Vol. 94, Issue 3, 1230-1241, March 2003
HIGHLIGHTED TOPICS
Plasticity in Respiratory Motor Control
Invited Review: Mechanisms underlying motor unit plasticity in the
respiratory system
Carlos B.
Mantilla and
Gary C.
Sieck
Departments of Anesthesiology and Physiology and Biophysics,
Mayo Medical School, Rochester Minnesota 55905
 |
ABSTRACT |
Neuromotor control of skeletal
muscles, including respiratory muscles, is ultimately dependent on the
function of the motor unit (comprising an individual motoneuron and the
muscle fibers it innervates). Considerable diversity exists across
diaphragm motor units, yet remarkable homogeneity is present (and
maintained) within motor units. In recent years, the mechanisms
underlying the development and adaptability of respiratory motor units
have received great attention, leading to significant advances in our understanding of diaphragm motor unit plasticity. For example, following imposed inactivity of the diaphragm muscle, there are changes
at phrenic motoneurons, neuromuscular junctions, and muscle fibers that
tend to restore the ability of the diaphragm to sustain ventilation.
The role of activity, neurotrophins, and other growth factors in
modulating this adaptability is discussed.
neurotrophins; diaphragm muscle; inactivity; respiration; phrenic
nerve
| |
INTRODUCTION |
NEUROMOTOR CONTROL OF THE diaphragm
muscle is organized similarly to other skeletal muscles, with the final
common output being the motor unit, comprising a phrenic
motoneuron and the diaphragm muscle fibers it innervates (28,
129). Properties of the motor unit population are critically
important in determining the functional characteristics of the
diaphragm during a variety of motor behaviors. In fact, diaphragm motor
units exhibit great diversity in terms of their mechanical and fatigue
properties (28, 129). Diversity is also evident by
structural and functional differences in phrenic motoneurons (3,
14, 54, 61, 71, 106, 143, 149), neuromuscular junctions
(69, 105, 107, 109, 110, 112, 135, 137), and muscle fibers
(35, 36, 130, 131, 133, 134).
As the major inspiratory muscle in mammals, activation of the diaphragm
is very unique in relation to most other skeletal muscles. The daily
duty cycle (ratio of active to inactive times) for hindlimb muscles
ranges from ~2% for the extensor digitorum longus muscle
(predominantly composed of type IIb fibers) to ~14% for the soleus
muscle (predominantly composed of type I fibers) (53). In
contrast, the duty cycle of the diaphragm muscle in most species is
~45%. Because of its remarkable and unique activation history, the
diaphragm may be particularly responsive to disuse, especially
inactivity. A variety of other factors may also influence diaphragm
muscle remodeling. For example, the diaphragm is not a load-bearing
muscle like the soleus and other hindlimb muscles. The diaphragm muscle
also differs with regard to afferent input derived from muscle
spindles, which are scarcely found in the diaphragm muscle.
Premotoneurons providing rhythmic excitatory drive to the phrenic
motoneuron pool are more remotely located in the medulla. This stands
in contrast to the close proximal location of premotoneurons providing
afferent input to limb motoneuron pools. Because of the remote location
of premotoneurons and lack of muscle spindle input, upper cervical
spinal cord injury completely disrupts rhythmic excitatory drive to
phrenic motoneurons, leading to complete paralysis of the diaphragm
muscle. In contrast, because premotoneurons providing afferent input to
limb motoneuron pools are locally distributed, afferent drive and the
potential for locomotor patterns remain largely intact after spinal
cord injury. These major differences are very important when
considering neuroplasticity in motor control.
| |
CLASSIFICATION OF MOTOR UNIT TYPES |
Although motor unit heterogeneity probably reflects a continuum of
properties, motor units have been categorized into different types
primarily based on the mechanical and fatigue characteristics of the
innervated muscle fibers (10-12, 28, 129).
Accordingly, motor units are classified into four types: 1)
slow-twitch, fatigue-resistant (type S), 2) fast-twitch,
fatigue-resistant (type FR), 3) fast-twitch, fatigue-intermediate (type FInt), and 4) fast-twitch,
fatigable (type FF) (Fig. 1). Muscle
fiber-type classification also generally follows a corresponding
scheme, whether based on histochemistry or myosin heavy chain (MHC)
isoform expression. Thus muscle fibers are classified into four types:
1) type I (MHCSlow), 2) type IIa (MHC2A), 3) type IIb (MHC2B), and
4) type IIx (MHC2X) (7, 99, 116-119,
129, 136, 138).
View larger version (39K):
[in this window]
[in a new window]
|
Fig. 1.
Different motor unit types in the diaphragm muscle are
distinguished by mechanical and fatigue properties of muscle fibers
(type S, slow; type FR, fast-twitch, fatigue resistant; type FInt,
fast-twitch, fatigue intermediate; and type FF motor units,
fast-twitch, fatigable) as well as myosin heavy chain (MHC) isoform
expression (MHCSlow, MHC2A, MHC2X,
and MHC2B).
|
|
| |
HETEROGENEITY OF MOTOR UNIT PROPERTIES |
The morphology of motoneurons within a pool varies considerably
(13-15, 106, 143). Heterogeneity in somal morphology
and dendritic arborization may contribute to differences in
electrophysiological properties across motoneurons. In fact, it has
been shown that the intrinsic electrophysiological properties of
motoneurons display considerable heterogeneity, which may depend on
motoneuron size and motor unit type. For example, it has been reported
that motoneurons belonging to type S motor units generally have the
highest input resistance, lowest rheobase, and slowest axonal
conduction velocities among motoneurons. In contrast, motoneurons
belonging to type FF motor units are the largest (lowest input
resistance), least excitable (highest rheobase), and display the
fastest axonal conduction velocities (10, 155).
The structural and functional properties of neuromuscular junctions
also vary considerably across different motor unit types (Fig.
2) (27, 62, 105, 107-112, 128,
132, 135). For instance, neuromuscular junctions at type IIx and
IIb diaphragm muscle fibers are larger and have a far more complex
structure compared with neuromuscular junctions at type I and IIa
fibers. Ultrastructural differences in the pre- and postsynaptic
elements of neuromuscular junctions also exist across motor unit types
(24, 25, 94, 152). For example, the presynaptic terminals
of neuromuscular junctions at type I and type IIa diaphragm muscle
fibers are smaller and contain fewer mitochondria compared with those
at type IIx and type IIb fibers. Postsynaptic folding is also less
complex at type I and type IIa fiber neuromuscular junctions, and, at these fibers, mitochondria, rough endoplasmic reticulum, free polysomes, and nuclei are interposed between postsynaptic
specializations and myofibrils. Consistent with these fiber-type
differences in the morphology of neuromuscular junctions,
electrophysiological properties of neuromuscular transmission have also
been reported to vary with motor unit type. For example, the amplitude
of excitatory postsynaptic potentials generated at neuromuscular
junctions correlates with the input resistance of the motoneuron
(10). In addition, differences in synaptic efficacy also
exist across motor unit types (37, 56). Gertler and
Robbins (37) compared the safety factor for neuromuscular
transmission (defined as the ratio of endplate potential amplitude to
muscle fiber activation threshold) of neuromuscular junctions at soleus
and extensor digitorum longus muscles of the rat (comprising type I and
IIb fibers, respectively). They found that the safety factor for
neuromuscular transmission was lower for type I fibers of the soleus
and remained stable with repetitive stimulation. In contrast,
neuromuscular junctions at type IIb fibers of the extensor digitorum
longus muscle had a higher initial safety factor for neuromuscular
transmission, but with repeated stimulation the safety factor
decreased. Accordingly, it is not surprising that neuromuscular
transmission failure in the rat diaphragm muscle is also dependent on
the rate of motor axon stimulation (27, 75), with the
incidence of action potential propagation failure and neuromuscular
transmission failure increasing with increasing stimulus frequency
(27, 62). In the cat diaphragm muscle, our laboratory
found that type FF motor units were more susceptible to neuromuscular
transmission failure compared with type S or FR motor units
(128). Similar results were reported for motor units from
other muscles (18, 114).
