From the Howard Hughes Medical Institute and
Department of Physiology, University of Iowa College of Medicine,
Iowa City, Iowa 52242 and the ¶ Department of Physiology,
University of Texas Southwestern Medical Center, Dallas, Texas
75390
The sarcolemma (muscle plasma membrane) plays a
central role in skeletal muscle structure and function (1). In addition to the housekeeping functions of a cell plasma membrane, the sarcolemma is directly involved in synaptic transmission, action potential propagation, and excitation-contraction coupling (1). Besides these
well established physiological functions, the sarcolemma, subsarcolemma
cytoskeleton, and surrounding basement membrane (extracellular matrix)
play an essential structural role in skeletal muscle (1-3). The
biological importance of the basement membrane-sarcolemma-cytoskeleton in skeletal muscle is underscored by the number of inherited muscle diseases caused by mutations in components of the basement membrane, or
cytoskeleton, or the sarcolemma protein complexes that link the
basement membrane to the cytoskelton (4-8). The minireview in this and
the following issues updates our understanding of the structure and
function of the basement membrane, cytoskeletal costameres, and the
major trans-sarcolemma links (integrins and dystroglycan) in skeletal muscle.
The basement membrane surrounds skeletal muscle fibers and is now known
to be critical in muscle fiber structure and function. The skeletal
muscle basement membrane is composed of the basal lamina and the
reticular lamina. Basal lamina is directly linked to the sarcolemma.
Genetic studies of muscular dystrophy patients and animal models of
muscular dystrophy have demonstrated the importance of the basement
membrane in maintenance of muscle integrity. In addition to maintenance
of muscle integrity, the basement membrane is essential in the
promotion of myogenesis and muscle development. Muscle regeneration is
also a process that depends on the skeletal muscle basement membrane.
Satellite cells (endogenous stem cells of skeletal muscle) reside
between the muscle fiber and the basal lamina. Following injury, new
muscle fibers regenerate within a basement membrane tube, which is
believed to act as a mechanical barrier to limit migration of satellite
cells, and a scaffold to orient myotube regeneration. Finally,
the basement membrane is structurally and functionally specialized in
areas of neuromuscular and myotendinous junctions and is required for
the assembly of these structures. In the first minireview of this
series entitled "The Basement Membrane/Basal Lamina of Skeletal
Muscle," Joshua R. Sanes reviews the structure and function of the
skeletal muscle basement membrane. In particular, he focuses on
recent molecular studies that have led to a better understanding of the
function of the basement membrane in skeletal muscle physiology and
pathophysiology (9).
A major cytoskeletal structure in muscle that has the unique
role of connecting the sarcomere to the basement membrane is the
costamere. Costameres were originally described as subsarcolemma protein complexes that align in register with the Z-disk and are physically coupled to the sarcomeres. Costameres may be equivalent to
focal adhesions that are expressed in non-muscle cells and are believed
to be involved in the lateral transmission of contractile forces from
sarcomeres across the sarcolemma to the basement membrane. In the
second minireview, entitled "Costameres: the Achilles Heel of
Herculean Muscle," James M. Ervasti reviews the structure and function of the striated muscle costamere (10). As with the basement
membrane, the importance of the costamere for normal muscle function
has been revealed by genetic studies of muscular dystrophies and
dilated cardiomyopathies. Dystrophin is known to be enriched in
costameres, but dystrophin is not required for costamere assembly. In
the absence of dystrophin, there is a disorganization of the costameric
lattice, as well as disruption of the sarcolemma integrity. Disruption
of the costameric lattice correlates with functional studies that show
reduction of contractile force in muscles lacking dystrophin.
Ervasti's minireview provides insights into the growing costameric
protein network and illustrates how these proteins can interact with
many components of both the sarcolemma and cytoskeleton. In addition,
the newly identified proteins suggest a role for costameric proteins in
converting mechanical stimuli to alterations in cell signaling and gene
expression. Finally, Ervasti discusses non-sarcolemmal mechanical
defects associated with the loss of costameric proteins.
It is well recognized that the function and maintenance of skeletal
muscle cell integrity is dependent upon interactions of the muscle cell
with the surrounding basement membrane and underlying cytoskeleton.
