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Skeletal Muscle Degenerative
Diseases and Strategies for
Therapeutic Muscle Repair
Mohammadsharif Tabebordbar,1 Eric T. Wang,2
and Amy J. Wagers1,3,∗
1
Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem
Cell Institute, Cambridge, Massachusetts 02138; email: [email protected],
[email protected]
2
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts
02139; email: [email protected]
3
Howard Hughes Medical Institute, Cambridge, Massachusetts 02138
Annu. Rev. Pathol. Mech. Dis. 2013. 8:441–75
Keywords
First published online as a Review in Advance on
November 1, 2012
myogenesis, muscular dystrophy, sarcopenia, cell therapy, gene
therapy, muscle regeneration
The Annual Review of Pathology: Mechanisms of
Disease is online at pathol.annualreviews.org
This article’s doi:
10.1146/annurev-pathol-011811-132450
c 2013 by Annual Reviews.
Copyright All rights reserved
∗
Corresponding author.
Abstract
Skeletal muscle is a highly specialized, postmitotic tissue that must withstand chronic mechanical and physiological stress throughout life to
maintain proper contractile function. Muscle damage or disease leads
to progressive weakness and disability, and manifests in more than 100
different human disorders. Current therapies to treat muscle degenerative diseases are limited mostly to the amelioration of symptoms,
although promising new therapeutic directions are emerging. In this
review, we discuss the pathological basis for the most common muscle
degenerative diseases and highlight new and encouraging experimental
and clinical opportunities to prevent or reverse these afflictions.
441
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Sarcolemma:
specialized cell
membrane of skeletal
muscle fibers
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ECM: extracellular
matrix
Satellite cells: adult
skeletal muscle stem
cells located between
the sarcolemma and
the basal lamina
Sarcoplasm: muscle
fiber cytoplasm
Sarcoplasmic
reticulum (SR):
specialized
endoplasmic reticulum
of skeletal muscle
fibers
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SKELETAL MUSCLE:
COMPOSITION, STRUCTURE,
AND FUNCTION
Skeletal muscle is composed of thousands of
muscle fibers, which are bundled together and
attached to the skeleton by tendons (Figure 1).
Skeletal muscle fibers (myofibers) are multinucleated and form during development by
the fusion of mononucleated myoblasts. Myofibers are surrounded by a specialized plasma
membrane, the sarcolemma, which transduces
signals from motor neurons and other external
stimuli into muscle fibers. Myofibers are
surrounded by a layer of extracellular matrix
(ECM) known as the basement membrane,
which is composed of both an internal basal
lamina and an external reticular lamina (1). The
basal lamina associates closely with the sarcolemma, providing a protective niche in which
muscle regenerative cells (satellite cells) reside.
Satellite cells are unipotent adult stem cells
that are activated in response to severe muscle
damage to proliferate and differentiate, thereby
forming myoblasts that can rebuild the muscle
through fusion with one another or with residual myofibers. Satellite cells also possess potent
self-renewal capacity, which ensures their
persistence within the muscle and preserves
the muscle’s ability to repair after injury.
The calcium-dependent contraction of
muscle fibers requires a specialized cytoplasm
(sarcoplasm) and modified endoplasmic reticulum (ER) [sarcoplasmic reticulum (SR)].
Transverse tubules (T-tubules) invaginate
the sarcolemma to properly transduce action
potentials and activate the SR (Figure 1). Myofibers contain abundant myofibrils, which act
as contraction units and are surrounded by SR.
Myofibrils are composed of thin myofilaments
(actin) and thick myofilaments (myosin) whose
calcium-dependent movement relative to one
another produces muscle contraction. The
Satellite cells
Sarcolemma
Myofibril
Muscle fiber
Bundle of muscle fibers
H-band
I-band
A-band
Sarcomere
Sarcoplasmic
reticulum
T-tubules
M-line
Z-line
Myosin
Actin
Figure 1
Skeletal muscle structure and composition. Skeletal muscle is composed of numerous bundles of muscle fibers. Each bundle consists of
multiple fibers, and individual fibers encompass many myofibrils. Sarcomeres are the structural units of myofibrils and are made up of
actin and myosin filaments. Abbreviation: T-tubule, transverse tubule.
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organization of myofilaments into myofibrils
underlies the normally striated appearance of
skeletal muscle under light microscopy; thin
filaments make up the light band (I-band), and
thick filaments make up the dark band (A-band)
(Figure 1). The Z-line defines the borders of
each sarcomere, which is the structural unit of
the myofibril (2).
Muscle contraction is induced by depolarization of the sarcolemma via action potential.
This depolarization opens sarcoplasmic calcium release channels, increasing the intracellular calcium concentration and triggering actinmyosin-mediated contraction of sarcomeres.
Protein assemblies known as costameres, which
consist mainly of proteins contained within
the dystrophin-glycoprotein complex (DGC)
(3) and the integrin-vinculin-talin complex (4),
transmit contraction forces from muscle fibers
to the ECM and, eventually, to neighboring
myofibers. Costameres align with the Z-line of
peripheral myofibrils and physically link myofibrils to the sarcolemma.
SKELETAL MUSCLE INJURY
AND REGENERATION
Mechanisms of Muscle Injury:
Acute Muscle Damage
Acute damage to skeletal muscle can occur by
physical or chemical insult. For example, sharp
or blunt trauma, or excessively hot or cold
temperatures, induces rapid myofiber necrosis. Likewise, envenomation by snakes or bees
causes acute myonecrosis. Such venoms contain
low-molecular-mass myotoxins (crotamine and
myotoxin a) (5), phospholipases A2 (PLA2s)
(6) and membrane-active cardiotoxins (7); bee
venom alone contains melittin (8). All of these
toxins cause depolarization and contraction of
myofibers, and all except the low-molecularmass myotoxins induce lysis of the sarcolemma
(9). In contrast, PLA2s disrupt sarcolemmal integrity by hydrolysis of glycerophospholipids.
Such membrane disruption provokes calcium
influx, leading to hypercontraction, mitochondrial calcium overload, and activation of cytosolic calcium-dependent PLA2s and calpains
(10). Myogenic satellite cells, nerves, and blood
vessels appear unaffected by PLA2s (10). In
addition, the basal lamina remains intact after envenomation, although some myotoxic and
neurotoxic PLA2s may induce degeneration of
nerve terminals (11, 12).
Cardiotoxins are single-chain small polypeptides that form pores in the muscle membrane (13). Myonecrosis induced by cardiotoxin
and melittin involves rapid lysis of the sarcolemma and hypercontraction of sarcomeres
following calcium influx (14). Muscle necrosis resulting from low-molecular-mass basic
myotoxins is much slower and is caused by
the induction of sodium influx via voltagesensitive sodium channels in the sarcolemma.
This sodium influx causes membrane depolarization, muscle contraction, and vacuolization
of the SR. Nevertheless, these myotoxins cause
no apparent sarcolemma or transverse tubule
damage (15).
Ischemia/reperfusion also causes acute muscle damage. Prolonged periods of zero blood
flow, which occur during organ-transplantation
surgery, stroke, and hypovolemic shock, induce muscle dysfunction through the loss of
cellular energy supplies and accumulation of
potentially toxic tissue metabolites. Restoration of blood flow is essential to the rescue
of ischemic muscle; however, reactive oxygen
species (ROS) produced during reperfusion
exacerbate tissue injury by directly damaging
cellular macromolecules and promoting the
infiltration of inflammatory leukocytes (16).
Oxygen insufficiency during ischemia converts
cellular metabolism to anaerobic pathways, initiating a cascade of reactions that generate large
quantities of superoxide and other free radicals
(17) and increase intracellular calcium concentrations. Calcium levels are further elevated following reperfusion, causing the activation of
calpain and phospholipases. These molecules,
in turn, can trigger proinflammatory mediator synthesis and leukocyte chemoattraction
(18), which further damage the muscle through
release of reactive oxygen and proteases, complement activation, and increased vascular permeability (19).
www.annualreviews.org • Skeletal Muscle Disease and Therapy
Transverse tubules
(T-tubules):
invaginations of the
sarcolemma that enter
the muscle fiber
perpendicular to the
long axis of the fiber
Myofibril:
contraction unit of
muscle fiber,
composed of actin and
myosin filaments
Sarcomere: structural
unit of the myofibril
DGC: dystrophinglycoprotein
complex
Ischemia: lack of
blood supply to tissues
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Mechanisms of Muscle Injury:
Contraction-Induced Damage
IMs: inflammatory
myopathies
Inflammation:
a complex response by
the immune system
evoked by tissue injury
and often involved in
initiating the healing
process
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PM: polymyositis
sIBM: sporadic
inclusion body
myositis
NAM: necrotizing
autoimmune myositis
CK: creatine kinase
Contraction of skeletal muscle can cause shortening (concentric contraction), lengthening
(eccentric contraction), or no change (isometric contraction) of muscle length. Concentric
contractions initiate movements, and eccentric
contractions slow or stop them. During eccentric contraction, the opposing force exceeds
the force generated by the muscle, leading
to its elongation. Contraction-induced injury
is most severe during eccentric contractions.
Electron microscopy reveals regions of overextended sarcomeres or half-sarcomeres, Z-line
streaming and regional disorganization of
myofilaments, and T-tubule damage in myofibers after lengthening contraction (20, 21).