View larger version (46K):
[in this window]
[in a new window]
|
Fig. 2.
Morphological differences in neuromuscular junctions at
type-identified diaphragm muscle motor units. Triple-labeled confocal
images of diaphragm muscle neuromuscular junctions (axon terminal shown
in red, motor end-plate in green, and MHC fiber type in blue) were used
to determine the morphology of pre- and postsynaptic elements. Notice
the differences in complexity, size, and extent of overlap evident
across motor unit types.
|
|
Despite the considerable diversity across motor unit types, there is
remarkable homogeneity in the properties of muscle fibers comprising an
individual motor unit. The mechanical and biochemical properties of
innervated muscle fibers are consistent within a motor unit and are
precisely matched to the properties of the motoneuron (10, 47,
76, 89, 90, 129, 130). This precise matching reflects
neuron-target cell interactions that could be mediated by the
activation history of the motor unit or the influence of neurotrophic
(or myotrophic) substances.
Although diversity in motor unit phenotype could be determined
genetically and established early during embryonic development, multiple lines of evidence indicate that communication between motoneurons and muscle fibers plays a continuing role in maintaining and remodeling motor units (8, 21, 45, 68, 113). This communication can take the form of neural electrical activity (propagated action potentials) or chemical influences derived from
either the motoneuron or muscle fiber (8, 41, 97). In
addition, a variety of environmental factors such as external load,
muscle blood flow, local oxygen tension, and accumulation of
metabolites can influence the properties of motor units (compare Refs.
97, 99, 101, 119,
142 for reviews). It is beyond the scope of the present
review to explore the multitude of factors that can influence motor
unit plasticity. Instead, we will focus on neural activity and
neurotrophic influences.
| |
MOTOR UNIT RECRUITMENT |
Phenotypic differences in the components of the motor unit are
likely to result in altered functional capacity of the diaphragm muscle. Based on the classic model of Sherrington and colleagues (77, 124), force development in skeletal muscle is
achieved through the orderly recruitment of motor units. Henneman and
colleagues (51, 52) provided a unifying principle for
motor unit recruitment based on the size of motoneurons and their
intrinsic electrophysiological properties (Henneman "size
principle"). According to the size principle, smaller motoneurons
with smaller axons and slower conduction velocities have lower membrane
capacitance, higher input resistance, and lower rheobase and thus are
recruited first for a given synaptic input. In support of the size
principle, it has been shown that phrenic motoneurons with
slower axonal conduction velocities are recruited first during
inspiratory efforts (61). Not inconsistent with
Henneman's size principle, specific motor unit types also appear to be
an important determinant of motor unit recruitment order (10, 26,
129, 140, 141). It has also been shown that type S and FR motor
units [comprising type I (MHCSlow) and IIa (MHC2A) muscle fibers, respectively] are recruited first
and more often, whereas type FInt and FF motor units [comprising type
IIx (MHC2X) and IIb (MHC2B) fibers,
respectively] are recruited later and less frequently. Assuming a
recruitment order based on motor unit type, the more sustained motor
behaviors of the diaphragm muscle can be achieved by the recruitment of
only type S and FR motor units (28, 125-127, 130, 134,
146). Recruitment of type FInt and FF motor units would be
required only during more forceful and less frequent motor behaviors of
the diaphragm muscle (28, 129). Thus it is likely that
phrenic motoneurons and diaphragm muscle motor units vary considerably
in their activation history.
| |
MOTONEURON-TARGET CELL INTERACTIONS |
Since the seminal papers of Buller and colleagues (8,
9), considerable evidence has accumulated to support the concept that motoneurons exert a predominant influence on the contractile and
metabolic properties of the muscle fibers they innervate. In addition
to the cross-innervation studies of Buller et al., support derives from
motor unit studies where homogeneous fiber-type composition has been
consistently reported (11, 12, 22, 47, 89, 90). For
example, diaphragm muscle motor units comprise muscle fibers with
remarkably similar enzymatic and contractile protein properties, e.g.,
succinate dehydrogenase activity and MHC isoform composition
(129, 130). Together, these results reflect the importance
of neuron-target cell interactions in providing a match between the
properties of motoneurons that dictate recruitment order and the
mechanical and energetic properties of muscle fibers that sustain motor
behaviors. However, these results do not shed light on whether this
match depends on activation history or the influence of neurotrophic factors.
| |
MOTOR UNIT PLASTICITY |
Motor unit plasticity can occur at each of its components, i.e.,
motoneuron, neuromuscular junctions, and/or muscle fibers. Adaptation
of diaphragm muscle motor units to altered use may underlie, at least
in part, the etiology of certain diseases. For example, in chronic
obstructive pulmonary diseases, diaphragm muscle activity increases,
but, to be effective, this increase in diaphragm muscle activity must
be met while avoiding fatigue. Therefore, diaphragm muscle neuromotor
control must adapt to the increased mechanical loads imposed by
respiratory diseases. Conversely, in situations requiring maintenance
of patients on mechanical ventilation, the diaphragm muscle is
unloaded. Altered use of the diaphragm muscle, whether it is an
increase or decrease in activity, may cause adaptations at each level
of the motor unit. For example, there may be hypertrophy or atrophy of
muscle fibers, altered expression of contractile proteins, and changes
in fiber mechanical properties. At neuromuscular junctions, there may
be remodeling of pre- and postsynaptic elements and changes in synaptic efficacy. At phrenic motoneurons, there may be changes in somal surface
area or dendritic branching. Such adaptations may affect motoneuron
recruitment, synaptic transmission, and/or the ability of the diaphragm
muscle to generate sufficient force for ventilation while resisting
fatigue. In considering plasticity in neuromotor control, it is
important to recognize that each diaphragm muscle motor unit type can
adapt to altered use in different ways depending on mechanical loads,
innervation patterns, activation history, and fiber-type composition.
Although the activation history and functional requirements of
diaphragm muscle motor units are unique, the innervation patterns and
fiber-type composition of the diaphragm muscle are similar to other
skeletal muscles.
| |
MUSCLE FIBER PHENOTYPE TRANSITION |
Role of innervation.