Trans-sarcolemma receptors are known to be involved in providing
critical mechanical links between the basement membrane and the
cytoskeleton. In addition, recent data suggest that these receptors
transmit signals from the basement membrane into the muscle cell. Over
the past 10 years there has been great progress in the identification
and characterization of the two sarcolemma protein complexes that
connect cytoskeleton to the basement membrane in skeletal muscle:
integrins and the dystrophin-glycoprotein complex
(DGC).1
Integrins form a large family of cell surface receptors that mediate
cell-extracellular matrix interactions. In the third minireview, entitled "Integrins, Redundant or Important
Players in Skeletal Muscle?," Ulrike Mayer focuses on the role of
integrins in skeletal muscle (11). Of the current members of this
family, a subset is expressed in skeletal muscle, in particular, at the sarcolemma, neuromuscular junction, myotendinous junction, and costameres. Expression of the integrin family is regulated during skeletal muscle development. Integrins play a major role in muscle differentiation, and In the final minireview, entitled "Dystrophin-Glycoprotein Complex:
Post-translational Processing and Dystroglycan Function," Daniel E. Michele and Kevin P. Campbell focus on the major sarcolemma membrane
complex in adult skeletal muscle that links the cytoskeleton to the
basement membrane (12). DGC is a large oligomeric complex of proteins
in the sarcolemma of skeletal muscle. The DGC is composed of both
integral and peripheral membrane proteins and provides a structural
connection between the basement membrane and the actin cytoskeleton and
has been hypothesized to protect the sarcolemma from mechanical damage
during muscle contraction. Several forms of muscular dystrophy arise
from primary mutations in genes encoding components of the DGC. The DGC
is grouped into three subcomplexes, dystroglycan ( Much progress has been made in our understanding of the role of
basement membrane-sarcolemma-cytoskeleton interactions in the
development, structure, and function of striated muscle. The field
continues to be a dynamic arena for future research, in which new
functional molecules, their interactions, and their functional
significance, continue to be identified from molecular genetics of
human diseases, biochemistry, cell biology, and gene targeting in the
mouse. Given the essential role of these molecules in human disease,
understanding the interactions of the skeletal muscle basement
membrane-sarcolemma-cytoskeleton will hopefully lead to a better
understanding of disease pathogenesis and therapeutic opportunity.
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REFERENCES
7
1 integrin is a
critical receptor for myoblast migration. In adult skeletal muscle,
integrins are concentrated at the neuromuscular junction and the
myotendinous junction and provide an important link to the basement
membrane in these specialized regions of muscle.
7
1 integrin is the major form found in
adult skeletal muscle. Integrins have also been implicated in skeletal muscle diseases, and the absence of
7 integrin leads to
a mild muscular dystrophy in both mice and humans. Myotendinous
junctions were severely disturbed in mouse models with
7
integrin deficiency. Both mouse and human studies suggest that muscle
weakness arises from destruction of the myotendinous junction, rather
than from compromised sarcolemma integrity. Finally,
7
1 integrin is reduced in several
muscular dystrophies, and
7
1 integrin
overexpression may provide a possible therapeutic approach for Duchenne
muscular dystrophy.
- and
-dystroglycan), the sarcoglycan-sarcospan subcomplex, and the
cytoskeletal components dystrophin, syntrophyin, and dystrobrevin.
Michele and Campbell review the current status of our understanding of
the DGC, and in particular focus on the structure and
post-translational processing of dystroglycan. Interestingly, recent
genetic data have demonstrated that proteins with homology similar to
glycosyltransferases are linked to muscular dystrophy and appear to
preferentially or exclusively modify
-dystroglycan. The role of
glycosylation in the function of dystroglycan is discussed, and the
mechanisms whereby the loss of functional dystroglycan leads to
clinical symptoms, including muscular dystrophy, and abnormal central
nervous system development and function are presented. Finally, new
insights into dystroglycan function revealed from the studies of mouse
models and patients with incomplete glycosylation (dystroglycanopathies) are reviewed.
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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.
§ To whom correspondence should be addressed: Howard Hughes Medical Institute, University of Iowa College of Medicine, 400 EMRB, Iowa City, IA 52242. Tel.: 319-335-7867; Fax: 319-335-6957; E-mail: kevin-campbell@uiowa.edu; Web address: www.physiology.uiowa.edu/ campbell/.
Published, JBC Papers in Press, January 29, 2003, DOI 10.1074/jbc.R300005200
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ABBREVIATIONS |
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The abbreviation used is: DGC, dystrophin-glycoprotein complex.
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REFERENCES |
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