myosin heavy chain (MHC) isoform polymorphism in single
fibers of the plantaris muscle in normal developing rats at 5, 20, and
40 days of age. The x-axis represents the fiber types based
on different combinations of coexpressed MHC isoforms. The
y-axis represents the %fiber type relative to the total
fiber population. The fill of each bar represents a specific MHC
isoform (see bar legend). The percentage of a given MHC isoform within
each fiber type can be determined by comparing height of bar for a
given isoform to total height of the corresponding bar. Note that other
fiber types are also found, but they represent only a minor proportion
(<2%); therefore, they are not shown on the graph for simplification.
E and Emb, embryonic; N and Neo, neonatal; I, type I; A, type IIa; X,
type IIx; B, type IIb. [Data adapted from di Maso et al.
(37).]
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Developmental impact.
Although the formation of the skeletal muscle system begins during the
latter stages of fetal development, it is important to recognize that,
in terms of MHC gene expression, both slow and fast muscles are still
in an undifferentiated state at the time of birth. For example, in the
rodent soleus muscle, which is destined to be composed chiefly of slow,
type I fibers, both the embryonic and neonatal isoforms are abundantly
expressed shortly after birth, accounting for ~50% of the total MHC
pool with the remaining protein comprised of the slow type I MHC
(3, 12, 27, 29). In fast muscles, the degree of
undifferentiation is even greater, as the embryonic and neonatal MHC
isoforms account for ~90% of the total MHC pool shortly after birth
(3, 37). During the first 3-4 wk of neonatal
development, both slow and fast muscles rapidly grow and differentiate
into their adult MHC phenotype (3, 29, 37). Although this
process requires an intact nerve (3), the two muscle types
appear to differ substantially in the primary factors that drive this
transformation process. On the basis of recent studies comparing muscle
development of neonatal rats raised in a microgravity environment of
spaceflight vs. rodents raised on Earth, it appears that slow muscle
types are heavily dependent on weight-bearing activity (which begins during the second week following birth) for both normal growth and the
optimal expression of type I MHC (1). In the absence of
the weight-bearing state, muscle growth is dramatically reduced, and
the MHC pool becomes biased to fast MHC expression, with the type IIa
MHC becoming the most predominant isoform that is expressed (1). In contrast, it appears that weight-bearing activity
is not essential for the fast-type muscles to achieve the adult fast MHC phenotype, which, as mentioned above, normally consists chiefly of
the fast IIx and IIb isoforms (1). Instead, an intact
thyroid state (e.g., circulating T3 levels) appears to be
necessary to downregulate the neonatal isoform and replace its
expression with the IIb isoform (1, 37). If insufficient
T3 is available, the fast muscle remains undifferentiated
for a longer duration; whether this undifferentiated state remains
permanent with severe TD remains to be determined (37).
Interestingly, TD in the neonatal state actually induces greater
expression of the slow type I MHC in both slow and fast skeletal
muscles, and this occurs independently of gravity (1).
Thus it appears that circulating T3 is necessary for the
normal growth axis of the body as well as the skeletal muscle system to
occur. However, weight-bearing activity is necessary for the ability of
skeletal muscle to fully express the type I () MHC gene in
antigravity muscles.
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MHC PLASTICITY IN ADULT SKELETAL MUSCLE IN RESPONSE TO INCREASED
ACTIVITY PARADIGMS |
In this review, we will focus on three models of increased
mechanical activity: 1) the continuous functional
overloading of targeted muscles by the surgical removal of their
synergists, 2) the intermittent periodic loading of muscles
through heavy resistance-training paradigms (e.g., high loading but
relatively low contraction frequencies), and 3) endurance
exercise such as running (i.e., relatively low force output but high
contractile frequencies during each training session). The functional
overload model has been primarily used on small animals to establish
the upper limits of muscle fiber remodeling in response to a chronic level of overload stress. This perturbation has been shown to cause
marked fiber enlargement (without concrete evidence of hyperplasia; Ref. 108) along with significant changes in the
contractile protein phenotype (11, 18, 101, 102, 113). The
resistance-training paradigms have been shown to induce modest degrees
of muscle fiber enlargement, and some evidence of hyperplasia under
extreme conditions involving certain human and animals subjects has
also been shown (48). Endurance exercise is not associated
with significant increases in muscle fiber enlargement; rather, the
adaptations are confined chiefly to increases in mitochondrial
expression and moderate fast-to-slower MHC isoform shifts
(41).