Classic studies demonstrated that the metabolic and mechanical
properties of skeletal muscles are altered in response to changes in
innervation (8, 21, 45, 68, 113). These studies clearly established that adult muscle fiber type is not fixed but mutable when
provided with an appropriate stimulus related to innervation. However,
this stimulus could be either the pattern of activity, which varies
across motor unit types, or due to specific motoneuron-derived trophic influences.
The effects of denervation on muscle fiber properties also demonstrate
the predominant role of innervation. As with cross-innervation studies,
the effects of denervation do not distinguish between the removal or
modification of a neurotrophic influence or inactivity. However,
results from denervation studies have shed some light on muscle fiber
phenotype transitions. Most importantly, it has been reported that
postdenervation changes are inconsistent with predenervation muscle
fiber phenotype. For example, denervation of the adult rat soleus
muscle results in the transition of only ~50% of the predenervation
slow fibers to fast fibers (1, 60). Thus it is possible
that the postdenervation muscle fiber phenotype may depend on the
embryological lineage of muscle fibers, reflecting genetically
determined patterns of motor unit differentiation.
Role of activity patterns.
A number of studies have demonstrated muscle fiber phenotype
transitions with altered patterns of electrical stimulation (see Refs.
97, 99, 142 for reviews). For
example, fibers in the rat soleus muscle, which predominantly express
MHCSlow, can be converted to a faster muscle phenotype by
imposing a higher rate of electrical stimulation. Conversely, muscles
such as the extensor digitorum longus, which comprise fibers
predominantly expressing MHC2X and MHC2B
isoforms, can be converted to a slower muscle phenotype by imposing a
slower rate of electrical stimulation (98, 99, 102).
Phenotypic transitions in muscle fibers exposed to altered patterns of
electrical stimulation (and including conditions of concurrent
denervation) involve not only transitions in the expression of MHC
isoforms but also the expression of other myofibrillar proteins (e.g.,
myosin light chains, troponin subunits, tropomyosin, and 
-actinin)
and Ca2+-regulatory and sarcoplasmic reticulum proteins
(e.g., Ca2+-ATPase, calsequestrin, and phospholamban).
Furthermore, transitions in the expression of enzymes associated with
glycolytic and oxidative pathways have also been reported following
electrical stimulation (see Refs. 99, 100 for
reviews). Thus it is widely accepted that the pattern of motor unit
activity can influence muscle fiber phenotype.
In previous studies, we examined the role of innervation
and activity patterns on diaphragm muscle fiber phenotype by comparing adaptations induced by unilateral denervation,
tetrodotoxin-induced nerve blockade and C2 spinal cord
hemisection (34, 85, 156-158) (Fig.
3). In each of these experimental models,
the right side of the diaphragm muscle was paralyzed. However, with
unilateral denervation, communication between phrenic motoneurons
and diaphragm muscle fibers was completely disrupted; with unilateral
tetrodotoxin-induced nerve blockade, communication between phrenic
motoneurons and diaphragm muscle fibers was conserved; and, with
C2 spinal hemisection, communication between phrenic
motoneurons and diaphragm muscle fibers remained intact, but
motoneurons were inactive. We found marked differences in the
plasticity of diaphragm muscle motor units induced by these three
experimental models. For example, our laboratory
(156-158) found that both denervation and
tetrodotoxin-induced diaphragm muscle paralysis caused selective
atrophy of type IIx and IIb diaphragm muscle fibers. Our laboratory
also found that denervation (34) and tetrodotoxin-induced
nerve blockade (unpublished observations) caused a reduction in MHC
content per half sarcomere and reduced specific force of type IIx and
IIb fibers. In contrast, diaphragm muscle paralysis induced by
C2 hemisection caused little if any change in fiber size,
MHC content, or mechanical properties (85). Based on these
results, we concluded that muscle inactivity per se is not the major
determinant of diaphragm muscle motor unit plasticity. With both
C2 hemisection and tetrodotoxin-induced nerve blockade,
communication between phrenic motoneurons and diaphragm muscle fibers
remains intact; however, after C2 hemisection, phrenic
motoneurons are inactive, whereas after tetrodotoxin-induced nerve
blockade, phrenic motoneuron activity increases by ~50% (156-158). Therefore, it is possible that a direct
trophic influence on diaphragm muscle fibers results from and is
affected by motoneuron activity, independent of actual inactivation of
muscle contraction. Furthermore, because the effects of denervation and
tetrodotoxin-induced nerve blockade on diaphragm muscle fibers were
similar, it would appear that a mismatch between phrenic motoneuron
activity and presynaptic inactivity, as exists with
tetrodotoxin-induced nerve blockade, has the same effect as the
complete disruption of communication between motoneurons and muscle
fibers. With both unilateral diaphragm muscle denervation and
tetrodotoxin-induced phrenic nerve block, it appears that a positive
trophic influence is removed, whereas with C2 hemisection
this trophic influence is preserved.
View larger version (23K):
[in this window]
[in a new window]
|
Fig. 3.
Experimental models used for the study of activity-dependent
plasticity of diaphragm muscle motor units. After unilateral
denervation, tetrodotoxin-induced nerve blockade, and C2
hemisection, the diaphragm muscle is paralyzed. However, differences in
communication between the phrenic motoneuron and muscle fibers and in
the activity of phrenic motoneurons across these models exist.
|
|
A fundamental unresolved question is whether the intrinsic ability of
skeletal muscle to adapt to changes in innervation and/or activity is
governed by molecular imprinting or activation patterns established
during myogenesis. In other words, although extrinsic factors (e.g.,
activity patterns, gravity, hormonal influences) can modify muscle
fiber phenotype at all stages of adult life, the overall effect of
these various influences may be constrained by genetic programming
appearing as early as the myotube stage, i.e., well before formation of
distinct fiber types. Other unresolved questions regarding muscle fiber
phenotype transitions include the role of intracellular
Ca2+ or Ca2+-dependent intracellular signaling
cascades, neurotrophic factors, and activation of transcription factors.
Role of intracellular Ca2+ and
calcineurin-related signaling.
Recent studies suggest that the molecular mechanism(s) responsible for
activity-dependent adaptation of muscle fibers may involve changes in
Ca2+ handling and calcineurin related pathways (4,
17, 96). Calcineurin is a Ca2+/calmodulin-dependent
serine/threonine protein phosphatase, which by dephosphorylating
cytosolic members of the NF-AT family (nuclear factors of activated T
cells) causes their nuclear translocation (72). Nuclear
NF-ATs then bind to specific nucleotide sequences in
promoter/enhancer regions and stimulate the transcription of slow fiber
genes (17, 122). In addition, the
peroxisome-proliferator-activated receptor-
coactivator 1 (PGC-1) has been shown to serve as a transcriptional coactivator for
slow fiber genes by acting in cooperation with the myogenic regulatory
factor Mef2 and as a target of calcineurin signaling (78).
However, it is possible that multiple pathways are involved in the
motor unit type-specific adaptations of muscle fibers. For example, Ras
signaling through the mitogen-activated protein kinase (MAPK) pathway
mimics the effect of slow-type electrical muscle stimulation on myosin
gene expression (87).