Weaker sarcomeres are overstretched during
eccentric contraction, and repeated overextension of sarcomeres leads to their disruption.
Disruption of multiple sarcomeres causes
membrane damage, beginning with tearing
of T-tubules and degradation of membrane
components involved in excitation-contraction
coupling (22). Increased intracellular calcium,
promoted by damage to the SR or induction
of stretch-activated channels, further drives
muscle contractile protein degradation, as well
as mitochondrial swelling and SR vacuolization
(23). Depending on the extent of contractioninduced damage, myofiber necrosis may occur,
which leads to a local inflammatory response
associated with tissue edema and soreness.
Mechanisms of Muscle Injury:
Inflammatory Myopathy
Inflammatory myopathies (IMs) represent
the largest group of acquired and potentially
treatable myopathies in people (24). This
heterogeneous group of subacute, chronic, or
sometimes acute muscle diseases commonly
involves muscle weakness and inflammation,
revealed in muscle biopsies (25). Four different
types of IMs have been identified by histological, immunopathological, and clinical manifestations: dermatomyositis, polymyositis (PM),
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sporadic inclusion body myositis (sIBM), and
necrotizing autoimmune myositis (NAM) (26).
Complement activation and the formation
of membranolytic attack complexes that damage endothelial cells of the endomysial capillaries are two of the earliest events in dermatomyositis (27). Autoantibodies directed against
endothelial cells may activate the complement
system, causing endothelial cell lysis, perivascular inflammation, capillary destruction, and
muscle ischemia (25). Thus, dermatomyositis
decreases capillary density in the muscle, causing dilation of the remaining vessels, which attempt to compensate for the ischemic condition (28). Complement activation also triggers
the expression of proinflammatory cytokines
and the recruitment of CD4+ T cells, B cells,
macrophages, and plasmacytoid dendritic cells
to muscle (29, 30).
A common feature in the immunobiology
of PM and sIBM is the ubiquitous expression of major histocompatibility complex 1
(MHC-1) antigen, which is normally undetectable on muscle fibers (31). CD8+ cytotoxic
T cells attack MHC-1-expressing myofibers,
causing fiber lesions. Spike-like processes from
CD8+ cells and macrophages may also extend
across the myofiber basal lamina and compress the fibers (32). Furthermore, perforin and
granzyme, released from CD8+ cells, promote
myofiber necrosis (33). Although there are significant immunobiological similarities between
PM and sIBM, sIBM is additionally characterized by the presence of a strong degenerative
process that involves rimmed vacuoles and intracellular deposition of β-amyloid and related
molecules (34). Other degenerative phenomena
in sIBM myofibers include an induced unfolded
protein response, lysosome and mitochondrial
abnormalities, and ER stress (34).
NAM is the least understood of the IMs.
Macrophages are thought to be responsible for
fiber necrosis in this disease, which causes high
creatine kinase (CK) levels in patients’ blood.
Neither infiltration of T cells nor expression of
MHC-1 on muscle fibers has been detected in
NAM (26); however, some patients harbor autoantibodies against signal recognition peptide,
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which implies an antibody-mediated cause of
the disease (35). Macrophage recruitment also
supports antibody-dependent cell-mediated cytotoxicity in NAM. Although there have been
cases of patients with cancer or active viral infection (e.g., HIV), it is unclear whether NAM
can be triggered by these factors or not (24).
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Mechanisms of Muscle Regeneration:
Membrane Patch
Many eukaryotic cell types can repair minor membrane disruptions and restore plasma
membrane integrity. Physiological disruptions
to the plasma membrane occur frequently in
skeletal muscle (36), and defects in mem-
a
brane resealing can cause muscular dystrophy
(37). The membrane repair process involves
calcium-dependent exocytosis of intracellular
vesicles, such as lysosomes and enlargeosomes,
which form a membrane “patch” (Figure 2)
(38, 39). Dysferlin, a protein that is present
predominantly at the muscle surface and in
cytoplasmic vesicles, is also a critical component in membrane repair (37); however, the
mechanism underlying dysferlin’s involvement
in this process remains poorly understood. Dysferlin may function as a calcium sensor, regulating vesicle-vesicle and vesicle-membrane fusion
during membrane repair (40). Dysferlin also interacts with annexins A1 and A2 (41). Annexin
A1 is required for membrane repair in HeLa
Muscular dystrophy:
a heterogeneous group
of inherited muscle
degenerative diseases
b
Calcium
Oxidative agents
Sarcolemma
Cytoskeleton
Calpain
Dysferlin
Annexin A2
Annexin A1
MG53
SH
Activated
calpain
Cleavage?
SH
SH
SH
SH
SH
SH
d
S
S
SH
S
SH
c
SH
SH
S
S
SH
S
Figure 2
Model for mechanism of membrane patching in muscle fibers. (a) In the intact muscle fiber, Mitsugumin 53 (MG53) is on sarcoplasmic
vesicles in a reduced form, and the concentration of calcium in sarcoplasm is lower than in the extracellular matrix. (b) Upon membrane
damage, exposure of the intracellular environment to oxidative agents leads to oxidation and oligomerization of MG53 proteins on
sarcoplasmic vesicles. Increased calcium concentration around the injury site also activates calpain. Activated calpain may cleave
annexin proteins, which subsequently mediate accumulation of vesicles near the site of damage. (c) Dysferlin senses the calcium that
floods into the fiber and triggers fusion of accumulated vesicles. Activated calpain also degrades the cytoskeleton near the damaged area,
making it easier for vesicles to fuse with plasma membrane. (d ) Vesicles fuse with the sarcolemma and form a patch that seals the
membrane. Abbreviation: SH, reduced sulfur moieties in MG53. Modified from Reference 262.
www.annualreviews.org • Skeletal Muscle Disease and Therapy
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cells (42), but its mechanism of action is currently unclear. Binding of annexins to phospholipids in the presence of calcium, together
with their ability to aggregate vesicles in vitro
and interact with actin, fueled speculation about
their involvement in vesicle-vesicle fusion and
vesicle movement (43). In addition to triggering vesicle fusion, calcium influx after membrane injury also activates calpain, which likewise is necessary for membrane repair (44, 45)
and may mediate the disassembly of the damaged actin cytoskeleton through degradation of
cytoskeletal proteins such as talin and vimentin.
Annexins are also proteolytic targets of calpain,
and calpain-mediated cleavage of annexins may
be critical for membrane repair (46). Recently,
Mitsugumin 53, a muscle-specific tripartite motif family protein (TRIM72) that is present on
the sarcolemma and intracellular vesicles, was
implicated in nucleating the assembly of the
repair machinery at injury sites (47, 48). This
process is independent of calcium influx and
triggered by changes in the intracellular oxidative environment (48). Figure 2 presents a simplified model of our current understanding of
membrane patching in skeletal myofibers.
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PM08CH17-Wagers
Mechanisms of Muscle Regeneration:
Muscle Satellite Cells
Satellite cells are mononuclear cells with a
high nucleus-to-cytoplasm ratio; they were first
identified in electron micrographs on the basis of their distinct anatomical position between the sarcolemma and the basal lamina
of muscle fibers (49). Satellite cells represent
the endogenous source of muscle progenitor
cells and account for the regenerative potential of adult muscle (50). Considering the infrequent turnover of myonuclei in adult muscle,
satellite cells remain mitotically and metabolically quiescent through most of life. However,
satellite cells are activated after muscle injury
and in the context of chronic degenerative diseases (see the section titled Muscle Degenerative Diseases) (51–53). Damage to skeletal muscle results in the release of growth factors (GFs)
and cytokines, such as hepatocyte growth fac446
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tor; epidermal growth factor; platelet-derived
growth factor BB; and members of the insulinlike growth factor (IGF) and fibroblast growth
factor family (54, 55) from the ECM (56), myofibers, endothelial cells, interstitial cells (57),
and leukocytes (58). Interaction among these
GFs and receptors on quiescent satellite cells
triggers satellite cell proliferation.
Quiescent satellite cells express various
proteins, including Pax7, CD34, c-met, Mcadherin, syndecan-3, and syndecan-4 (59–61),
that are important for their activation and proliferation in response to muscle damage (62).
Activated satellite cells downregulate Pax7 expression and increase synthesis of the early
myogenic regulatory factors MyoD and Myf5
(63). These activated cells undergo a rapid proliferation stage regulated in part by Notch signaling (64). Notch inhibition and activation
of Wnt signaling can induce the progression
of muscle satellite cells along the myogenic
lineage to promote the production of fusioncompetent myoblasts (65) and trigger the expression of late myogenic regulatory factors,
including myogenin. Fusion of terminally differentiated myoblasts into myofibers marks the
final stage of muscle regeneration.
Efficient repair of skeletal muscle after repeated injuries indicates that satellite cells
must be replenished after muscle regeneration.