Functional overload.
Studies on the functional overload model clearly show that, in fast
muscles such as the plantaris, the relative expression of the fast type
IIb and IIx MHCs decreases at both the protein and mRNA levels, whereas
both the fast IIa and slow type I are increased in expression at both
the mRNA and protein level (14, 18, 90, 101, 104). If an
endurance-exercise stimulus is imposed on muscles that are functionally
overloaded, the exercise stimulus enhances the repression of the fast
IIb MHC while further augmenting the expression of the fast IIa MHC
(97). Thus the combined intervention of overload and
endurance exercise further biases MHC expression in a direction toward
a slower phenotype. Recent studies using transgenic mice (74,
112, 118) and rodent muscles transfected with the type I MHC
promoter (43) showed that functionally overloaded
plantaris muscles increase type I MHC gene expression by a tight
coupling of transcriptional and translational events. The control of
transcription appears to be mediated by factors that interact with
regions in the type I MHC gene promoter that reside in the first 300 base pairs upstream of the initiation start site (43, 74, 75,
112, 117, 118).
Resistance training.
Studies using resistance-training paradigms have used both small
animals, such as rats, and humans as subjects. In the rodent model,
contraction paradigms of either the concentric, eccentric, or isometric
type, in which the targeted muscle group is electrically stimulated to
contract against a computer-driven ergometer system (14,
19), have been shown to induce significant decreases in type IIb
expression (protein and mRNA) and concomitant increases in the
expression of the fast type IIx MHC. In humans, resistance training has
been shown to produce a similar response with the exception that it is
the fast type IIx MHC that is downregulated and the fast IIa MHC that
is upregulated (2, 7, 22, 63). If the subjects are
detrained for several weeks, it appears that this process is reversed
and the reexpression of the fast type IIx appears to be even greater
than the level that was originally expressed in the pretraining period
(5). Furthermore, although it appears that the level of
type IIa expression in human subjects is associated to a greater extent
in individuals involved in resistance training, it is uncertain whether
the MHC profiling exerts a strong influence on strength adaptations,
especially in the initial stages of training (22).
Endurance exercise.
The effects of endurance exercise, such as running, on the MHC profile
appear to be both muscle specific and dose dependent. For example, in
rodents, when the animals are trained to run at moderate to high
intensity (~30 m/min; ~20% incline at ~75% maximal O2 uptake) for several weeks, the running effects on the
MHC profile of the soleus are manifest only when running lasted for
longer durations (60 and 90 min/day), with the overall profile
maintained with a slow, type I MHC predominance (32). In
mixed fast muscles and in portions of fast muscles (red vastus and
gastrocnemius), which have an intrinsic bias to type IIx and
IIa MHC expression, both the type IIa and IIx MHCs are upregulated
relative to the sedentary state, whereas the IIb MHC is significantly
downregulated (32). If the running is extended for more
extreme durations, it is possible to induce increased expression of the
type I MHC (32, 49). An exception to these high-intensity
exercise-induced MHC shifts to a slower muscle phenotype appears to
occur when rodents are trained at moderate to high running intensity
without the added stress of working against a steep incline. Under
these conditions, the exercise induces upregulation of the IIb MHC, whereas that of the IIx MHC is decreased (97). To our
knowledge, this is the first report that a specific activity paradigm
can enhance the expression of a fast isoform (e.g., IIb) in an already fast-twitch muscle. This type of regulation has been primarily associated with inactivity paradigms as described below.
