From the Department of Anatomy and Neurobiology, Washington University Medical School, St. Louis, Missouri 63110
Many cells, including skeletal muscle fibers,
are coated by a layer of extracellular matrix material called the
basement membrane (BM).1 The
BM, in turn, is composed of two layers: an internal, felt-like basal
lamina (BL) directly linked to the plasma membrane, and an external,
fibrillar reticular lamina. BMs contain protein and carbohydrate but no
lipid or nucleic acid. Virtually all the protein is glycosylated, and
nearly all the carbohydrate is covalently bound to protein. The fibrils
of the reticular lamina are collagenous, and they are embedded in an
amorphous proteoglycan-rich ground substance. The BL contains
non-fibrillar collagen, non-collagenous glycoproteins, and
proteoglycans (1).
Initially, the BM was viewed as a static structure that provides
mechanical support; essentially something for the cells to sit on. A
key advance was the discovery that, because the acellular BM survives
injury to associated cells, it can provide a scaffold to orient and
constrain cells during regeneration (2). A more radical transformation
over the past few decades was the realization that BM components play
active roles and that these roles extend to developmental as well as
regenerative processes (1). In skeletal muscle, these processes include
myogenesis and synaptogenesis. Most recently, emphasis has shifted to a
search for the matrix-associated signals and membrane-associated
receptors that underlie cell-matrix interactions. The purpose of this
minireview is to relate results from the new molecular analyses to the
early cellular observations that motivated them. For more detailed
descriptions of what happened in between, see Refs. 3-5.
Although we now know that BMs are present in nearly all tissues,
their existence was first appreciated in muscle. In his 1840 report
"On the Minute Structure and Movements of Voluntary Muscle," Bowman
(6) described a "highly delicate, transparent, and probably elastic" sheath encircling individual muscle fibers. This sheath, which he called the sarcolemma, became apparent when muscle
fibers were injured during dissection; the cell itself lysed and
retracted, leaving the sarcolemma behind (Fig.
1). Over a century later, electron
microscopy revealed that the BM is the main component of such tubes and
that the BL is a main component of the BM. Today the term sarcolemma is
often used to refer to the plasma membrane alone, although only
fragments of it were present in Bowman's tubes (3). The terms BL and
BM are often used interchangeably, but should not be; I will attempt to
use them appropriately here.
INTRODUCTION
Muscle Strength
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Fig. 1.
Drawings of basement membrane sheaths that
survived injury to muscles from diverse species. These sketches,
by Bowman (6), were the first to show basement membranes in any
tissue.
Bowman's view of what we now know to be BM and particularly his evidence for its "strength and tenacity" (6) led directly to appreciation of its role in muscle function. Muscles are strong, flexible, and stress-resistant. Formal models of their mechanical properties include both contractile and elastic elements. The contractile element is, of course, the sarcomere, and extracellular matrix accounts for much of the elasticity. In fact, several matrix-rich structures contribute to muscle strength and elasticity, but a sizable fraction has been shown to reside in the BM (7).
Direct biophysical analysis of BM is lacking, but keys to its strength
most likely are its major structural components (8, 9). The most
abundant protein of the BL is triple-helical collagen IV, the subunits
of which, called chains, have prominent terminal non-collagenous
domains. The major non-collagenous protein is laminin, which is also a
heterotrimer of related chains, in this case called
,
, and
.
Both collagens IV and laminins exist in multiple isoforms, with the
most abundant in muscle being collagen (
1(IV))2(
2(IV))1 and laminin
2
1
1
(also called laminin-2). The basic structure of BLs appears to involve
distinct networks of collagens IV and laminin, each of which is capable
of self-assembly. The collagen network becomes cemented by covalent
cross-links, and the two networks are linked to each other by another
non-collagenous glycoprotein, entactin/nidogen. These core components
bear a multitude of recognition sites that bind other BL components,
anchor reticular lamina components to the BL, and serve as ligands for
membrane-associated receptors. Among the transmembrane receptors are
the integrins and dystroglycans, both of which interact with the
cytoskeleton (10, 11). Thus, one can envision a series of direct
linkages that together span the distance from reticular lamina to BL to plasma membrane to cytoskeleton. The BM provides a significant fraction
of the tensile strength of the whole structure (3), presumably via the
collagen/laminin networks of BL, which run orthogonal to this axis.