Genetic fate-mapping studies strongly implicate satellite cells themselves as the endogenous source of such cell replacement; however, the mechanisms regulating satellite cell
self-renewal are not fully understood. Some
reports suggest that nonrandom segregation
of DNA strands or asymmetric distribution of
Numb, an inhibitor of Notch signaling, in the
daughters of dividing satellite cells (66, 67) may
drive asymmetric division of satellite cells and
preservation of the satellite cell pool. A recent study (68) provided evidence suggesting
that asymmetric division in satellite cells expressing high levels of Pax7 causes segregation of template DNA to daughter cells with a
more immature phenotype, whereas daughters
inheriting newly synthesized DNA acquire a
more differentiated phenotype. This study also
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a
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b
Homeostasis
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c
Degeneration
Inflammation
d
Regeneration
Blood
vessel
Damage
Satellite cell
activation
Repair
Muscle
fibers
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Figure 3
Mechanisms of satellite cell activation and regulation during muscle repair. (a) During homeostasis, satellite cells ( green) reside in close
association with muscle fibers (red ). Resting muscle also contains resident fibro-adipogenic precursors [FAPs ( purple)]. (b) Damage to
muscle induces myofiber degeneration and inflammation, beginning with infiltration by neutrophils and M1 macrophages (dark yellow)
from blood vessels (red oval ). (c) During the regenerative phase, elaboration of growth factors and cytokines by muscle fibers,
infiltrating M2 macrophages (light yellow) and activated FAPs ( purple with yellow border) activate satellite cells ( green with yellow border) to
proliferate and differentiate to form myoblasts (orange ovals with yellow border) that exit the cell cycle and fuse with one another and with
residual myofibers to replenish myofibers as well as the satellite cell pool (d ).
demonstrated that satellite cells harboring low
levels of Pax7 exhibit random segregation of
DNA strands during mitosis (68). Myostatin,
a member of the transforming growth factor
(TGF)-β superfamily, may also promote satellite cell quiescence, given the increased percentage of activated and proliferating satellite cells
in myostatin-null mice (69) and the involvement of the myostatin antagonist, follistatin, in
myoblast fusion (70). However, direct analyses
of postnatal satellite cells in mice suggest that
these cells lack expression of myostatin receptors and that they fail to respond to exogenous
myostatin in ex vivo proliferation assays (71).
In addition to soluble GFs and cytokines,
satellite cell function is also regulated by infiltrating and interstitial cell populations, including recruited inflammatory cells (72) and
resident fibro-adipogenic precursors (FAPs)
(Figure 3) (73, 74). The impact of inflammatory cells on muscle repair is quite complex.
In the absence of any recruited immune cells,
satellite cell regenerative activity appears to be
blocked (72); however, as discussed above, an
overexuberant or unbalanced immune response
can lead to myopathic tissue destruction that is
not recoverable through satellite cell–mediated
repair processes. Neutrophils appear to be the
first immune cells recruited to damaged muscle
(75). Their recruitment signals subsequent infiltration by M1 macrophages, followed by M2
macrophages (76, 77). M1 macrophages are efficient inducers and effectors of inflammatory
processes, whereas M2 macrophages are more
often involved in tissue repair, remodeling, and
immunoregulation (78). Both neutrophils and
macrophages participate in the clearance of myofiber debris at the injury site and in the production of inflammatory and immune-regulatory
cytokines, but macrophages (particularly M2
macrophages) appear to have an additional,
unique function in directly regulating muscle
regeneration through induction of satellite cell
activation and myoblast proliferation (79–81).
In addition to recruited immune cells,
muscle-resident mesenchymal cells also appear
to be critical for proper muscle repair. For
example, skeletal muscle contains a unique
population of Sca-1-expressing precursor cells,
which can differentiate to form fibroblasts
(82) and white or brown adipocytes (73, 83).
Although these FAPs exhibit no intrinsic
myogenic activity, they are potent inducers of
myogenesis by satellite cells (Figure 3) (73, 74).
Intriguingly, whereas undifferentiated FAPs
promote myofiber formation, the presence
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FAPs:
fibro-adipogenic
precursors
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of differentiated myofibers appears to inhibit
FAP-mediated adipogenesis (74). Although
the exact mechanisms by which this functional
cross-antagonism is accomplished remain to
be determined, studies have suggested a role
for paracrine signaling [by soluble mediators
such as IGF-1, Wnts, and interleukin (IL)-6]
between FAPs and muscle satellite cells in
the FAP-dependent promotion of myogenesis
(73). In contrast, cocultures of FAPs with differentiated myotubes implicate direct cell-cell
interaction in the inhibition of FAP-mediated
adipogenesis by muscle fibers (74). Thus, in
addition to alterations in satellite cell number
and intrinsic signaling responses, numerous
non-cell-autonomous inputs clearly influence
the extent and efficacy of satellite cell–mediated
muscle repair.
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PM08CH17-Wagers
MUSCLE DEGENERATIVE
DISEASES
Genetic Diseases of Skeletal Muscle:
Duchenne and Becker Muscular
Dystrophies
Duchenne muscular dystrophy (DMD) is the
most common X-linked genetic disorder in
humans; it affects one in 3,500 males. Most
boys with DMD manifest symptoms within the
first years of life. Progressive muscle weakening delays walking and causes repeated falls,
leaving patients wheelchair bound, typically by
∼12 years of age. Most patients experience premature death due to respiratory or cardiovascular failure in the second decade. Mutations in
the dystrophin gene leading to genetic frameshift
or loss of expression and complete absence
of protein function are the cause of DMD
(Table 1) (84). Dystrophin extends over 2.4 Mb
of the X chromosome and represents the largest
gene in the human genome. Point mutations in
dystrophin are responsible for ∼40% of DMD
cases; the remaining ∼60% are caused by large
deletions or duplications in this gene (85).
Dystrophin is a structural protein, a component of the DGC (Figure 4) (86), and an
essential part of the costamere. Dystrophin’s
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primary function is to link the myofiber cytoskeleton to the ECM and thereby stabilize
the sarcolemma (87). Dystrophin binds cytoplasmic actin through its amino terminus as well
as its rod-shaped domain, which is composed
of 24 spectrin repeats and four hinge points
(88). The C-terminal cysteine-rich domain of
dystrophin directly binds to transmembrane βdystroglycan protein. β-Dystroglycan is linked
to the highly glycosylated α-dystroglycan
(αDg), which completes the connection between the myofiber cytoskeleton and ECM
by interacting with laminin in the basal lamina (89). Absence of functional dystrophin
protein destabilizes the DGC, increasing
the susceptibility of dystrophic muscle fibers
to contraction-induced injury (90). Increased
cytosolic calcium following mechanical stress,
activation of proteases (particularly calpains),
destruction of membrane constituents, and ultimately myofiber necrosis occur frequently in
dystrophic muscles. Thus, satellite cells in these
patients must support repeated rounds of regeneration in an attempt to compensate for
damage. As the disease advances, satellite cells
show reduced capacity for muscle regeneration, possibly due to proliferation-induced reductions in telomere length (91) or damageassociated cell attrition (92). Absent an adequate
muscle regenerative response, fat and fibrotic
tissue replace muscle fibers, leading to further
weakening and wasting (93).
In addition to mechanical stress, other secondary mechanisms induce damage in dystrophic muscle. Loss of functional dystrophin
leads to reduced expression and mislocalization
of neuronal nitric oxide synthase (nNOS) from
the sarcolemma (Figure 4) (94). Absence of
nNOS signaling impairs blood supply to contracting muscles, exposing dystrophic muscles
to continuous ischemic insult (95). Various immune cells are also recruited to the dystrophic
muscle as a result of persistent damage; these
cells can cause secondary damage through inflammatory responses and elaboration of ROS
(96).