In humans, word-class marathon runners and extreme endurance athletes
have been shown to possess a strong bias to expression of the slow type
I MHC in that 80-90% of the MHC pool is composed of the slow type
I MHC, with the remainder being type IIa MHC (9). In the
context of these observations, it has been shown that, in humans, a
short period of high-intensity endurance training induces a shift from
fast MHC isoforms toward the slow variety within histochemically typed
fibers of the vastus lateralis muscle (92). Furthermore, a
recent report by O'Neill et al. (83) demonstrated that 7 days of cycling exercise induced a significant downregulation of fast
IIx MHC mRNA. Thus, although gifted athletes may have a genetic
predisposition to excelling in certain athletic events due to their
inherent leg muscle MHC profiles, it appears that one's MHC gene
profile can be altered via chronic increases in contractile activity
such as physical training, as the data from the rodent and human
experiments strongly suggest. Also, it appears that the apparent
changes in human muscle isoform profiles result in hybrid fibers that
express a combination of isoforms such as IIx/IIa and type I/IIa
(9).
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MHC PLASTICITY IN RESPONSE TO DECREASED WEIGHT-BEARING ACTIVITY
PARADIGMS |
A variety of approaches have been used to examine muscle fiber
plasticity in response to reduced weight-bearing activity, and this
review will summarize results on four key models: 1) spaceflight, in which the lower limb muscles remain active but are
unloaded (i.e., they produce low force output); 2) hindlimb suspension, in which only the lower limbs are prevented from weight bearing; 3) spinalization (spinal transection, ST), in which
the cord has been either injured or severed; and 4) spinal
isolation (SI), in which the cord is severed in two places and afferent (sensory) input is eliminated between the two lesions. It is important to point out that in the first two models, although the lower limbs
(leg muscles) become relatively unloaded in terms of their force-generating requirements, the extensor muscles remain electrically active, based on the electromyographic patterns that are elicited under
these conditions (105). However, in spinalization or
spinal injury, electrical activity of the motoneuron pools can be
activated by sensory input, but the force-generation outputs of the
muscles are dramatically reduced (105). In the case of the
unique model of SI, the motoneurons connected to the muscle remain
intact, but the neurons are electrically silent due to their
inactivation (50). Thus the key feature of this latter
model is that it establishes a true inactivity baseline in that the
muscles are electrically silent and unloaded, but they still can be
influenced by trophic factors released from the neurons. In each of
these experimental settings, the extensor muscles of the legs undergo
marked degrees of atrophy, and the MHC profiles can be significantly
altered to reflect slow to fast transitions in MHC phenotype,
especially in the antigravity muscles (105).
Spaceflight and hindlimb suspension.
Exposure of rodents to the microgravity environment of spaceflight of
varying duration (4-16 days) induces, in addition to the atrophy
response, significant transitions in the MHC isoforms. These effects
are most prominent in slow muscle types involved in antigravity
function. These adaptations chiefly involve downregulation of the slow
type I MHC with the concomitant de novo expression of the fast type IIx
MHC (1, 10, 11, 20). These transitions appear to consist
of hybrid fibers that express both the slow type I and fast type IIx
MHC (20, 105). Additional findings show that these
transformations are regulated by pretranslational events, since the
mRNA profiles are generally consistent with those observed at the
protein level (1, 20). Similar patterns are observed with
the hindlimb suspension model (15, 16, 57, 111), with the
exception that, over time, the slow to fast transitions become more
exaggerated because the unloaded conditions can be extended for longer
durations, i.e., up to 8 wk (111). Although human studies
involving spaceflight and ground-based models of unloading have not
been extensive, the available information suggests that human muscle
undergoes type I to type II MHC transitions similar to those reported
for rodents; these transformations occur on a relatively similar time
scale as those reported above for rodents (105).