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Muscle Maintenance |
---|
Genetic studies of muscle disease show that the BM is critical for
the maintenance of muscle integrity. Positional cloning in humans and
analysis of naturally occurring and targeted mutants in mice have
revealed that muscular dystrophy can arise from loss of any of several
components in the reticular lamina-BL-membrane-cytoskeleton linkage.
These include laminin 2 (congenital muscular dystrophy), its major
transemembrane receptors, integrin
7 and
dystroglycan; dystrophin, which links dystroglycan to the cytoskeleton
(Duchenne muscular dystrophy); the dystroglycan- and
dystrophin-associated sarcoglycans (limb-girdle muscular dystrophies);
and the
chains of collagen VI, which help connect the BL to the
reticular lamina (Bethlem myopathy) (10-15). Importantly, in all of
these diseases, muscles develop normally but then degenerate. Thus,
even though the BL does play roles in myogenesis (see below) it is
separately required for muscle maintenance. In part, this requirement
may be a passive, mechanical one, but more active mechanisms also contribute. The core BL components, laminin and collagen IV, are signaling as well as structural molecules, and their receptors, dystroglycan and integrins, are signal transducers. For example, active
signaling from laminin
2 may provide a survival signal for muscle,
and its absence in congenital dystrophy is associated with particularly
high levels of apoptosis (16). In short, muscle maintenance requires
both the structural and signaling properties of BL.
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Myogenesis |
---|
In one of the first clear demonstrations that extracellular matrix
influences cellular differentiation, Hauschka and Konigsberg (17)
showed that substrate-bound collagen could replace "conditioned medium" factors in promoting the formation of myotubes from cultured myoblasts. Subsequent work showed that several matrix components affect
myogenesis. Of these, laminin appears to be particularly critical.
Laminin enhances proliferation of myoblasts, stimulates their motility,
and leads them to assume the bipolar shape characteristic of fusing
cells (18). Myotube formation is decreased, although not abolished, in
the absence of laminin (19). In contrast, fibronectin selectively
promotes adhesion of fibroblasts and may lead to dedifferentiation of
myoblasts (20). The locations of these proteins also differ; laminin
adjoins myotubes whereas fibronectin is initially excluded from
myogenic regions (20). Therefore, laminin and fibronectin may be
involved in sorting myoblasts from fibroblasts as well as in
orchestrating their differentiation. In addition, laminin and collagen
IV provide binding sites for proteoglycans, the principal one in muscle
being perlecan (8). The glycosaminoglycan chains of the proteoglycans,
in turn, provide binding sites that concentrate and present bioactive
polypeptides such as fibroblast growth factors and transforming growth
factors, which are critical for myogenesis (21, 22). Indeed, these nominally soluble factors are predominantly matrix-associated in
vivo. Thus, major BL components not only promote myogenesis directly but also orchestrate muscle development by presentation of
morphogenic, mitogenic, and trophic factors.
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Muscle Regeneration |
---|
Bowman's discovery of the BM arose from its persistence following injury during dissection. When injury occurs in vivo, new muscle fibers regenerate from a resident population of stem cells, called satellite cells, which are wedged between muscle fiber and BL. Bowman (6) noted that the BM "provides an effectual barrier between the parts within and those without"; as predicted from this property, most satellite cells remain within the BL as they divide and form myotubes (2, 23). Thus, by constraining the growth and migration of activated satellite cells, BL orients the regeneration of new muscle fibers. From what we know about myogenesis, it seems likely that the BL also actively promotes regeneration. In addition, BL acts as a mechanical barrier to prevent migratory loss of satellite cells from normal muscle and could be involved in repressing satellite cell mitosis and differentiation in the absence of damage.
The guidance that BL provides is of functional importance. Muscles do
regenerate if the BL is disrupted, but myotubes are not oriented in
parallel so the regenerate as a whole may develop little net force (3).
Furthermore, because BLs of nerves and blood vessels also act as
scaffolds for regeneration (2, 24), the integrity of connective tissue
favors rapid revascularization and reinnervation. In general, recovery
of function is good following injuries that minimally disrupt the
integrity and orientation of the sheaths and poor following injuries
that destroy these scaffolds.
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Integrity of Neuromuscular and Myotendinous Junctions |
---|
The extracellular matrix is structurally and functionally
specialized in areas where muscle abuts tendon or nerve. At the neuromuscular junction, BL but not reticular lamina passes between nerve and muscle membranes and extends into junctional folds that invaginate the postsynaptic membrane (Fig.
2). The BL thus constitutes a sizable
fraction of the synaptic cleft material of the neuromuscular junction.