Like DMD, Becker muscular dystrophy
(BMD) is also caused by mutations in dystrophin;
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Table 1 Causative genetic lesions in inherited muscle degenerative diseases
Disease name
Duchenne muscular dystrophy
(DMD) and Becker muscular
dystrophy (BMD)
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Myotonic dystrophy (DM)
Limb girdle muscular dystrophy
(LGMD)
Protein (gene); disease subtype
Dystrophin (DMD)
Dystrophia myotonica protein kinase (DMPK); DM1
Zinc-finger nuclease 9 (ZFN9/CNBP); DM2
Myotilin (MYOT ); LGMD1A
Lamins A and C (LMNA); LGMD1B
Caveolin-3 (CAV3); LGMD1C
Calpain-3 (CAPN3); LGMD2A
Dysferlin (DYSF); LGMD2B
γ-Sarcoglycan (SGCG); LGMD2C
α-Sarcoglycan (SGCA); LGMD2D
β-Sarcoglycan (SGCB); LGMD2E
δ-Sarcoglycan (SGCD); LGMD2F
Telethonin (TCAP); LGMD2G
Tripartite motif–containing 32 (TRIM32); LGMD2H
Fukutin related protein (FKRP); LGMD2I
Titin (TTN); LGMD2J
Protein-O-mannosyltransferase 1 (POMT1); LGMD2K
Anoctamin 5 (ANO5); LGMD2L
Fukutin (FCMD); LGMD2M
Protein-O-mannosyltransferase 2 (POMT2); LGMD2N
Protein O-linked mannose β1, 2-N-acetylglucosaminyltransferase (POMGnT1); LGMD2O
Dystroglycan (DAG1); LGMD2P
Emery–Dreifuss muscular dystrophy
(EDMD)
Emerin (EMD); X-linked EDMD
Lamins A and C (LMNA); autosomal EDMD
Nesprin-1 (SYNE1)
Nesprin-2 (SYNE2)
Congenital muscular dystrophy
(CMD)
Fukutin-related protein (FKRP); Walker–Warburg syndrome (WWS), Fukuyama CMD, or
muscle–eye–brain disease
Like-glycosyl transferase (LARGE); WWS, Fukuyama CMD, or muscle–eye–brain disease
Fukutin (FCMD); WWS, Fukuyama CMD, or muscle–eye–brain disease
Protein-O-mannosyltransferase 1 (POMT1); WWS, Fukuyama CMD, or muscle–eye–brain
disease
Protein-O-mannosyltransferase 2 (POMT2); WWS, Fukuyama CMD, or muscle–eye–brain
disease
Protein O-linked mannose β1, 2-N-acetylglucosaminyltransferase (POMGnT1); WWS,
Fukuyama CMD, or muscle–eye–brain disease
Laminin-2 (LAMA2)
Collagen type VI, subunit α1 (COL6A1); Ullrich syndrome or Bethlem myopathy
Collagen type VI, subunit α2 (COL6A2); Ullrich syndrome or Bethlem myopathy
Collagen type VI, subunit α3 (COL6A3); Ullrich syndrome or Bethlem myopathy
Integrin-α7 (ITGA7), Selenoprotein N1 (SEPN1); rigid spine syndrome
Lamins A and C (LMNA)
Facioscapulohumeral muscular
dystrophy (FSHD)
Double-homeobox protein 4 (Dux4); FSHD1A
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Collagen
Dystroglycans
Biglycan
Sarcoglycans
β
Laminin
Sarcospan
Glycan moieties
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γ
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δ
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α-Dystrobrevin
α
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Dystrophin
nNOS
β
Sarcoplasm
C terminus
Syntrophins
N terminus
F-actin
Figure 4
Dystrophin glycoprotein complex (DGC). Dystrophin connects the muscle fiber cytoskeleton to the extracellular matrix (ECM) via
interaction with actin filaments in the sarcoplasm and β-dystroglycan in the sarcolemma. β-Dystroglycan interacts with
α-dystroglycan, which is connected to laminin in the ECM through its glycan moieties. The sarcoglycan-sarcospan complex is also a
part of DGC that includes α-, β-, γ-, and δ-sarcoglycans and sarcospan. This subcomplex is connected to the ECM through
interaction with biglycan. Dystrophin also interacts with α-dystrobrevin and α- and β-syntrophins through its C-terminal domain.
Neuronal nitric oxide synthase (nNOS) is localized to the DGC via its interaction with syntrophins.
however, Becker mutations maintain the dystrophin reading frame. Thus, most BMD patients express a partially functional dystrophin
protein, which lacks the internal spectrin repeats but contains the critical actin-binding
and C-terminal domains (97). BMD patients
show a milder phenotype and a more heterogeneous clinical manifestation of the disease.
Some BMD patients remain ambulatory after
their forties, and a few can survive more than
60 years (98).
Genetic Diseases of Skeletal Muscle:
Myotonic Dystrophy
Myotonic dystrophy type 1 [also known as dystrophia myotonica type 1 (DM1)] was first described by Hans Steinert in 1909 (99). DM1
affects more than 1 in 8,000 individuals worldwide but has an increased incidence (up to 1 in
500) in certain populations due to founder effects. DM1 is an autosomal dominant disease
Myotonia: the
inability to relax
muscles after
contraction
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caused by a trinucleotide repeat expansion in
the 3 untranslated region (3 UTR) of DMPK
on chromosome 19 (100–102). Normal individuals have fewer than 30 repeats, and expansions
above this range can initiate DM symptoms.
Age of onset and disease severity appear to correlate with repeat expansion length. Typically,
expansions greater than 1,000 repeats yield a
severe congenital form of DM. DM repeats are
unstable over time and across cell types, and repeat lengths in muscle, heart, brain, and other
tissues can significantly exceed those measured
in blood (103).
Although the pathognomonic symptom
of DM is myotonia, or the inability to relax
muscles after contraction, DM affects multiple
body systems and therefore is not exclusively a
muscular dystrophy. Additional DM symptoms
include muscle wasting and weakening, cardiac
conduction block, smooth muscle dysfunction,
so-called Christmas tree cataracts, insulin
resistance, neuropsychiatric abnormalities,
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hypersomnia, fatigue, sleep dysregulation, and
testicular atrophy (99). Muscle wasting often
occurs in the distal-to-proximal direction,
first affecting hand, face, and tongue muscles,
leading to grip weakness, ptosis, and speech
difficulties. Weakness of the tibialis muscle
leads to foot drop, and progressive weakness
in all major skeletal muscle groups occurs over
time. Although centralized myofiber nuclei,
heterogeneous fiber cross-sectional areas, and
fibrosis are commonly observed, regeneration
and immune cell infiltration are not; thus, the
central nuclei are believed to reflect processes
that are unrelated to regeneration. Heart
block in DM can cause atrial fibrillation and
occasionally ventricular tachycardia, making
sudden death a significant risk for DM patients; however, this risk can be mitigated by
pacemakers or implantable cardioverter defibrillators. Smooth muscle dysfunction in DM
can dysregulate gastrointestinal tract motility
and cause gallbladder dysfunction. Executive
functioning and other central nervous system
functions, particularly involving the prefrontal
cortex, are also especially affected in DM
(99).
The penetrance of symptoms among DM
patients is so wide ranging that it has been described as the most variable disease known to
mankind (99). DM exhibits genetic anticipation, and its pattern of inheritance is similar
to that of other microsatellite repeat diseases,
such as Huntington’s disease and spinocerebellar ataxias. Often, entire families are diagnosed
only after a hypotonic newborn, suffering from
congenital DM1, inspires a cascade of diagnoses
up the family tree (104).
Haploinsufficiency of the DMPK protein,
observed in DM1 patient tissue, was initially hypothesized to play a central role in DM1 pathogenesis, and epigenetic effects of expanded repeats on the expression of neighboring genes
were also proposed to play a role (Figure 5).
Yet, mice lacking DMPK develop only minor
cardiac and muscle defects later in life, distinct from those observed in DM1 patients
(105). Discovery of a second type of myotonic
dystrophy, DM2, caused by a tetranucleotide
(CCUG) repeat expansion in the first intron
of the CNBP gene on chromosome 3q21, provided critical clues about molecular pathogenesis in DM (106). DM2 is estimated to account
for less than 10% of all DM cases. Although
the phenotype of DM2 patients is not identical
to that of DM1 patients (muscle wasting occurs
in a proximal-to-distal fashion, and symptoms
are generally more mild than in DM1), DM2
patients also experience myotonia, cataracts,
frontal balding, insulin resistance, and executive functioning difficulties, among other symptoms. The discovery of DM2, combined with
the observation that nuclei of DM1 and DM2
cells contain CUG- or CCUG-rich RNA foci
(107, 108), shifted the focus of investigators
from cis to trans mechanisms, and to a model
in which the pathogenic molecule may be the
expanded CUG- or CCUG-containing RNA
(Figure 5).
Transgenic mice expressing CUG repeats
in the 3 UTR of an unrelated gene (human
skeletal actin) in a muscle-specific fashion exhibit myotonia, centralized muscle nuclei, and
heterogeneous myofiber cross-sectional areas
(109). Members of the Muscleblind-like family of RNA-binding proteins (MBNLs) bind to
CUG repeat RNA in a length-dependent fashion, and MBNL1 knockout mice exhibit myotonia and centralized muscle nuclei (110, 111).
Furthermore, the introduction of exogenous
MBNL1 protein by an adeno-associated virus
(AAV) into the muscle of CUG repeat–carrying
mice significantly rescued myotonia (112).
The MBNLs were first discovered in
Drosophila, where their loss results in defects
in eye and muscle development (113). MBNLs
can both repress and activate alternative mRNA
splicing, and their endogenous binding sequences are similar to those of CUG or CCUG
sequences (114). For example, aberrant inclusion of exon 7a of the chloride channel
1 (CLCN1) gene, which contains a premature stop codon and normally is repressed by
MBNL, causes degradation and loss of CLCN1
at the sarcolemma, leading to myotonia
(Figure 5) (115). Loss of MBNLs appears to
account for ∼80% of the splicing changes in
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(CTG))80
80–2,500+
2,5
DMPK genomic locus
Somatic instability
G
U
C
G
U
C
G
U
C
G
U
C
G
U
C
G
U
C
G
U
C
G
U
C
G
U
C
DMPK mRNA
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Gppp
AAAAA...
MBNLs
CLCN1 pre-mRNA
C
U
G
C
U
G
C
U
G
C
U
G
C
U
G
C
U
G
C
U
G
C
U
G
C
U
G
PKC activation,
hyperphosphorylation of CELFs,
disruption of CELF-mediated
RNA processing in the nucleus
P–
P–
P–
CELFs
Nuclear retention of DMPK mRNA,
sequestration of MBNLs,
disruption of MBNL-mediated
RNA processing in the nucleus
Nonsense-mediated decay,
loss of CLCN1, myotonia
P–
P–
P–
Stable mRNA,
CLCN1
Exon 7a
Disruption of CELF functions
in the cytoplasm
Disruption of MBNL functions
in the cytoplasm
Figure 5
Molecular pathogenesis in myotonic dystrophy (type 1). CTG repeat expansions at the DMPK locus are transcribed into RNA and
form intranuclear foci with Muscleblind-like family of RNA-binding proteins (MBNLs), leading to nuclear retention of DMPK
messenger RNA (mRNA). MBNLs, which normally regulate precursor mRNA (pre-mRNA) splicing, cannot bind to their normal
targets, causing aberrant alternative splicing patterns and downstream phenotypic consequences, such as myotonia. Through an
independent pathway, CELF proteins are hyperphosphorylated via protein kinase C (PKC) activation.
one mouse model of DM. This finding supports
the model that expanded CUG/CCUG repeat
expression functionally sequesters MBNLs,
which leads to splicing changes that cause DM
phenotypes (116). Several MBNL-dependent
splicing events have been proposed to account
for DM phenotypes, including Bin1 exon 7
splicing (muscle wasting) (117), insulin receptor exon 11 (insulin resistance) (118), CaV1.1
(muscle wasting) (119), and cardiac troponin T
exon 5 (cardiac function) (120).