Myogenic regulatory factors.
Myogenic regulatory factors were initially implicated as possible
mediators of the transition of muscle fiber phenotype in response to
altered motor unit activity because of their demonstrated role in
muscle differentiation (58, 59, 144). Accordingly, a
fiber-type-specific effect of the myogenic regulatory factors, MyoD,
myogenin, MRF-4, on muscle phenotype has been recently suggested (123, 147). However, changes in MyoD and myogenin
expression after chronic low-frequency stimulation of type FF motor
units are only modest and are not associated with a shift in the ratio of MyoD to myogenin (74, 91). Thus the actual role of
myogenic regulatory factors in muscle fiber phenotypic transitions in
response to changes in neuromuscular activity remains to be determined.
| |
PLASTICITY AT THE NEUROMUSCULAR JUNCTION |
Maintenance of synaptic efficacy may be the driving force behind
neuromuscular junction remodeling (145, 151). In previous studies, our laboratory (85, 108, 109) found that the
changes in diaphragm muscle neuromuscular junction morphology and
function induced by C2 hemisection and tetrodotoxin-induced
nerve blockade were quite different. After 2 wk of C2
hemisection, there was an expansion of neuromuscular junction size at
type IIx and IIb diaphragm muscle fibers and a marked improvement in
neuromuscular transmission. After 2 wk of tetrodotoxin-induced nerve
blockade, there was some evidence of nerve terminal sprouting, but
otherwise there was no overt change in neuromuscular junction
morphology. However, tetrodotoxin-induced nerve blockade resulted in a
marked increase in neuromuscular transmission failure.
In addition to the remodeling of diaphragm muscle neuromuscular
junctions evident after altered activity, neuromuscular junction plasticity has been examined in a variety of other conditions. For example, motor unit-type-specific differences in neuromuscular junction morphology and function have been reported during
embryogenesis (86), aging (44, 70, 110),
hypothyroidism (105), and chronic testosterone
(5) or corticosteroid (20, 137) treatment.
Role of neurotrophins.
Recent evidence, primarily from neuronal culture systems, indicates
that neurotrophins participate in activity-induced modification of
synaptic transmission (19, 103, 139). These studies have shown that neurotrophin synthesis and release are regulated by neuronal
activity and that neurotrophins can also directly modulate synaptic
efficacy (19, 66, 67, 121). There are a number of
potential neurotrophins that might affect nerve-muscle interactions (Fig. 4). Specifically, brain-derived
neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) have been
shown to affect neuromuscular transmission (6, 80). In a
series of studies, Poo and colleagues (80) demonstrated
that BDNF rapidly potentiates both spontaneous and evoked synaptic
activity of developing neuromuscular junctions of Xenopus
laevis studied in culture. Furthermore, they found that this
effect was presynaptic in origin and was mediated by TrkB receptors.
More recently, they demonstrated that BDNF-induced potentiation of
synaptic efficacy at developing Xenopus laevis neuromuscular
junctions was greatly facilitated by presynaptic depolarization
(6). These investigators also demonstrated that the effect
of BDNF on synaptic transmission in cultured hippocampal neurons
depended on specific properties of the target cells innervated. Exogenous BDNF induced a rapid and persistent potentiation of evoked
glutamate release when the target cell neuron was also glutamatergic
but not when the target cell was GABAergic (-aminobutyric acid).
These results suggest that individual nerve terminals can be
independently modified by BDNF, depending on the specific target (120).
View larger version (39K):
[in this window]
[in a new window]
|
Fig. 4.
The family of neurotrophins includes nerve growth factor
(NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3),
and neurotrophin-4/5 (NT-4/5). The effects of neurotrophins are
mediated by a family of tyrosine kinase receptors (TrkA, TrkB, and
TrkC), which show the following preferences: TrkA for NGF, TrkB for
BDNF and NT-4/5, and TrkC for NT-3.
|
|
The tyrosine kinase receptor for BDNF and NT-4/5 (TrkB) is found at
diaphragm muscle neuromuscular junctions (both at presynaptic and
postsynaptic sites) (23, 40), suggesting that BDNF and NT-4/5 might influence neuromuscular transmission at diaphragm muscle
motor units. It is possible that BDNF and/or NT-4/5 plays an important
role in regulating synaptic transmission at neuromuscular junctions
under normal conditions. Pre- and/or postsynaptic release of
neurotrophins may tightly regulate neurotransmitter release and thus
synaptic efficacy (Fig. 5). For example,
NT-4/5 has been shown to potentiate presynaptic acetylcholine release
in Xenopus nerve-muscle cocultures (148). In
addition, BDNF may stimulate synapsin I phosphorylation in a
MAPK-dependent manner (64, 65) and therefore regulate
neurotransmitter release (55). TrkB activation within the
presynaptic terminal may thus exert immediate effects (mediated by MAPK
or other pathway activation) in addition to longer-term effects
(mediated by transcriptional regulation following retrograde transport
of the activated neurotrophin-receptor complex) (121).
Accordingly, it is possible that BDNF and/or NT-4/5 may play an
important role in the remodeling of diaphragm muscle neuromuscular junctions that occurs following C2 hemisection or
tetrodotoxin-induced inactivation of presynaptic terminals. However,
these possibilities remain to be explored.
View larger version (59K):
[in this window]
[in a new window]
|
Fig. 5.
Schematic demonstrating the possible pre- and
postsynaptic effects of the neurotrophins BDNF and NT-4/5 on synaptic
efficacy. Neurotrophins released from pre- or postsynaptic sites may
activate presynaptic TrkB receptors, leading to synapsin
phosphorylation via a mitogen-activated protein kinase (MAPK) pathway
and thus have short-term effects on neurotransmitter (ACh) release. In
addition, retrograde transport of the activated neurotrophin-Trk
receptor complex may have longer term transcriptional effects within
motoneurons.
|
|
Other growth factors may also regulate the number and/or function of
synaptic connections between a motoneuron and its target muscle fibers.
Glial-derived neurotrophic factor (GDNF) is a potent survival factor
for motoneurons that is synthesized by muscle fibers and Schwann cells
(50, 57, 153, 154). Production of GDNF by limb skeletal
muscle was reported to be activity dependent (150), and
overexpression of GDNF, but not NT-4/5 or NT-3, in developing limb
muscles leads to hyperinnervation of neuromuscular junctions
(92). It is certainly possible that different neurotrophic factors may have motor unit pool-specific effects, which could be
mediated by selective expression of factors, their receptors, or
individual signaling pathway components.
| |
MOTONEURON PLASTICITY |
An important model of functional reorganization of respiratory
motor output has been advanced by Mitchell and colleagues
(30) and has been termed "long-term facilitation."
Long-term facilitation refers to the prolonged augmentation of
respiratory motor output reported following repeated carotid sinus
nerve stimulation (29, 48, 84) or repeated episodic
hypoxia (2). In fact, a robust effect on respiratory
output has been shown in both the phrenic and hypoglossal nerves, even
lasting upward of 1 h, and has been observed in awake rats
(95). Importantly, long-term facilitation has been
reported to be serotonin dependent (30, 32, 79). However,
a specific range of hypoxia may exist for the induction of long-term
facilitation (83), and this may explain reports with
conflicting success in inducing long-term facilitation.