The cleft is 50-nm-wide, which is a greater distance than that spanned
by membrane-associated adhesion molecules (e.g. cadherins).
Based on these considerations alone, it is evident that the BL must
contribute to the tight adhesion of pre- and postsynaptic partners.
Indeed, when muscles are treated with proteases that digest BL but not
plasma membrane, nerve terminals lose their firm attachment to the end
plate and can easily be pulled away (25). Moreover, when muscle is
damaged but not denervated, nerve terminals remain at their original
sites on the BL for months after the muscle fiber has degenerated (22,
26). Adhesion is likely to be mediated in part by integrins and
dystroglycan (27, 28). Other potential adhesive systems are mentioned
below.
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At the myotendinous junction, the surface of the muscle fiber is thrown
into invaginations that resemble junctional folds but are deeper. BL
extends into these invaginations and is attached to the plasma membrane
by periodically arrayed microfibrils (29). These fibrils and the
increased area of membrane-matrix apposition provided by the
invaginations are adaptations for the transmission of force from muscle
to tendon. Some molecular differences have been noted between the BL at
the myotendinous junction and that coating adjoining regions of the
sarcolemma (30, 31), but the functional significance of these
differences is unknown.
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Neuromuscular Transmission |
---|
The key events in neuromuscular transmission are release of acetylcholine from the nerve terminal and activation of acetylcholine receptors in the postsynaptic membrane. One might imagine that the BL would block movement of acetylcholine across the synaptic cleft, but kinetic studies show that its diffusion to receptors is unimpeded (32). This result is consistent with conclusions reached from analysis of glomerular BL in kidney, which is an effective filter only for macromolecules (33). Thus, diffusion of transmitter to receptors and the passive components of its subsequent dispersal are not significantly affected by BL.
On the other hand, the BL is involved in the hydrolysis of
acetylcholine by acetylcholinesterase (AChE), which terminates transmitter action faster than would occur by diffusion alone. It was
initially believed that AChE was attached to the membrane, as is the
case in neuron-neuron synapses. Subsequent studies showed, however,
that a major fraction of AChE at the neuromuscular synapse is stably
associated with synaptic BL (34, 35). The key to the association is a
collagen-like "tail" that is disulfide-bonded to tetramers of
catalytic AChE subunits; much of the synaptic enzyme in muscle but
little in brain is associated with the tail (35). The tail eluded
molecular analysis until recently, but its gene, named ColQ
("queue" is French for "tail") has now been cloned and
characterized (36, 37). Mutation of the ColQ gene in mice
leads to loss of synaptic AChE, and mutations of ColQ in humans underlie some cases of congenital myasthenia gravis (38, 39).
ColQ, in turn, binds to perlecan in the BL (40, 41). It is a
fascinating testament to the adaptive powers of the synapse that
genetic loss of ColQ or AChE is detrimental but not fatal, whereas
acute inactivation of AChE by nerve gas leads to fatal respiratory paralysis.
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Reinnervation |
---|
Following peripheral nerve injury, motor axons regenerate to form new neuromuscular junctions. Over 100 years ago, Tello (42) reported that the regenerating axons show a remarkable preference for original synaptic sites. Indeed, when trauma to nerve and muscle are minimized, over 95% of the contacts formed by regenerating axons on muscle fibers occur at original sites, even though these sites occupy only about 0.1% of the muscle fiber surface (5). Some of this precision reflects regrowth of axons along the connective tissue pathways that had been associated with the original nerve, a process in which the nerve BL plays a prominent role (24). Once the axons reach denervated muscle fibers, however, they reoccupy original sites at a submicron level of precision, demonstrating the existence of recognition factors closely associated with the muscle fiber surface.
Experiments on deliberately injured muscle showed that some of these
factors are associated with BL; when muscles were denervated, damaged,
and then x-irradiated to prevent muscle regeneration, axons
reinnervated original synaptic sites on the surviving BL sheaths (23).
Based in part on this result, several groups searched for BL components
selectively associated with synaptic sites. By now, several have been
identified, including site-restricted laminin and collagen IV variants,
proteoglycans, and growth factors held in place by proteoglycans (Fig.
2). A few components, such as the collagen IV 1 and
2 chains, are
excluded from synaptic sites, and a third class, including entactin and
perlecan, is present both synaptically and extrasynaptically (4, 30,
43-49). It is still not clear which if any of these components are
responsible for selective reinnervation of synaptic sites, but several
have now been shown to influence pre- and postsynaptic differentiation.