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A separate line of investigation indicates that
overexpression of CUG repeats may stabilize a
distinct RNA-binding protein, CELF1 (121),
via hyperphosphorylation by protein kinase C,
which is aberrantly activated through unknown
mechanisms by expanded CUG repeat expression in the context of the DMPK 3 UTR
(Figure 5) (122). CELF1 is elevated in DM1
patient tissues and myoblasts, and CELF1 overexpression in heart or muscle leads to cardiac
defects and muscle wasting, respectively (123),
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suggesting that CELF1 activation can mediate
additional, MBNL-independent changes that
may cause other DM1 symptoms.
Although it remains unclear exactly which
events downstream of MBNL sequestration
cause the plethora of DM phenotypes, it has
been firmly established that DM is a disease of
RNA toxicity. Thus, eliminating the expanded
repeat RNA or preventing it from sequestering RNA-binding proteins is likely to represent a viable therapeutic strategy for both DM1
and DM2. Thus, similar approaches are being
pursued for both diseases, although a small but
increasingly recognized number of patients experience DM symptoms in the absence of expanded repeats in DMPK or CNBP (124). Further investigation is needed to determine the
causative loci in this subset of patients and to
evaluate whether similar molecular pathways
may be perturbed.
Genetic Diseases of Skeletal Muscle:
Limb Girdle Muscular Dystrophies
Limb-girdle muscular dystrophy (LGMD)
refers to a phenotypically related group of
dystrophies, each caused by a distinct genetic
defect. All LGMDs show progressive muscle
weakness beginning from the proximal limb
muscles, elevated CK, and in some cases
cardiomyopathy. Disease onset varies from
early childhood to late adulthood. LGMD may
be either autosomal dominant (LGMD1) or
autosomal recessive (LGMD2) (125), and the
causative genetic defect may occur in genes encoding DGC-associated proteins, sarcolemmal
proteins, muscle fiber enzymes, sarcomeric
proteins, or nuclear lamina. In approximately
one-third of LGMD patients, the mutated gene
has yet to be identified. Autosomal dominant
LGMD patients exhibit a milder phenotype,
and the disease onset is typically in adulthood.
Eight loci are known to cause LGMD1 so far,
but only three genes, which encode myotilin
(LGMD1A), lamins A and C (LGMD1B), and
caveolin-3 (LGMD1C), have been implicated.
Mutations in the myotilin gene are responsible for LGMD1A (126). Myotilin is
localized to the Z-line and interacts with
α-actinin, which cross-links actins in Z-lines
(127). LGMD1A muscle biopsies analyzed
by electron microscopy exhibit extensive
Z-line streaming. The mean age of onset of
LGMD1A is 27 years, and some patients show
a dysarthic pattern of speech in addition to the
usual LGMD features (126).
Lamins A and C are intermediate filament
proteins found in the nuclear membrane.
Mutations in LMNA, which encodes lamins A
and C, cause several different muscle diseases,
including hypertrophic cardiomyopathy, congenital muscular dystrophy (CMD), familial
partial lipodystrophy, Emery–Dreifuss muscular dystrophy (EDMD), and LGMD1B (125).
Most LGMD1B patients exhibit cardiomyopathy. Skeletal myopathy is slowly progressive
and mild in these patients, and their CK levels
are slightly elevated (128). Given that lamins
are expressed in most postmitotic cells, the
muscle specificity of these diseases is not well
understood.
LGMD1C is caused by mutations in the
CAV3 gene, which encodes the caveolin-3
protein (129). Caveolae are membrane invaginations involved in localizing proteins in the
membrane. Caveolin-3 is expressed in muscle
tissue (130) and interacts with dysferlin in the
sarcolemma (131). On one hand, accumulation
of dysferlin in the Golgi apparatus of cells
lacking caveolin-3 led to the speculation that
caveolin may help to transport dysferlin to
the sarcolemma (132). On the other hand, a
recent report indicates that caveolin-3 may
associate with the calcium release complex
in the sarcolemma (133). CK levels typically
are increased in LGMD1C patients, but
their disease phenotype is generally mild and
some patients show no clinical muscle disease
symptoms (125).
Mutations in the calpain-3 gene (CAPN3)
cause LGMD2A, which accounts for 20% to
40% of LGMD cases. Calpain-3 is a musclespecific intracellular calcium–activated protease associated with connectin and titin in the
sarcomere (134), as well as with dysferlin (135).
How mutations in calpain lead to muscular
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dystrophy is poorly understood; deregulation of
sarcomere remodeling (136), membrane repair
(46), cytoskeleton–membrane interaction and
cytoskeleton structure (137, 138), and apoptotic
cell death (139) have been proposed as potential
mechanisms.
LGMD2B is a type of dysferlinopathy in
which defective membrane repair may lead to
extensive myonecrosis. Dysferlin is a 230-kDa
transmembrane protein and, as discussed
above, has been implicated in membrane
patching (37). Dysferlin-deficient cells in
patients and mouse models show accumulation
of submembranous vesicles and membrane
discontinuities, implicating a defect in vesiclemembrane fusion (140, 141). Impaired fusion
and differentiation of dysferlin-null myoblasts
in vitro further support a role for this protein
in myogenesis (142). Interestingly, recent data
indicate that genetic manipulations that correct
defects in membrane resealing in certain assays
may be insufficient to correct muscle pathology
in dysferlin-deficient mice, raising the possibility that additional pathological mechanisms
may contribute to this disease (143). Mutations
in dysferlin can cause LGMD2B, Miyoshi myopathy (MM), or distal myopathy with onset
in the anterior tibial muscles (144). LGMD2B
patients exhibit proximal myopathy and substantially elevated CK levels, and disease onset
usually occurs in the patients’ twenties. An
additional symptom in LGMD2B that distinguishes it from the other LGMDs is infiltration
of inflammatory immune cells into muscle
(145). Interestingly, identical mutations can
cause LGMD2B or MM symptoms, which suggests that genetic modifiers or environmental
factors may influence disease pathology (146).
The sarcoglycans are N-glycosylated transmembrane proteins that form a heterotetrameric glycoprotein subcomplex within the
DCG (147). Six sarcoglycan proteins have been
cloned thus far, and the major proteins existing in the muscle sarcolemma are the α-, β-,
γ-, and δ-sarcoglycans. Mutations in the γ-, α, β-, and δ-sarcoglycans cause LGMD2C, -D,
-E, and -F, respectively. Defects in any of
the sarcoglycans, except γ-sarcoglycan, desta-
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bilize the entire DCG, which suggests that
the α-, β-, and δ-sarcoglycans are closely associated (148, 149). Loss of dystrophin also
leads to the disappearance of sarcoglycan subunits from DGC, but mutations in sarcoglycan
genes do not interfere with the localization of
dystrophin. Sarcoglycanopathies usually have a
childhood onset and greater severity than that
of other LGMDs. Cardiomyopathy is present
in all sarcoglycanopathies, although it is rarer
in LGMD2D (150).
The sarcomeric proteins telethonin and titin
are mutated in LGMD2G and LGMD2J, respectively. Titin is an enormous protein that
spans half the length of the sarcomere and provides a scaffold for myofibrils. Telethonin is a
substrate of titin kinase, which binds to its N
terminus and provides spatially defined binding sites for sarcomeric proteins to help assemble the sarcomere (151). LGMD2H results
from deficient sarcomere recycling. TRIM32,
the gene responsible for LGMD2H, encodes
an ubiquitin ligase that marks sarcomeric proteins for degradation by the proteasome (152).
Recently, a putative calcium-activated chloride
channel, Anoctamin 5 (ANO5), was identified
as the defective gene in LGMD2L. This report
also suggests that ANO5 may function in the
dysferlin-dependent muscle membrane repair
pathway (153).
Mutations in proteins involved in dystroglycan glycosylation are known to cause
CMDs, Walker–Warburg syndrome (WWS),
or muscle–eye–brain disease. Nonetheless, specific mutations in some of these genes, including FKRP (LGMD2I), POMT1 (LGMD2K),
fukutin (LGMD2M), POMT2 (LGMD2N),
and POMGnT1 (LGMD2O), can also cause
LGMD (154). LGMD2P, another type of
LGMD, is caused by disruption of dystroglycan (DAG1).
Genetic Diseases of Skeletal
Muscle: Facioscapulohumeral
Muscular Dystrophy
Facioscapulohumeral muscular dystrophy
(FSHD) is the third most common form of
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muscular dystrophy and was first described in
1884 (155). FSHD patients typically experience
symptoms first in the skeletal muscles of the
face (facio), scapula (scapulo), and upper arms
(humeral) but ultimately develop progressive
muscle weakness throughout the body (155).