Phrenic motoneurons have also been shown to exhibit an enhancement of
long-term facilitation in response to cervical deafferentation (71). A significant increase in the number and density of
serotonin immunoreactive terminals in the vicinity of phrenic
motoneuron soma and dendrites was reported. However, phrenic motoneuron
somal surface areas were found to increase, suggesting a decrease in motoneuron excitability (71). These findings suggest that
motor unit plasticity may result from a complex interplay of structural (morphological) changes and synaptic inputs, which contribute to the
functional output of phrenic motoneurons. Chronic cervical deafferentation via bilateral cervical dorsal rhizotomy
(C3-C6) has also been shown to enhance the
recovery of ipsilateral phrenic motor function (crossed-phrenic
phenomenon, see below) following a C2 spinal
hemisection, although serotonin receptor activation was not necessary
for this effect (31). It is possible that the synaptic
plasticity of descending serotonergic innervation and the morphological
alterations of phrenic motoneurons following chronic deafferentation
mediate the functional reorganization of respiratory motor output.
Functional adaptations of phrenic motoneurons to inactivity have also
been shown to involve potentiation of the cross-phrenic phenomenon and
include partial recovery of motor function under increased ventilatory
drive (42, 43, 88, 93). The so-called "crossed-phrenic
phenomenon" refers to the restoration of ipsilateral diaphragm muscle
activity after C2 spinal hemisection when the contralateral
diaphragm is paralyzed by denervation (104). Several studies by Goshgarian and colleagues (43, 46) have
demonstrated significant ultrastructural changes in the cervical spinal
cord after C2 spinal hemisection. For example, within hours
after C2 spinal hemisection, there is a significant
increase in the number of "double synapses" and the length of
dendro-dendritic appositions. Similar changes were also reported after
cold-induced blockade of descending cervical drive (16).
It has been suggested that retraction of glial processes facilitates
these ultrastructural changes (43), unmasking previously
ineffective synaptic connections within the spinal cord, and thus serve
as substrate for the crossed-phrenic phenomenon. In fact, a
time-dependent restoration of diaphragm muscle function after
C2 spinal hemisection has been reported (38,
39). Our laboratory has also found that contralateral denervation 4 wk following unilateral C2 spinal hemisection
results in reactivation of the ipsilateral paralyzed hemidiaphragm,
especially when a hypoxic stimulus is applied (W. Zhan, C. Mantilla, G. Sieck, unpublished observations).
In a recent study (81), our laboratory examined
C2 hemisection and tetrodotoxin-induced changes in the
morphology of phrenic motoneurons. Phrenic motoneuron inactivation
associated with C2 hemisection resulted in an overall
decrease in motoneuron size, primarily affecting somal dimensions
rather than dendrites. In contrast, tetrodotoxin-induced diaphragm
muscle paralysis without concomitant inactivity of phrenic motoneurons
resulted in an overall increase in motoneuron size, again primarily
restricted to somal dimensions. It is possible that changes in phrenic
motoneuron size are motor unit specific, with larger motoneurons
being disproportionately affected after C2 hemisection and
smaller phrenic motoneurons being disproportionately affected after
tetrodotoxin-induced nerve blockade.
Role of neurotrophins.
BDNF and NT-4/5 have been shown to be produced by motoneurons
(33, 49, 73, 115). In fact, after 7 days of cervical dorsal rhizotomy, an increase in BDNF and NT-3 expression in the cervical spinal cord was reported (63). The authors
reported that immunohistochemistry localized BDNF and NT-3 to
motoneurons and interneurons of the ventral spinal cord. We have
documented BDNF and NT-4/5 immunoreactivity in retrogradely labeled rat
phrenic motoneurons (unpublished observations), suggesting a potential role of these neurotrophins in phrenic motor unit plasticity. After
C2 spinal hemisection, a rapid (3 day) increase in BDNF and
NT-4/5 mRNA in the ventral cervical spinal cord and a gradual return to
prehemisection levels by 14 days posthemisection were shown
(82). It is possible that, in addition to effects of
motoneuron-derived neurotrophins, retrograde transport of the activated
neurotrophin-Trk receptor complex from presynaptic terminals may affect
transcriptional regulation within motoneurons. These retrograde
signals may serve to regulate the matching of motoneuron and
presynaptic terminal activity and thus contribute to the different
morphological adaptations of phrenic motoneurons following diaphragm
muscle paralysis induced by C2 hemisection vs. tetrodotoxin
nerve blockade. Although neurotrophins likely contribute to
spinal cord plasticity, there is currently a dearth of knowledge
regarding specific neurotrophin-mediated effects on motoneuron
structural, synaptic, and functional adaptations to altered activity.
| |
CONCLUSIONS AND FUTURE DIRECTIONS |
Although much is now known about the plasticity of respiratory
motor units in response to altered activity, many questions remain
unanswered. Adaptations in motor units may occur at any and all of its
components: the motoneuron, the neuromuscular junction, and/or the
target muscle fibers. Motor unit-type-specific adaptations are critical
when determining the final output of motor pools and the resulting
motor behaviors. Further studies are needed to evaluate the relative
contribution of specific neurotrophic factors, signaling pathways, and
transcriptional activators to the plasticity of motor units in response
to altered activity and other environmental factors.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: G. C. Sieck, Dept. of Physiology and Biophysics, Mayo Medical School, 200 First St. SW, Joseph 4-184W, Rochester, MN 55905 (E-mail: sieck.gary{at}mayo.edu).
10.1152/japplphysiol.01120.2002
| |
REFERENCES |
1.
Ansved, T,
and
Larsson L.
Effects of denervation on enzyme-histochemical and morphometrical properties of the rat soleus muscle in relation to age.
Acta Physiol Scand
139:
297-304,
1990.
2.
Bach, KB,
and
Mitchell GS.
Hypoxia-induced long-term facilitation of respiratory activity is serotonin dependent.
Respir Physiol
104:
251-260,
1996.
3.
Berger, AJ.
Phrenic motoneurons in the cat: subpopulations and nature of respiratory drive potentials.
J Neurophysiol
42:
76-90,
1979.
4.
Bigard, X,
Sanchez H,
Zoll J,
Mateo P,
Rousseau V,
Veksler V,
and
Ventura-Clapier R.
Calcineurin co-regulates contractile and metabolic components of slow muscle phenotype.
J Biol Chem
275:
19653-19660,
2000.
5.
Blanco, CE,
Zhan WZ,
Fang YH,
and
Sieck GC.
Exogenous testosterone treatment decreases diaphragm neuromuscular transmission failure in male rats.
J Appl Physiol
90:
850-856,
2001.
6.
Boulanger, L,
and
Poo MM.
Presynaptic depolarization facilitates neurotrophin-induced synaptic potentiation.
Nat Neurosci
2:
346-351,
1999.
7.