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Differentiation of Nerve Terminals |
---|
When axons innervate myotubes, they form nerve terminals that contain clusters of neurotransmitter-filled synaptic vesicles and membrane-associated release sites called active zones (5). Importantly, these presynaptic specializations occur only in the tiny fraction of the axon that directly contacts the postsynaptic cell, indicating that myotube-derived factors organize presynaptic differentiation. Portions of axons contacting BL sheaths from which muscle fibers had been removed (see above) also acquired active zones and synaptic vesicles as well as the ability to recycle vesicles when electrically stimulated. Moreover, new active zones formed in these terminals precisely in register with struts of BL that marked sites where junctional folds (and active zones) had once been (23). This association (Fig. 2) showed that some organizers of presynaptic differentiation were contained within the BL.
Among the muscle-derived organizers of presynaptic differentiation are
the synaptic laminins. The laminin 2 chain was initially identified
by virtue of its concentration in synaptic BL (50). Myotubes are able
to target
2 to postsynaptic specializations (51), leading to
formation of a BL in which synaptic sites bear primarily
2-containing trimers whereas extrasynaptic regions are enriched in
1-containing trimers. Moreover,
2 fragments or
2-containing
laminin-11 causes motor axons in vitro to stop growing and
to start differentiating into nerve terminals (52, 53). This behavior
contrasts with the robust neurite outgrowth that
1-containing
trimers promote. Together these results suggested a rationale for the
existence of multiple laminins; they generate local functional
diversity (here, synaptic versus extrasynaptic) in a common
structural framework.
In direct support of this model, presynaptic differentiation is
aberrant at neuromuscular junctions in 2 "knock-out" mutant mice: few active zones form, transmitter release is decreased, Schwann
cell processes invade the synaptic cleft, and animals die of
neuromuscular weakness around the time of weaning (Fig. 3B) (54, 55). Thus,
2
laminins qualify as muscle-derived organizers of presynaptic
differentiation. On the other hand, the fact that presynaptic
differentiation proceeds to a considerable extent in the absence of
2 indicates that additional organizers exist.
|
Additional analysis of muscle laminins revealed the presence of three
chains in synaptic BL (laminin
2,
4, and
5) but only one
(
2) extrasynaptically (46). Thus, synaptic BL may contain
laminins-4, -9, and -11 (
2
2
1,
4
2
1, and
5
2
1), all of which might be involved in presynaptic differentiation. Genetic
studies and analyses in vitro suggest distinct roles for each trimer (Fig. 3, B-D). Laminin-11 promotes presynaptic
differentiation and repels Schwann cell processes; laminin-9 promotes
the precise alignment of pre- and postsynaptic specializations; and
laminin-4 may be important for structural integrity, as is
2-containing laminin-2 extrasynaptically (30, 46, 56, 57). Thus,
three members of the same gene family collaborate to promote, organize, and maintain presynaptic differentiation.
The distinct activities of synaptic laminins suggest that they have
multiple receptors on axons and Schwann cells. Receptors presumably
include integrins, which bind laminins generally; indeed, integrin
3 is concentrated at active zones (27). In addition, laminins-9 and -11 co-purify with distinct presynaptic membrane components, the calcium channels that trigger transmitter release and
the vesicle-associated protein, SV2, respectively (58, 59). These
associations raise the possibility that laminins could organize presynaptic differentiation in part by direct interactions with critical components of the release apparatus.
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Differentiation of the Postsynaptic Membrane |
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Acetylcholine receptors (AChRs) are diffusely distributed in newly formed myotubes but highly concentrated in the postsynaptic membrane of adult muscle (~10,000/µm2 synaptically versus <10/µm2 extrasynaptically). Myotubes can cluster diffuse AChR clusters on their own, but classical studies demonstrated a striking ability of ingrowing axons to organize postsynaptic specializations, including AChRs, precisely at sites of nerve-muscle contact (5, 60). Once formed, synaptic specializations are stable. Aggregates of AChRs, associated with synaptic cytoskeletal, transmembrane, and BL components, persist at synaptic sites for many weeks following denervation. The stability of BL suggested that it might play a role in maintaining postsynaptic integrity, and experiments on BL sheaths supported this idea. When myotubes regenerated in these sheaths, following damage and denervation (see above), new postsynaptic specializations, including AChRs, formed in apposition to synaptic BL, even though the axon was absent (61). These results raised the possibility that some of the nerve-derived organizers of postsynaptic differentiation might be stably maintained in or presented by the BL. In fact, of numerous candidate postsynaptic organizers, only one has unequivocally been shown to play a role in vivo, and this is a nerve-derived synaptic BL component, z-agrin.