These alterations in both muscle mass and MHC phenotype involving
rodents are also associated with significant changes in the contractile
properties of whole muscles and isolated single fibers (that is, faster
contractile properties) but reduced force- and power-generating
profiles (17, 41). Additional studies (44, 74,
75) strongly suggest that the downregulation of the type I MHC
gene that occurs in these models of reduced weight-bearing activity are
controlled chiefly by transcriptional processes. These reports clearly
show that a segment in the type I MHC promoter (within 400 base pairs
upstream of the initiation start site) is highly sensitive to the
unloading stimulus (44, 74, 75). Additional studies are
necessary to determine whether these promoter segments indeed contain
gravity-sensitive response elements that interact with specific
transcription factors under the control of gravity-related transducing processes.
ST and SI.
ST of both cats and rats has been shown to cause transformations in MHC
expression that are qualitatively similar in fashion to those reported
for spaceflight/hindlimb suspension experiments (105). In
the cat, the type I MHC is downregulated and the fast IIx MHC (the
fastest MHC isoform identified in cat muscle; there is little evidence
that type IIb MHC is expressed) becomes predominantly expressed
(105). However, rodents show a higher degree of MHC isoform transformation after ST in that there is greater downregulation of the type I MHC with accompanying increases in the relative expression of all three fast MHC isoforms (105, 107).
Interestingly, the type IIx MHC, which is normally not expressed in the
soleus muscle, increases extensively in relative expression and can
account for almost 50% of the total MHC pool (105, 107).
Furthermore, there is also de novo expression of the IIb isoform, but
this isoform only accounts for ~10% of the MHC pool. Clearly, the
slow muscle of ST rats is essentially converted to a fast muscle, based on the MHC profile and shortening velocities seen in these muscles after 3 and 6 mo of ST (105). Importantly, in humans
suffering spinal cord injuries with lower extremity paralysis and the
inability to weight bear, there appears to be a considerable delay in
the transformation of slow to fast MHC profiles compared with that seen
in animal models (8, 23, 24, 105). For example, although there is little evidence for these transitions occurring during the
first ~10 mo following the initial trauma, patients with long-term spinal cord injuries show significant type I to IIa and IIx transitions after many months, and the type IIa and IIx MHCs isoforms have been
reported to account for as much as 90% of the MHC protein pool in some
of these patients (8). The reason for such a slow transition process is unknown. Also, these changes in MHC gene expression seem to be uncoupled from the rapid muscle atrophy that
takes place as the muscles lose their weight-bearing capacity.
This latter feature of spinal cord injury is also seen in the rodent SI
model in which the muscles becomes completely silent and thus unloaded
but their innervation remains intact. Under these conditions, the
muscles undergo rapid atrophy during the first 2 wk as well as a
progressive downregulation of the type I MHC (50). This
response is closely coupled to the progressive upregulation of chiefly
the type IIx MHC, a transition that was first reported to span a period
of 60 days (50). In a more recent report
(59), it was further demonstrated that the downregulation of type I MHC and the upregulation of the type IIx MHC took as long as
90 days to be fully manifest. These changes were mirrored by changes in
mRNA expression that mimicked the pattern seen for the MHC protein
(59). These findings also demonstrated that the
downregulation of the type I MHC gene is regulated by transcriptional processes that are impacted early on during the initial stage of SI.
Thus it is curious that these transitions take such a long time given
the fact that the muscles are completely inactivated mechanically.