Brooke, MH,
and
Kaiser KK.
Muscle fiber types: how many and what kind?
Arch Neurol
23:
369-379,
1970.
8.
Buller, AJ,
Eccles JC,
and
Eccles RM.
Interactions between motoneurones and muscles in respect of the characteristic speeds of responses.
J Physiol
150:
417-439,
1960.
9.
Buller, AJ,
Mommaerts WF,
and
Seraydarian K.
Enzymic properties of myosin in fast and slow twitch muscles of the cat following cross-innervation.
J Physiol
205:
581-597,
1969.
10.
Burke, RE.
Motor units: anatomy, physiology and functional organization.
In: Handbook of Physiology. The Nervous System. Motor Control. Bethesda, MD: Am. Physiol. Soc, 1981, vol. II, p. 345-422, sect. 1, pt. 1, chapt. 11.
11.
Burke, RE,
Levine DN,
Tsairis P,
and
Zajac FE, III.
Physiological types and histochemical profiles in motor units of the cat gastrocnemius.
J Physiol
234:
723-748,
1973.
12.
Burke, RE,
Levine DN,
and
Zajac FE, III.
Mammalian motor units: physiological-histochemical correlation in three types in cat gastrocnemius.
Science
174:
709-712,
1971.
13.
Burke, RE,
Marks WB,
and
Ulfhake B.
A parsimonious description of motoneuron dendritic morphology using computer simulation.
J Neurosci
12:
2403-2416,
1992.
14.
Cameron, WE,
Averill DB,
and
Berger AJ.
Morphology of cat phrenic motoneurons as revealed by intracellular injection of horseradish peroxidase.
J Comp Neurol
219:
70-80,
1983.
15.
Cameron, WE,
Averill DB,
and
Berger AJ.
Quantitative analysis of the dendrites of cat phrenic motoneurons stained intracellularly with horseradish peroxidase.
J Comp Neurol
230:
91-101,
1985.
16.
Castro-Moure, F,
and
Goshgarian HG.
Morphological plasticity induced in the phrenic nucleus following cervical cold block of descending respiratory drive.
Exp Neurol
147:
299-310,
1997.
17.
Chin, ER,
Olson EN,
Richardson JA,
Yang Q,
Humphries C,
Shelton JM,
Wu H,
Weiguang Z,
Bassel-Duby R,
and
Williams RS.
A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type.
Genes Dev
12:
2499-2509,
1998.
18.
Clamann, HP,
and
Robinson AJ.
A comparison of electromyographic and mechanical fatigue properties in motor units of the cat hindlimb.
Brain Res
327:
203-219,
1985.
19.
Cohen-Cory, S.
The developing synapse: construction and modulation of synaptic structures and circuits.
Science
298:
770-776,
2002.
20.
Drakontides, AB.
The effect of glucocorticoid treatment on denervated rat hemidiaphragm.
Brain Res
239:
175-189,
1982.
21.
Dubowitz, V.
Cross-innervated mammalian skeletal muscle: histochemical, physiological, and biochemical observations.
J Physiol
193:
481-496,
1967.
22.
Edstrom, L,
and
Kugelberg E.
Histochemical composition, distribution of fibres and fatiguability of single motor units. Anterior tibial muscle of the rat.
J Neurol Neurosurg Psychiatry
31:
424-433,
1968.
23.
Escandon, E,
Soppet D,
Rosenthal A,
Mendoza-Ramirez JL,
Szonyi E,
Burton LE,
Henderson CE,
Parada LF,
and
Nikolics K.
Regulation of neurotrophin receptor expression during embryonic and postnatal development.
J Neurosci
14:
2054-2068,
1994.
24.
Fahim, MA,
Holley JA,
and
Robbins N.
Scanning and light microscopic study of age changes at a neuromuscular junction in the mouse.
J Neurocytol
12:
13-25,
1983.
25.
Fahim, MA,
Holley JA,
and
Robbins N.
Topographic comparison of neuromuscular junctions in mouse slow and fast twitch muscles.
Neuroscience
13:
227-235,
1984.
26.
Fleshman, JW,
Munson JB,
Sypert GW,
and
Friedman WA.
Rheobase, input resistance, and motor-unit type in medial gastrocnemius motoneurons in the cat.
J Neurophysiol
46:
1326-1338,
1981.
27.
Fournier, M,
Alula M,
and
Sieck GC.
Neuromuscular transmission failure during postnatal development.
Neurosci Lett
125:
34-36,
1991.
28.
Fournier, M,
and
Sieck GC.
Mechanical properties of muscle units in the cat diaphragm.
J Neurophysiol
59:
1055-1066,
1988.
29.
Fregosi, RF,
and
Mitchell GS.
Long-term facilitation of inspiratory intercostal nerve activity following carotid sinus nerve stimulation in cats.
J Physiol
477:
469-479,
1994.
30.
Fuller, DD,
Bach KB,
Baker TL,
Kinkead R,
and
Mitchell GS.
Long term facilitation of phrenic motor output.
Respir Physiol
121:
135-146,
2000.
31.
Fuller, DD,
Johnson SM,
Johnson RA,
and
Mitchell GS.
Chronic cervical spinal sensory denervation reveals ineffective spinal pathways to phrenic motoneurons in the rat.
Neurosci Lett
323:
25-28,
2002.
32.
Fuller, DD,
Zabka AG,
Baker TL,
and
Mitchell GS.
Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia.
J Appl Physiol
90:
2001-2006,
2001.
33.
Funakoshi, H,
Frisen J,
Barbany G,
Zachrisson O,
Verge VM,
and
Persson H.
Differential expression of mRNAs for neurotrophins and their receptors after axotomy.
J Cell Biol
123:
455-465,
1993.
34.
Geiger, PC,
Cody MJ,
Macken RL,
Bayrd ME,
and
Sieck GC.
Effect of unilateral denervation on maximum specific force in rat diaphragm muscle fibers.
J Appl Physiol
90:
1196-1204,
2001.
35.
Geiger, PC,
Cody MJ,
Macken RL,
and
Sieck GC.
Maximum specific force depends on myosin heavy chain content in rat diaphragm muscle fibers.
J Appl Physiol
89:
695-703,
2000.
36.
Geiger, PC,
Cody MJ,
and
Sieck GC.
Force-calcium relationship depends on myosin heavy chain and troponin isoforms in rat diaphragm muscle fibers.
J Appl Physiol
87:
1894-1900,
1999.
37.
Gertler, RA,
and
Robbins N.
Differences in neuromuscular transmission in red and white muscles.
Brain Res
142:
160-164,
1978.
38.
Golder, FJ,
Reier PJ,
and
Bolser DC.
Altered respiratory motor drive after spinal cord injury: supraspinal and bilateral effects of a unilateral lesion.
J Neurosci
21:
8680-8689,
2001.
39.
Golder, FJ,
Reier PJ,
Davenport PW,
and
Bolser DC.
Cervical spinal cord injury alters the pattern of breathing in anesthetized rats.
J Appl Physiol
91:
2451-2458,
2001.
40.