Like myotonic dystrophy, FSHD is inherited
in an autosomal dominant fashion, but the
genetics of the disease have proven challenging
to unravel. More than 95% of FSHD cases
are associated with deletion of the tandemly
repeated D4Z4 units at the subtelomeric
region of chromosome 4q35 (FSHD1) (156).
Other, rarer forms of FSHD also exist, but
the genetic bases for these variants either are
dissimilar to FSHD1 or remain unclear.
Whereas normal individuals have 11–100
D4Z4 repeats at the end of chromosome
4, FSHD1 patients have 10 or fewer (157).
Translocations between these repeat units and
a similar repeating unit on the subtelomeric
region of chromosome 10q occur frequently.
Although contractions occur within the 10q repeats, these never lead to FSHD (157). A particular polymorphism found exclusively on chromosome 4, downstream of the last repeating
DUX4 unit, is essential for manifestation of
FSHD1, which explains why 10q contractions
fail to cause disease. This polymorphism encodes a polyadenylation signal that stabilizes
DUX4 transcripts that normally would be degraded (158). Thus, aberrantly stabilized expression of DUX4 may be the causative event
in FSHD pathogenesis.
Overexpression of DUX4 in various cell
types leads to apoptosis, but aberrant DUX4
expression has been reported in only a minority of cells. Yet, several DUX4 transcriptional targets appear to be robustly upregulated in FSHD muscle relative to control
muscle, suggesting that relatively restricted
DUX4 misexpression can lead to widespread
changes in gene expression, possibly through
the release of secreted factors and immunomodulators (159). Proposed strategies for mitigating FSHD pathology include downregulation
or repression via a dominant negative splice isoform of aberrant DUX4 expression (159).
Genetic Diseases of Skeletal Muscle:
Emery–Dreifuss Muscular Dystrophy
EDMD is caused by mutations in nuclear membrane proteins. EDMD can be X-linked or
autosomal; it causes progressive muscle weakness, contractures, and cardiac defects (160).
X-linked EDMD was mapped to the emerin
gene (EMD) (161), and mutations in LMNA and
in the nesprin-1 and nesprin-2 genes (SYNE1
and SYNE2) cause autosomal dominant and
autosomal recessive EDMD, respectively
(Table 1) (162–164). Emerin localizes to the
inner nuclear membrane and interacts directly
with nuclear lamin proteins (Figure 6) (165).
Emerin also binds to barrier-to-autointegration
factor (BAF), and BAF oligomers directly associate with chromatin (166). Furthermore,
nuclear lamins are indirectly linked to the actin
cytoskeleton via SUN and nesprin proteins
(167). Thus, emerin, lamin, nesprin, and other
nuclear proteins are considered to be involved
in organizing chromatin structure, thereby
providing a scaffold for proteins involved
in gene regulation and linking the nuclear
skeleton to the cytoskeleton. Both lamin and
emerin are expressed in all tissues, and the
particular impact of mutations in these genes
on skeletal muscle is not well understood. One
hypothesis (the mechanical-stress hypothesis)
holds that contraction-induced forces to
which striated muscles are specifically exposed
cause myonuclear damage and ultimately
death in muscle cells with defective nuclear
membrane proteins (168). Another hypothesis
(the gene-expression hypothesis) suggests that
LMNA and EMD mutations alter specific
chromatin sites, thereby deregulating muscle
differentiation, mechanotransduction, and
apoptosis-associated genes. Of course, these
two hypotheses are not mutually exclusive;
defects in nuclear membrane proteins may
cause both increased sensitivity to contraction
force and aberrant gene expression.
Genetic Diseases of Skeletal Muscle:
Congenital Muscular Dystrophies
Infants with hypotonia, muscle weakness,
histological manifestation of dystrophic
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Actin filaments
Nesprin
Outer nuclear membrane
SUN dimer
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Inner nuclear membrane
Nuclear lamin
Emerin
BAF complex
Chromatin
Figure 6
Nuclear matrix proteins involved in Emery–Dreifuss muscular dystrophy. Emerin acts as a bridge between chromatin and the nuclear
lamin. Nuclear lamin interacts with the SUN dimer, which is indirectly linked to the actin cytoskeleton via nesprin. Thus, mutation of
any of these genes interrupts the normal linkage between the cytoskeleton and the nuclear matrix. Abbreviation: BAF, barrier-toautointegration factor.
myopathy, and delayed motor development
are diagnosed with CMD. CMDs are a genetically heterogeneous group of neuromuscular
disorders that vary widely in severity. In some
forms of CMD, neurologic features result in
involvement of the eye and brain as well. On
the basis of the genes found to be mutated in
CMD patients thus far, and the function of
their protein products, CMDs can be classified
into five groups. The first and most-studied
group is caused by abnormalities in the glycosylation state of the αDg protein (169). αDg
undergoes extensive O-linked glycosylation,
and defects in protein glycosylation interfere
with its interaction with laminin (170), thereby
disrupting the link between the myofiber
cytoskeleton and the ECM. Mutations in
six genes (LARGE, fukutin, FKRP, POMT1,
POMT2, and POMGnT1) cause reduced αDg
glycosylation in CMD patients (171). POMT1,
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sponsible for transferring O-mannosyl glycans
to αDg. LARGE, fukutin, and FKRP may also
be involved in αDg glycosylation; however,
a detailed understanding of their mechanism
of action is lacking (172). Mutations in these
genes can lead to WWS, Fukuyama CMD,
or muscle–eye–brain disease, according to the
severity of the effect on αDg glycosylation.
The second group of CMDs results from
defects (a) in genes encoding the ECM proteins laminin-211/merosin (LAMA2) and collagen type VI (COL6A1, COL6A2, and COL6A3)
or (b) in ITGA7 (which encodes integrin-α7, the
merosin receptor) present on the sarcolemma
(173). These genetic defects also disrupt the
association between the fiber contraction machinery and the basal lamina. Allelic mutations
in each of the genes encoding different subunits of collagen type VI (COL6A1, COL6A2,
and COL6A3) can cause severe Ullrich CMD
or mild Bethlem myopathy.
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The third group of CMDs includes a rare autosomal recessive disease caused by abnormalities in the ER protein Selenoprotein N1. The
molecular mechanism behind this type of CMD
is poorly understood; however, this seleniumcontaining glycoprotein may be involved in
protein posttranslational modification, given its
localization to the ER. Evidence also supports
a role for Selenoprotein N1 in protecting muscle from oxidative stress (174) and in supporting myogenesis in early development (175). A
relatively new study demonstrated that, in addition to LMNA’s previously reported role in
LGMD2G and EDMD, defects in this gene
may cause the fourth type of CMD (176). Another recent case report described a new type
of CMD in which a mutation in a 12-yearold French boy in the gene encoding sarcomeric protein telethonin (TCAP), associated previously with LGMD2G (177), caused muscle
weakness and mildly delayed motor development during infancy that progressed over the
first decade of life (178).
Sarcopenia
Sarcopenia, the progressive loss of skeletal muscle mass and strength as a result of advancing
age, is a present and growing global health concern; it affects ∼25% of individuals older than
70 and 40% of individuals older than 80. Individuals suffering from sarcopenia experience
decreased independence, including a progressive loss of the ability to perform normal activities of daily living and a significantly reduced
quality of life. The underlying molecular mechanisms that contribute to the onset and progression of sarcopenia remain ill defined. Studies
have implicated an increase in chronic inflammation, both systemically and in the muscle tissue itself; alterations in metabolic processes that
lead to increased insulin resistance and activation of catabolic pathways; accumulation of
genotoxic DNA damage; mitochondrial dysfunction and oxidative stress; loss of motor
neurons leading to motor-unit remodeling and
denervation-induced atrophy; and deficits in
satellite cells that impair the normal muscle
regenerative response (reviewed in References
179 and 180). Strategies to reverse sarcopenia
have focused largely on behavioral interventions. Introduction of resistance or endurance
training slows sarcopenia in elderly subjects, enhancing muscle function and even increasing
the apparent content of muscle satellite cells
(181). Hormone therapy also has proven effective in some instances, which has prompted the
initiation of large-scale human trials to evaluate
the impact of testosterone supplementation on
muscle function. Finally, studies aimed at understanding the age-related decline in muscle
regenerative potential implicate both local influences [including Notch signaling (182) and
TGF-β (183)] and systemic influences (184,
185). Results from these studies could eventually be translated into pharmacological interventions to boost muscle repair potential in elderly individuals.
Sarcopenia:
age-related decline in
muscle mass and
strength
THERAPEUTIC POSSIBILITIES
FOR MUSCLE WASTING
DISEASES
Current treatment options for muscular
dystrophy are disappointingly limited and
focus mainly on managing symptoms and
suppressing the immune and inflammatory
response (186, 187). Therapeutic approaches
that aim instead to cure these disorders have
been a subject of research for many decades and
can be grouped broadly into two categories on
the basis of their strategic approach. The first
category seeks to repair or replace the mutated
gene, whereas the second aims to reduce the
impact of the mutation by activating alternative pathways or intervening downstream to
correct the pathological consequences. Each
of these strategies presents unique advantages
and challenges, and past experiences have
helped inform and focus the direction of future
research and the design of future clinical trials.