Agrin was isolated by McMahan and colleagues (62) in a search for
bioactive components of synaptic BL. Agrin is a heparan sulfate
proteoglycan with C-terminal domains that interact with the muscle
membrane and an N-terminal domain that mediates binding to laminin in
the BL (62-64). It is synthesized by motoneurons, transported down
axons, and released into the synaptic cleft (48). Loss- and
gain-of-function studies support the idea that agrin is necessary and
sufficient for postsynaptic differentiation. Targeted deletion of the
agrin gene in mice leads to devastating defects in neuromuscular
synaptogenesis, and local expression of agrin in denervated muscle
leads to assembly of a complete postsynaptic apparatus (65-67). A
potential complication is that muscles as well as motoneurons
synthesize agrin. However, only the latter express isoforms generated
by inclusion of C-terminal exons called "z"; z-containing isoforms
are 1000-fold more active than z-minus isoforms at clustering AChRs
in vitro, and targeted deletion of just the z exons leads to
postsynaptic defects as severe as those seen in the absence of all
agrin (68).
As a large, multidomain protein, it is not unexpected that agrin
interacts with many cellular receptors, including the neural cell
adhesion molecules, N-CAM, dystroglycan, and integrins (5). Genetic analysis has shown, however, that none of these are required for AChR clustering; instead, the critical receptor of agrin, at least
for this function, is a receptor tyrosine kinase called MuSK.
Activation of MuSK, in turn, leads to association of AChRs with the
cytoskeleton via a cytoplasmic protein called rapsyn (60). By
binding agrin, the BL both localizes the signal and allows its
persistence delivered by the nerve. In addition, dystroglycan and
proteins associated with it are involved in the maturation and
maintenance of the postsynaptic membrane in adult animals (60, 69); it
seems likely that the dystroglycan ligands in synaptic BL, agrin and
laminin, are involved in regulating the dynamic stability of the synapse.
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Conclusions |
---|
The BL of skeletal muscle plays a remarkable range of roles during
development and in adults. None is understood in detail, but all have
been documented convincingly, and molecular analysis is now well
underway. Muscle emerges, therefore, as one of the tissues in which we
are best able to relate the molecular architecture of BL to its
function. Some tentative conclusions, which may be applicable to other
tissues, are as follows. 1) The original view of the BL as a strictly
mechanical support has been augmented (but not replaced) by the
realization that it also has organizing and inductive functions
mediated by individual components. 2) The major components of BL,
laminins and collagens IV, are not only structural proteins, which form
networks within BL and links to neighboring structures, but they are
also signaling molecules that activate signal-transducing receptors in
the membrane. 3) Both laminins and collagens IV are families of
molecules that cells can target to particular domains within a single
BL. This diversity provides a means for fine localization of signals
within a uniform structural framework. 4) Binding sites on the core BL components mediate association of less abundant components such as
proteoglycans. The glycosaminoglycan components of the proteoglycans, in turn, bind, concentrate, and present nominally soluble signaling molecules, such as growth factors. To the structural and inductive roles of BL can therefore be added its ability to serve as a
"molecular bulletin board" in which adjoining cells can post
messages that direct the differentiation and function of the underlying cells.
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ACKNOWLEDGEMENT |
---|
I thank Bruce Patton for permission to use Fig. 3.
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FOOTNOTES |
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* This minireview will be reprinted in the 2003 Minireview Compendium, which will be available in January, 2004. The work performed in this author's laboratory was supported by the National Institutes of Health. This is the first article of four in the "Skeletal Muscle Basement Membrane-Sarcolemma-Cytoskeleton Interaction Minireview Series."
To whom correspondence should be addressed: Dept. of Anatomy and
Neurobiology, Washington University Medical School, 660 South Euclid
Ave., St. Louis, MO 63110. Tel.: 314-362-2507; Fax: 314-747-1150; E-mail: sanesj@pcg.wustl.edu.
Published, JBC Papers in Press, January 29, 2003, DOI 10.1074/jbc.R200027200
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ABBREVIATIONS |
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The abbreviations used are: BM, basement membrane; BL, basal lamina; AChE, acetylcholinesterase; AChR, acetylcholine receptor; MuSK, muscle-specific kinase.
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