Gonzalez, M,
Ruggiero FP,
Chang Q,
Shi YJ,
Rich MM,
Kraner S,
and
Balice-Gordon RJ.
Disruption of Trkb-mediated signaling induces disassembly of postsynaptic receptor clusters at neuromuscular junctions.
Neuron
24:
567-583,
1999.
41.
Gordon, T,
and
Pattullo MC.
Plasticity of muscle fiber and motor unit types.
Exerc Sport Sci Rev
21:
331-362,
1993.
42.
Goshgarian, HG,
Ellenberger HH,
and
Feldman JL.
Decussation of bulbospinal respiratory axons at the level of the phrenic nuclei: a possible substrate for the crossed-phrenic phenomenon.
Exp Neurol
111:
135-139,
1991.
43.
Goshgarian, HG,
Yu XJ,
and
Rafols JA.
Neuronal and glial changes in the rat phrenic nucleus occurring within hours after spinal cord injury.
J Comp Neurol
284:
519-533,
1989.
44.
Gosselin, LE,
Prakash YS,
Masters DB,
and
Sieck GC.
Effect of aging on diaphragm neuromuscular junction morphology (Abstract).
Neurosci Abstr
21:
1664,
1995.
45.
Guth, L,
Watson PK,
and
Brown WC.
Effects of cross-reinnervation on some chemical properties of red and white muscles of rat and cat.
Exp Neurol
20:
52-69,
1968.
46.
Hadley, SD,
Walker PD,
and
Goshgarian HG.
Effects of serotonin inhibition on neuronal and astrocyte plasticity in the phrenic nucleus 4 h following C2 spinal cord hemisection.
Exp Neurol
160:
433-445,
1999.
47.
Hamm, TM,
Nemeth PM,
Solanki L,
Gordon DA,
Reinking RM,
and
Stuart DG.
Association between biochemical and physiological properties in single motor units.
Muscle Nerve
11:
245-254,
1988.
48.
Hayashi, F,
Coles SK,
Bach KB,
Mitchell GS,
and
McCrimmon DR.
Time-dependent phrenic nerve responses to carotid afferent activation: intact vs. decerebellate rats.
Am J Physiol Regul Integr Comp Physiol
265:
R811-R819,
1993.
49.
Henderson, CE,
Camu W,
Mettling C,
Gouin A,
Poulsen K,
Karihaloo M,
Rullamas J,
Evans T,
McMahon SB,
Armanini MP,
Berkemeier L,
Phillips HS,
and
Rosenthal A.
Neurotrophins promote motor neurons survival and are present in embryonic limb bud.
Nature
363:
266-270,
1993.
50.
Henderson, CE,
Phillips HS,
Pollack RA,
Davies AM,
Lemeulle C,
Armanini M,
Simpson LC,
Moffet B,
Vandlen RA,
Koliatsos VE,
and
Rosenthal A.
GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle.
Science
266:
1062-1064,
1994.
51.
Henneman, E.
Relation between size of neurons and their susceptibility to discharge.
Science
126:
1345-1346,
1957.
52.
Henneman, E,
Somjen G,
and
Carpenter DO.
Functional significance of cell size in spinal motoneurons.
J Neurophysiol
28:
560-580,
1965.
53.
Hernsbergen E and Kernell D. Daily duration of activity in ankle
muscles of cats. XXXIInd IUPS, Glasgow,
Scotland, 1993.
54.
Hilaire, G,
Monteau R,
and
Khatib M.
Determination of recruitment order of phrenic motoneurons.
In: Respiratory Muscles and Their Neuromotor Control, edited by Sieck GC,
Gandevia SC,
and Cameron WE.. New York: Liss, 1987, p. 249-261.
55.
Hilfiker, S,
Pieribone VA,
Czernik AJ,
Kao HT,
Augustine GJ,
and
Greengard P.
Synapsins as regulators of neurotransmitter release.
Philos Trans R Soc Lond B Biol Sci
354:
269-279,
1999.
56.
Hofmann, WW.
Electrical responses of mammalian slow and fast fibres.
Nature
212:
904-906,
1966.
57.
Houenou, LJ,
Oppenheim RW,
Li L,
Lo AC,
and
Prevette D.
Regulation of spinal motoneuron survival by GDNF during development and following injury.
Cell Tissue Res
286:
219-223,
1996.
58.
Hughes, SM,
Koishi K,
Rudnicki M,
and
Maggs AM.
MyoD protein is differentially accumulated in fast and slow skeletal muscle fibres and required for normal fibre type balance in rodents.
Mech Dev
61:
151-163,
1997.
59.
Hughes, SM,
Taylor JM,
Tapscott SJ,
Gurley CM,
Carter WJ,
and
Peterson CA.
Selective accumulation of MyoD and myogenin mRNAs in fast and slow adult skeletal muscle is controlled by innervation and hormones.
Development
118:
1137-1147,
1993.
60.
Jakubiec-Puka, A,
Ciechomska I,
Morga J,
and
Matusiak A.
Contents of myosin heavy chains in denervated slow and fast rat leg muscles.
Comp Biochem Physiol B Biochem Mol Biol
122:
355-362,
1999.
61.
Jodkowski, JS,
Viana F,
Dick TE,
and
Berger AJ.
Electrical properties of phrenic motoneurons in the cat: correlation with inspiratory drive.
J Neurophysiol
58:
105-124,
1987.
62.
Johnson, BD,
and
Sieck GC.
Differential susceptibility of diaphragm muscle fibers to neuromuscular transmission failure.
J Appl Physiol
75:
341-348,
1993.
63.
Johnson, RA,
Okragly AJ,
Haak-Frendscho M,
and
Mitchell GS.
Cervical dorsal rhizotomy increases brain-derived neurotrophic factor and neurotrophin-3 expression in the ventral spinal cord.
J Neurosci
20:
RC77,
2000.
64.
Jovanovic, JN,
Benfenati F,
Siow YL,
Sihra TS,
Sanghera JS,
Pelech SL,
Greengard P,
and
Czernik AJ.
Neurotrophins stimulate phosphorylation of synapsin I by MAP kinase and regulate synapsin I-actin interactions.
Proc Natl Acad Sci USA
93:
3679-3683,
1996.
65.
Jovanovic, JN,
Czernik AJ,
Fienberg AA,
Greengard P,
and
Sihra TS.
Synapsins as mediators of BDNF-enhanced neurotransmitter release.
Nat Neurosci
3:
323-329,
2000.
66.
Kafitz, KW,
Rose CR,
Thoenen H,
and
Konnerth A.
Neurotrophin-evoked rapid excitation through TrkB receptors.
Nature
401:
918-921,
1999.
67.
Kang, H,
and
Schuman EM.
Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus.
Science
267:
1658-1662,
1995.
68.
Karpati, G,
and
Engel WK.
Transformation of the histochemical profile of skeletal muscle by "foreign" innervation.
Nature
215:
1509-1510,
1967.
69.
Kelly, SS,
and
Robbins N.
Bimodal miniature and evoked end-plate potentials in adult mouse neuromuscular junctions.
J Physiol
346:
353-363,
1984.
70.