However, if one considers the relatively long half-life of MHC (several
days) (73, 109, 113, 122), it is not surprising to observe
that it would take several half-lives before the type I protein is
markedly depleted in a completely inactive/unloaded muscle.
| |
DOES THE THYROID STATE MODULATE ACTIVITY/INACTIVITY-INDUCED CHANGES
IN SKELETAL MHC EXPRESSION? |
In the past two decades, it has become increasingly apparent that
thyroid hormone (T3) exerts a profound effect on the
plasticity of striated muscle given its strong influence on the
expression of the MHC gene family of motor proteins (17, 26, 65,
81, 121). The altered T3 state as well as the
altered loading state (mechanical activity) induce similar shifts in
MHC gene expression in striated muscles. For example, under conditions
of either hypothyroidism (TD) or increased loading state, all muscles
are transformed to a slower phenotype. The magnitude and specific
isoform shifts in this transformation vary with the muscle type. For
example, IIa/IIx-to-type I MHC transformations are observed in slow
muscles, whereas IIb/IIx-to-IIa/type I shifts are observed in fast,
mixed muscles (17). In contrast, it has been shown that
either hyperthyroidism (+T3) or unloading induces muscle
transformation to a faster phenotype involving repression of type I
() MHC expression and enhancement of fast IIx/IIb MHC
isoforms (17). In these latter transformations, the impact of +T3 on the type II MHCs appears to differ
from that of unloading-induced stimuli, depending on the muscle in
question. In soleus muscle, the type IIa MHC is upregulated in response to +T3 treatment, whereas the type IIx MHC is increased in
response to unloading (15, 16). Also, in the vastus
intermedius muscle, which is normally biased to expressing the slow
type I MHC but also expresses all three fast type II MHCs,
T3 treatment induces the upregulation of all three type II
MHCs, whereas unloading primarily upregulates expression of the IIx
MHC, as is the case for the soleus. Consequently, although the
mechanical loading state and the T3 state demonstrate
similar effects on mainly the type I MHC gene, subtle differences,
which appear to be muscle specific, are seen in terms of type II MHC expression.
Nevertheless, given the general similarities between the effects of
mechanical loading and effects of the thyroid state on MHC gene
regulation and the fact that both stimuli impact transcriptional events
(44, 74, 75, 87), the question arises as to whether the
effects of mechanical loading on, for example, type I MHC gene
expression are mediated via the action of the thyroid hormone, a potent
modulator of type I MHC transcriptional activity (87, 89,
119). In an attempt to address this issue, our group has used
several different experimental paradigms in which thyroid hormone
(T3) either 1) was competed against altered
loading states (i.e., +T3 vs. functional overload; TD vs.
hindlimb suspension; Refs. 34, 101) or
2) was used in conjunction with an altered loading state
(+T3 plus hindlimb suspension or TD plus functional overload; Refs. 15, 18, 57) to
test possible interactions between the two stimuli on MHC gene
expression. We reasoned that, if thyroid hormone and mechanical
interventions acted through different processes (signaling pathways and
transcriptional control mechanisms), one intervention would override
the other when they were competed, whereas the two would act
synergistically when they were allowed to interact. The findings
suggest the following. 1) When +T3 was competed
against functional overload and hypothyroidism was competed against
hindlimb suspension, the thyroid state effectively neutralized the
mechanical intervention altering type I MHC expression (34,
101). These results suggested that the two stimuli could be
acting via either a common pathway or two independent pathways; in the
latter case, they would neutralized one another. 2) When the
+T3 stimulus was administered in conjunction with hindlimb suspension and TD was used in conjunction with functional overload, their combined effects were synergistic (more than additive) in terms
of affecting type I MHC gene expression (15, 18, 57). These latter findings suggest that T3 and the mechanical
loading state exert their regulation through different pathways and/or mechanisms. In support of this conclusion, we have also demonstrated that, in the T3 plus hindlimb suspension model and in the
model of TD plus functional overload, thyroid treatment by itself,
mechanical intervention by itself, and their combined interactions
exert their respective effects by inducing a MHC gene distribution
profile that is clearly different from one experimental condition to
another as manifest across the spectrum of individual fibers comprising the test muscles (15). This conclusion was based on
observations that there is a uniquely different polymorphic
distribution (two or more MHC isoforms become expressed in a different
fiber) pattern of the various MHCs that comprise the individual fibers
making up the muscles of the above-mentioned experimental groups when the data are plotted in a MHC histogram distribution profile (see Figs.