Here we discuss several promising therapeutic
avenues, including cell transplantation, gene
supplementation or correction, and oligonucleotide and small-molecule delivery, each
of which has been considered as a basis for
curative treatment of muscle disease.
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Therapeutic Possibilities:
Cell Transplantation
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Because satellite cells represent a robust and exclusive source of new myofibers during normal
muscle regeneration, these cells and their
derivatives have long been considered attractive targets for cell-replacement therapy in
muscle. In this approach, cells from an unaffected donor, or gene-corrected autologous
cells (see the section titled Therapeutic Possibilities: Gene Supplementation or Correction),
could be infused into patients, where they
would presumably produce donor-engrafted
muscle fibers carrying the normal allele of
the affected gene, thereby reconstituting gene
function. Indeed, this strategy of precursor cell
transplantation has been successful in the treatment of some hematopoietic disorders, wherein
bone marrow transplantation now represents
a relatively common (although certainly not
risk-free) clinical intervention. However, limitations in the numbers of satellite cells that can
be obtained from human muscle, and the lack
of viable methods to expand these cells ex vivo,
have thus far restricted clinical application of
this approach and have simultaneously spurred
consideration of alternative sources of cells
for transplantation. Early clinical trials evaluated the efficacy of transplanted myoblasts,
generated by long-term culture from explants
of donor muscle and injected directly into the
muscle. However, these trials yielded largely
disappointing results (188), perhaps due to significant cell loss upon transplantation, caused
by the death of up to 90% of the transferred cells
within days of transplantation (189). Progress
in the ability to isolate and expand primitive
satellite cells, which may show enhanced
survival ability after transplantation (92), will
probably be essential in reinvigorating this
conceptually attractive therapeutic approach.
Also, such enhancements in satellite cell acquisition should be coupled with improvements
in cell-delivery strategies, given that satellite
cells cannot currently be delivered systemically
and do not migrate far from the site of intramuscular injection. These limitations pose a
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daunting challenge for the delivery of donor
cells to affected muscles throughout the body.
In addition to satellite cells, non–satellite
cell populations that reside in muscle have been
considered as alternative cell-therapy vehicles.
Particularly encouraging (190) have been studies in dog models with cultured mesangioblasts,
which may be related to blood vessel–associated
pericytes (191), and exhibit broad differentiation potential in culture, including production
of cells expressing markers of the skeletal muscle, smooth muscle, and vascular lineages (191–
193). Trials are ongoing to assess the efficacy
of these cells in human patients. An attractive
attribute of mesangioblasts, as well as the probably related populations of CD133+ (194) and
muscle-derived “side-population” cells (195),
for cell therapy is their apparent ability to home
from the circulation into dystrophic muscle tissue (190 196), which allows them to be delivered via vascular, rather than intramuscular, injection. Similar promise for vascular delivery
of muscle regenerative cells was excited by observations that transfusion of donor bone marrow cells may lead to detectable contributions
of these cells in skeletal myofibers (197, 198);
however, further evaluation of such approaches
indicated that the rate of engraftment was far
below that predicted to be necessary for therapeutic effect (82, 199). Indeed, in a DMD
patient who received a bone marrow transplant for coincident severe combined immunodeficiency, although evidence of rare donor
cell engraftment in muscle was found, no improvement in dystrophic phenotype could be
attributed to the transplanted cells (200).
In an effort to overcome the pervasive
limitations in obtaining adequate numbers
of immunologically matched donor cells
when working with adult somatic cells for
muscle regenerative medicine, several groups
have attempted to derive engraftable muscle
precursor cells from pluripotent stem cell
sources. Such cells, including embryonic stem
cells (ESCs), derived from human embryos,
and induced pluripotent stem cells (iPSCs),
derived by transcription factor–dependent “reprogramming” of differentiated somatic cells,
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can be propagated indefinitely in culture and
can, in principle, differentiate into any cell type
in the body (201, 202). Thus, a robust strategy
for producing muscle precursors from these
cells would provide an inexhaustible source
of donor cells for transplant. Moreover, when
coupled with gene-correction strategies, iPSCs
generated in a patient-specific manner would
produce immunologically matched donor cells
that could eliminate, or at least reduce, the
threat of graft destruction due to recognition
by the host immune system. However, a major
challenge in realizing the potential of pluripotent stem cells for skeletal muscle therapy has
been the difficulty of deriving fully mature,
“adult” somatic cells from ESCs or iPSCs (203).
Nonetheless, important advances have been
made, including the demonstration that transient induction of the satellite cell–associated
transcription factors Pax3 and Pax7, or cell
sorting with satellite cell–specific surface markers, in differentiating mouse ESCs or iPSCs can
promote the recovery of myogenic precursors,
which have been successfully engrafted in
models of DMD and FSHD (204–208).
Therapeutic Possibilities: Gene
Supplementation or Correction
Rather than relying on transplanted cells as vehicles for complementing defective alleles in
muscular dystrophy patients, some investigators in the area of muscle regenerative medicine
have focused instead on achieving direct gene
therapy in affected muscle fibers through exogenous delivery of a normal copy of the mutated gene or, more recently, by introduction
of genome-modifying nucleases that may enable in situ gene repair. Most gene-delivery
approaches have employed recombinant viral
vectors, particularly adenoviruses, because they
can carry very large inserts (a significant challenge when attempting genetic complementation of the largest gene in the human genome!),
and AAVs, because of their relatively high
efficiency of transduction in skeletal muscle
and their low immunogenicity (187). However,
even AAVs are susceptible to antiviral host im-
mune responses, which may necessitate host
immunosuppression and can prevent repeated
gene-delivery attempts (186). Attempts have
also been made to produce pared-down versions of dystrophy genes (e.g., mini- and microdystrophin) that could provide at least partial restoration of gene function and enable
packaging of target sequences into AAV, as
well as retro- or lentiviral vectors (186). Finally,
strategies that may support the transfer of entire regions of the human chromosome, including those areas that encompass the human dystrophin gene and its regulatory elements, have
been pursued using human artificial chromosomes, which can be introduced into target cells
and maintained episomally to support tissuespecific expression of the exogenous gene (209).
A second and emerging approach in the
gene therapy realm has been to attempt direct
correction of the mutated allele(s) in the patient’s own cells. This process could, in theory,
be accomplished in situ or by genetic modification in autologous somatic cells or patientspecific iPSCs, which would otherwise be genetically matched to individual patients and
could be transplanted therapeutically to restore
gene function in patient muscles. Early efforts
toward this goal have employed site-specific
zinc-finger nucleases (ZFNs), which are experimentally engineered DNA-binding proteins
that are modified by fusion to the Fok1 nuclease domain. Site-specific nuclease activity, directed by the ZFN DNA-binding domain, is
used to induce a strand break in the target genomic sequence, which can then be repaired by
nonhomologous end joining or, in the case of
therapeutic gene correction, by homologous recombination with a normal donor sequence to
generate a gene-corrected allele. However, despite more than 15 years of development and recent progress in the application of some of these
technologies in clinical trials aimed at suppressing HIV-1 in vivo, ZFNs remain cumbersome
to design and employ, due in part to the context
specificity of ZFN sequences, nonspecific DNA
binding that can lead to off-target gene cleavage, and a relative stranglehold on the technology by a single biotech company that has
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ZFN: zinc-finger
nuclease
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TALEN:
transcription
activator–like effector
nuclease
8:58
limited ZFNs’ availability and greatly increased
their cost for research and clinical studies (210).
Happily, the emergence of a related technology, based on DNA-binding virulence factors
produced by plant pathogens, may circumvent
these obstacles. Transcription activator–like effector nucleases (TALENs), like ZFNs, exhibit
sequence-specific binding to target DNA sequences; yet, unlike ZFNs, TALENs appear to
be considerably more approachable in design
and may show greater efficacy with lower cellular toxicity (210).
However, in all of these approaches, a persistent concern even with the use of autologous
cells is that the ectopic or induced expression
of a gene not normally present in patient cells
could provoke an autoimmune response, which
would lead to clearance of the gene-corrected
cells. Indeed, some studies have supported the
idea that induced expression of dystrophin can
stimulate both humoral and cellular immune
responses (211). Overcoming such immunological barriers represents a significant challenge
for the future of gene-therapy approaches in
dystrophic disease.
Therapeutic Possibilities:
Recombinant Protein Administration
Different groups have attempted direct administration of a few recombinant proteins to ameliorate DMD symptoms, mostly in the mdx
mouse model of the disease. IGF-I is a hormone
produced by many different tissues, including
skeletal muscle, and is elevated in dystrophic
muscle (212). IGF-I is implicated in stimulation of satellite cell proliferation and differentiation during muscle regeneration, growth, and
hypertrophy (213). Administration of recombinant IGF-I protein to mdx mice reportedly
increases the resistance of the extensor digitorum longus and soleus muscles to fatigue (214).
In addition, mdx mice treated with recombinant IGF-I showed increased resistance of the
diaphragm muscle to fatigue and enhanced specific force output compared with untreated controls (215). IGF-I administration also increased
muscle force–producing capacity and size in
laminin-deficient mice (216).