Kelly, SS,
and
Robbins N.
Statistics of neuromuscular transmitter release in young and old mouse muscle.
J Physiol
385:
507-516,
1987.
71.
Kinkead, R,
Zhan WZ,
Prakash YS,
Bach KB,
Sieck GC,
and
Mitchell GS.
Cervical dorsal rhizotomy enhances serotonergic innervation of phrenic motoneurons and serotonin-dependent long-term facilitation of respiratory motor output in rats.
J Neurosci
18:
8436-8443,
1998.
72.
Klee, CB,
Ren H,
and
Wang X.
Regulation of the calmodulin-stimulated protein phosphatase, calcineurin.
J Biol Chem
273:
13367-13370,
1998.
73.
Koliatsos, VE,
Clatterbuck RE,
Winslow JW,
Cayouette MH,
and
Price DL.
Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo.
Neuron
10:
359-367,
1993.
74.
Kraus, B,
and
Pette D.
Quantification of MyoD, myogenin, MRF4 and Id-1 by reverse-transcriptase polymerase chain reaction in rat muscles
effects of hypothyroidism and chronic low-frequency stimulation.
Eur J Biochem
247:
98-106,
1997.
75.
Kuei, JH,
Shadmehr R,
and
Sieck GC.
Relative contribution of neurotransmission failure to diaphragm fatigue.
J Appl Physiol
68:
174-180,
1990.
76.
Larsson, L,
Edstrom L,
Lindegren B,
Gorza L,
and
Schiaffino S.
MHC composition and enzyme-histochemical and physiological properties of a novel fast-twitch motor unit type.
Am J Physiol Cell Physiol
261:
C93-C101,
1991.
77.
Liddell, EGT,
and
Sherrington CS.
Recruitment and some other factors of reflex inhibition.
Proc R Soc Lond B Biol Sci
97:
488-518,
1925.
78.
Lin, J,
Wu H,
Tarr PT,
Zhang CY,
Wu Z,
Boss O,
Michael LF,
Puigserver P,
Isotani E,
Olson EN,
Lowell BB,
Bassel-Duby R,
and
Spiegelman BM.
Transcriptional co-activator PGC-1 drives the formation of slow- twitch muscle fibres.
Nature
418:
797-801,
2002.
79.
Ling, L,
Fuller DD,
Bach KB,
Kinkead R,
Olson EB, Jr,
and
Mitchell GS.
Chronic intermittent hypoxia elicits serotonin-dependent plasticity in the central neural control of breathing.
J Neurosci
21:
5381-5388,
2001.
80.
Lohof, AM,
Ip NY,
and
Poo M.
Potentiation of developing neuromuscular synapses by the neurotrophin NT-3 and BDNF.
Nature
363:
350-353,
1993.
81.
Mantilla CB, Zhan WZ, Prakash YS, Zhan P, and Sieck GC.
Inactivity-induced structural plasticity of phrenic motoneurons.
J Comp Neurol In press.
82.
Mantilla, CB,
Zielinska W,
Zhan WZ,
and
Sieck GC.
C2 hemisection alters TrkB and NT-4/5 mRNA expression in both diaphragm muscle and spinal cord (Abstract).
FASEB J
16:
A771,
2002.
83.
McGuire, M,
Zhang Y,
White DP,
and
Ling L.
Effect of hypoxic episode number and severity on ventilatory long-term facilitation in awake rats.
J Appl Physiol
93:
2155-2161,
2002.
84.
Millhorn, DE,
Eldridge FL,
and
Waldrop TG.
Prolonged stimulation of respiration by a new central neural mechanism.
Respir Physiol
41:
87-103,
1980.
85.
Miyata, H,
Zhan WZ,
Prakash YS,
and
Sieck GC.
Myoneural interactions affect diaphragm muscle adaptations to inactivity.
J Appl Physiol
79:
1640-1649,
1995.
86.
Muniak, CG,
Kriebel ME,
and
Carlson CG.
Changes in MEPP and EPP amplitude distributions in the mouse diaphragm during synapse formation and degeneration.
Dev Brain Res
5:
123-138,
1982.
87.
Murgia, M,
Serrano AL,
Calabria E,
Pallafacchina G,
Lomo T,
and
Schiaffino S.
Ras is involved in nerve-activity-dependent regulation of muscle genes.
Nat Cell Biol
2:
142-147,
2000.
88.
Nantwi, KD,
and
Goshgarian HG.
Alkylxanthine-induced recovery of respiratory function following cervical spinal cord injury in adult rats.
Exp Neurol
168:
123-134,
2001.
89.
Nemeth, PM,
Pette D,
and
Vrbova G.
Comparison of enzyme activities among single muscle fibres within defined motor units.
J Physiol
311:
489-495,
1981.
90.
Nemeth, PM,
Solanki L,
Gordon DA,
Hamm TM,
Reinking RM,
and
Stuart DG.
Uniformity of metabolic enzymes within individual motor units.
J Neurosci
6:
892-898,
1986.
91.
Neufer, PD,
and
Benjamin IJ.
Differential expression of B-crystallin and Hsp27 in skeletal muscle during continuous contractile activity. Relationship to myogenic regulatory factors.
J Biol Chem
271:
24089-24095,
1996.
92.
Nguyen, QT,
Prasadanian AS,
Snider WD,
and
Lichtman JW.
Hyperinnervation of neuromuscular junctions caused by GDNF overexpression in muscle.
Science
279:
1725-1729,
1998.
93.
O'Hara, TEJ,
and
Goshgarian HG.
Quantitative assessment of phrenic nerve functional recovery mediated by the crossed phrenic reflex at various time intervals after spinal cord injury.
Exp Neurol
111:
244-250,
1991.
94.
Oki, S,
Matsuda Y,
Kitaoka K,
Nagano Y,
Nojima M,
and
Desaki J.
Scanning electron microscope study of neuromuscular junctions in different muscle fiber types in the zebra finch and rat.
Arch Histol Cytol
53:
327-332,
1990.
95.
Olson, EB, Jr,
Bohne CJ,
Dwinell MR,
Podolsky A,
Vidruk EH,
Fuller DD,
Powell FL,
and
Mitchel GS.
Ventilatory long-term facilitation in unanesthetized rats.
J Appl Physiol
91:
709-716,
2001.
96.
Olson, EN,
and
Williams RS.
Calcineurin signaling and muscle remodeling.
Cell
101:
689-692,
2000.
97.
Pette, D.
Historical Perspectives: plasticity of mammalian skeletal muscle.
J Appl Physiol
90:
1119-1124,
2001.
98.
Pette, D,
and
Staron RS.
Mammalian skeletal muscle fiber type transitions.
Int Rev Cytol
170:
143-223,
1997.
99.
Pette, D,
and
Staron RS.
Myosin isoforms, muscle fiber types, and transitions.
Microsc Res Tech
50:
500-509,
2000.
100.
Pette, D,
and
Staron RS.
Transitions of muscle fiber phenotypic profiles.
Histochem Cell Biol
115:
359-372,
2001.
101.<
TOP
ABSTRACT
INTRODUCTION