2 and 3).
The idea that a given fiber expresses only a single MHC
isoform appears to hold true only in the case of the slow MHC fibers
that are expressed in the soleus muscle of normal animals (Fig. 3). In
normal, fast muscles and in both fast and slow muscles that undergo
alterations in MHC gene expression as reviewed herein, the pattern of
MHC expression becomes more polymorphic such that multiple isoforms are
contributing to the biochemical composition of the individual fibers
and the polymorphic pattern differs significantly with different
perturbations (15, 18, 57).
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Fig. 2.
Single-fiber MHC protein isoform composition of plantaris
muscles after 6 wk of experimental manipulations. All possible
combinations of adult MHC isoform expression are shown along the
x-axis. Each bar represents the proportion of a given
population relative to the total population of fibers examined for that
experimental group. Solid, dark gray, light gray, and open bars
represent relative amounts of slow type I, fast type IIa, fast type
IIx, and fast type IIb MHC protein isoforms, respectively, found within
any given fiber type. Note that the control (CON) plantaris muscles
contained a large number of polymorphic fibers, with the predominant
population coexpressing the fast type IIx and IIb MHC protein isoforms.
The combined treatment of thyroid deficiency and overloading
( T3+OV; T3 = 3,5,3'-triiodothyronine)
produced a significant reduction in the proportion of population of IIx
to IIb fibers and a large increase in fibers coexpressing all 4 MHC
protein isoforms. [Adapted from Caiozzo et al. (18).]
|
|
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|
Fig. 3.
Single-fiber MHC protein isoform composition of soleus
muscles after 4 wk of experimental manipulations. All possible
combinations of adult MHC isoform expression are shown along the
x-axis. Each bar represents the proportion of a given
population relative to the total population of fibers examined for that
group. Solid, dark gray, light gray, and open bars represent relative
amounts of slow type I, fast type IIa, fast type IIx, and fast type IIb
MHC protein isoforms, respectively, found within any given fiber type.
Note that the control soleus muscles predominantly contained fibers
expressing only type I MHC isoform (>70%). T3 is
associated with reduction in homogeneous type I fibers to <10% and an
increase in polymorphic fibers coexpressing I/IIa and I/IIa/IIx.
Similarly, hindlimb suspension (HS) is associated with a decrease in
pure type I fibers to ~40%, with the remaining fibers expressing at
least three (I, IIa, IIx) or all 4 MHC isoforms. Interestingly, the
combined treatment (T3+HS) transformed the normally
homogeneous soleus fiber population into one possessing a most
heterogeneous profile. In fact, fibers expressing all 4 MHC isoforms
were predominant. N = number of analyzed fibers per
group. [Data adapted from Caiozzo et al. (15).]
|
|
Are transitions in MHC gene expression obligated to follow a
prescribed sequence?
Previous reports proposed that, in adult muscles, the normal transition
in MHC expression, especially in response to a powerful model of
chronic electrical stimulation (not covered in this review), proceeds
in an ordered sequence in the direction IIb 
IIx IIa I and vice versa, depending on the type of perturbation imposed on the
target muscle (85, 95, 105, 109). In this scheme, it is
proposed that, if a muscle initially expressed only the type I MHC and
was subjected to an unloading stimulus, the muscle would be expected to
proceed by first expressing the IIa MHC; from this point, if the IIx
were to be upregulated, the transition would proceed via the coupled
downregulation of the IIa MHC and so forth. In other words, the muscle
fiber would be obligated to express the type IIa before being
programmed to express the IIx and vice versa. However, in several of
the rodent models examined in this review (e.g., SI, hindlimb
suspension, hindlimb suspension plus T3 treatment, TD plus
functional overload) unique patterns of MHC isoform expression were
observed as a result of the quantitative analyses of MHC expression
that occurred at the single-fiber level in these collective experiments
(15, 18, 106) (see Figs. 2 and 3). These observations
revealed that a significant percentage of the fibers simultaneously
expressed either type I/IIx hybrids, type I/IIb hybrids, or type
I/IIx/IIb hybrids, i.e., patterns of MHC gene transition that do not
conform to the model of ordered sequence of transition presented above.
Interestingly, in the +T3 plus suspension model
(15), after as little as 1 wk of intervention, ~15% of
the fiber pool of the soleus muscle simultaneously and abundantly
expressed all four adult MHCs (type I, IIa, IIx, and IIb). This same
pattern was observed in the plantaris muscle after 6 wk of TD plus
functional overload (18). Furthermore, it is noteworthy to
mention that this exception in single-fiber polymorphism was also
observed in human muscle fibers when subjects were on bed rest. A small
proportion of fibers was found to coexpress type I and IIx in the
absence of IIa (6). These fibers were termed jump fibers
(6) in that they do not conform to proposed sequential
transition of the continuum theory of MHC isoform expression (95). Collectively, these findings suggest that
1) individual muscle fibers comprising both fast and slow
muscles are not obligated to follow a fixed sequence of transitioning
MHC gene expression, and 2) the majority of fibers
comprising both fast and slow muscles have the genetic machinery to
express all the adult MHC isoforms known to be expressed in the limb
muscles of rodents. These findings suggest that there is a tremendous
degree of plasticity in MHC gene expression that can be induced in
striated muscle, depending on the environmental conditions imposed on a
given muscle.
| |
CONCLUSIONS AND FUTURE DIRECTIONS |
The findings reported in this brief review clearly show that both
cardiac and skeletal muscles of experimental animals are initially
undifferentiated at the time of birth and that these tissues undergo a
marked level of growth and differentiation in attaining the adult MHC
phenotype. In rodents, both an intact thyroid axis and weight-bearing
activity appear to be needed for normal muscle growth and the MHC
differentiation process to occur in both antigravity and locomotor
muscles. The cardiac muscle of small mammals is highly sensitive to TD,
diabetes, energy deprivation, and hypertension, and each of these
interventions induces either downregulation or maintained expression of
the fast -MHC, which is coupled to marked upregulation of the
-MHC to increase the expression of an isoform that functions to
economize myocardial contractile function. In skeletal muscle,
interventions that unload or reduce the weight-bearing activity of the
muscle cause slow-to-fast MHC conversions, whereas fast-to-slow
conversions are seen when the muscles become either chronically
overloaded or subjected to intermittent loading, as occurs during
resistance training and endurance exercise. The regulation of MHC gene
expression appears to be strongly regulated by transcriptional events,
based on recent findings on transgenic models and animals transfected with promoter-reporter constructs. Findings also show that the thyroid
state exerts equally profound transitions in the MHC phenotype in
skeletal muscles, which appear to mimic that seen in the
mechanical-loading paradigms. However, the mechanisms by which
T3 and mechanical stimuli exert their control on
transcriptional processes appear to be different. Additional findings
show that individual skeletal muscle fibers have the genetic machinery
to express simultaneously all of the adult MHCs in unique combinations
under certain experimental conditions. This degree of heterogeneity
among the individual fibers would ensure a large functional diversity
in performing complex movement patterns. Future studies must now focus
on the signaling pathways and the underlying mechanisms of the
transcriptional/translational machinery that controls these marked
degrees of plasticity; these studies may help us understand the
morphological organization and functional implications of the muscle
fiber's capacity to express such a diversity of motor proteins.
| |
ACKNOWLEDGEMENTS |
Research by K. M. Baldwin cited in this review was supported
in part by National Institutes of Health Grants AR-30346 and HL-38819
and National Space Biomedical Research Institute Grant NCC9-58-A.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: K. M. Baldwin, Dept. of Physiology and Biophysics, Univ. of California, Irvine, CA 92697 (E-mail: kmbaldwi{at}uci.edu).
| |
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TOP
ABSTRACT
INTRODUCTION