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Proteins inhibiting myostatin also have
been reported to ameliorate symptoms when
administered to mdx mice. Myostatin (GDF8)
is a member of the TGF-β superfamily and
a negative regulator of muscle growth. Mutations in myostatin cause increased muscle mass
in mice (217), cattle (218), and humans (219).
Delivery of a monoclonal antibody against
myostatin into mdx mice resulted in increased
body weight, muscle mass, and strength;
however, resistance to contraction-induced
injury was not improved according to ex vivo
evaluations (220). Another study used a myostatin propeptide to inhibit myostatin in mdx
mice and reported improvements in muscle
size and strength but not in susceptibility
to eccentric contraction–induced damage
(221). However, systemic or intramuscular
injection of laminin-111 into mdx mice was
reported to prevent exercise-induced muscle
damage, increase the expression of integrin-α7
as part of the costamere, and reduce serum
CK to normal levels (222). Laminin-111 also
reportedly enhances myoblast transplantation
into immunodeficient mdx mice when used as
a coadjuvant (223).
Utrophin is the autosomal homolog of
dystrophin, and these two proteins share significant structural similarities (224). Utrophin
is upregulated in mdx mice, and utrophin
overexpression both prevents and ameliorates
disease symptoms in dystrophic mice (225,
226). Systemic injection of a recombinant
TAT-μ-utrophin protein [a truncated form
of utrophin that lacks parts of the internal
rod-shaped domain and is conjugated to the
arginine-rich TAT (transactivator of transcription) cell–penetrating peptide] into mdx mice
resulted in improved histopathology, increased
specific force production, and reduced force
drop after eccentric exercise (227). TATμ-utrophin also improved pathophysiology
when administered to dystrophin/utrophin
double-knockout mice (228).
A recent report suggests that recombinant human biglycan (rhBGN) may upregulate
utrophin in the sarcolemma in mdx mice (229).
Biglycan is an ECM protein that binds αDg and
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α- and γ-sarcoglycans and is both critical for
timely muscle regeneration (230) and important for neuromuscular junction stability (231).
Mdx mice treated with rhBGN also upregulated
some DGC components, and interestingly,
muscles from these mice showed a reduced drop
in force after multiple rounds of eccentric contractions in vitro, which suggests increased resistance to contraction-induced injury.
Therapeutic Possibilities:
Oligonucleotide-Mediated
Approaches
Oligonucleotide-mediated approaches for the
muscular dystrophies offer the advantage of
specificity for targets and for mechanisms
of action, whether based on RNA interference (RNAi), antisense, splicing modulation, or
steric hindrance (Figure 7). Oligonucleotides
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Splice-switching oligonucleotides
Dystrophin pre-mRNA
(DMD patient missing exon 50)
46
47
48
With AVI-4658
49
50
51
52
Restoration of reading frame,
truncated functional dystrophin protein produced
from stable mRNA
51
Without AVI-4658
AVI-4658
splice site-switching oligonucleotide
Nonsense-mediated decay of mRNA,
no dystrophin protein produced
Release of MBNLs
Antisense (steric blocking)
DMPK mRNA
Gppp
Gppp
AAAAA...
AAAAA...
CAGCAGCAGCAG
Antisense (CAG)n oligonucleotide
Antisense (gap-mers)
DMPK mRNA
Gppp
AAAAA...
CAGCAGCAGCAG
RNase H
AAAAA...
AAAAA...
Degradation of CUG repeats
and DMPK mRNA
DNA
Modified bases
Antisense gap-mer
Figure 7
Oligonucleotide-mediated therapeutic approaches for muscular dystrophies. Aside from RNA interference–mediated approaches, at
least three major oligonucleotide-based approaches are under active investigation; these approaches include splice-site modulation,
antisense via steric blocking, and antisense via gap-mer function. Several of these approaches have been effective in clinical and
preclinical studies of Duchenne muscular dystrophy (DMD) and dystrophia myotonica type 1. Abbreviations: MBNL, Muscleblind-like
family of RNA-binding protein; mRNA, messenger RNA; pre-mRNA, precursor mRNA.
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have been used in the context of DMD to alter
splice site usage in order to modulate the dystrophin open reading frame (232); positive results have recently been obtained in the clinic.
These antisense oligonucleotides are basically
designed to mask the splice site for mutated
or additional exons, thereby removing these
exons from the messenger RNA and creating an internally deleted protein that maintains
its crucial N- and C-terminus-associated functions. Such shortened forms of dystrophin are
found in BMD patients, whose disease is usually
much milder than DMD. Phosphorodiamidate
morpholino oligomer (PMO) and 2 -O-methylphosphorothioate (2 OMP) are two types of antisense oligonucleotides that have been used in
DMD exon skipping studies and clinical trials.
Both PMO and 2 OMP contain modifications
that make them more biologically stable and resistant to nucleases. 2 OMPs designed to target
exon 23 of the DMD gene in mdx mice restored
dystrophin expression in skeletal muscle when
injected intramuscularly (233) or intravascularly (234). This promising result led to testing of a 2 OMP targeting exon 51 of the DMD
gene (PRO051) in clinical trials. Intramuscular injection of PRO051 resulted in dystrophin
expression in 64% to 97% of muscle fibers at
levels between 17% and 35% of normal fibers
(235). A Phase I/II clinical trial for PRO051
has also been performed by subcutaneous injection of the compound in patients; the injections led to the expression of dystrophin in a
dose-dependent manner without apparent adverse effects (236). A Phase III clinical trial of
PRO051 is under way.
PMOs are effective in skipping exon 23 of
the DMD gene in mdx mice (237, 238). The
MDEX Consortium and Sarepta (formerly AVI
BioPharma) tested the efficacy of a 30-mer morpholino (AVI-4658 or eteplirsen) in skipping
exon 51 of human DMD in patients. Intramuscular injection of AVI-4658 (239) and systemic delivery of the morpholino in clinical
trials led to exon 51 skipping and expression
of dystrophin when higher morpholino doses
were used. A Phase II clinical trial for eteplirsen
is now ongoing (clinicaltrials.gov identifier:
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NCT01396239), and Sarepta has begun preclinical studies that use a drug to skip exon 50
of the human DMD gene (AVI-5038).
A unique feature of DMD is the leakiness
of the muscle membrane, which facilitates
delivery of macromolecules to skeletal muscle,
a challenge that must still be overcome in many
other muscular dystrophies. Exon skipping of
chloride channel exon 7a has been achieved
in a mouse model of myotonic dystrophy and
leads to rescue of myotonia (240). Steric blocking approaches have also been successful in
myotonic dystrophy in displacing MBNL from
expanded CUG repeats by targeting the RNA
directly with CAG repeat oligonucleotides
(241, 242), and RNase H–competent gap-mers
are effective in degrading expanded CUG
repeat–containing transcripts (243). Still, a
significant challenge facing oligonucleotidemediated approaches is delivery; solutions
to this problem could usher in a new era of
rational and specific therapies.
Therapeutic Possibilities:
Small-Molecule Therapy
The first small molecules used to treat DMD
patients were anti-inflammatory compounds
from the family of glucocorticoid corticosteroids. Deflazacort, prednisone, and prednisolone have been most commonly used in the
clinic. In some cases, treated patients showed
improved muscle strength, prolonged ambulation, and slowed disease progression; however,
these interventions are not a cure for the disease, and major side effects, including hypertension, diabetes, weight gain, and cataract, present
obstacles to their prescription (244, 245).
Approximately 10–15% of DMD cases are
caused by mutations that introduce premature
stop codons (246). Some chemicals can interact
with ribosomal subunits to cause the translational machinery to skip such nonsense mutations by introducing an amino acid in those
positions instead. Differences in the context of
nucleotide sequence surrounding premature
and normal stop codons allow for specificity of
action of these compounds (247). Gentamicin,
an aminoglycoside antibiotic that promotes
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such ribosomal “read-through,” can induce
dystrophin expression in mdx muscle to up
to 20% of normal levels (248); however, this
compound has not been effective in human
trials (249).
A high-throughput screen of ∼800,000
R
,
chemicals, performed by PTC Therapeutics
R
identified ataluren (PTC-124 ) as a compound
that efficiently induced nonsense mutation
read-through. Ataluren, which has no structural similarity with aminoglycosides, restores
dystrophin expression in cultured myotubes
from mdx mice and DMD patients. When
administered to mdx mice in vivo, ataluren
improved muscle-specific force and resistance
to contraction-induced injury and restored
dystrophin expression in up to 25% of fibers
(250). Phase I trials of PTC-124 revealed
that the compound is well tolerated; however,
three Phase II clinical trials were terminated
in March 2010 when the predetermined
primary outcome (the 6-min walk test) was not
achieved. A Phase III clinical trial (clinicaltrials.gov identifier: NCT01247207) is currently
recruiting DMD and BMD participants who
have previously been exposed to ataluren.
Another small molecule, BMN-195 (SMTC1100), emerged from a screen for chemicals
that upregulate the expression of utrophin.
Daily administration of BMN-195 to mdx mice
ameliorated dystrophic pathology (251), but
when tested in a Phase I clinical trial, plasma
concentrations of this compound failed to reach
the required level (see http://phx.corporateir.net/phoenix.zhtml?c = 106657&p = irolnewsArticle&ID = 1455247&highlight).
However, no adverse effects were reported for
BMN-195, and Summit PLC is working to get
a new formulation of the compound back into
clinical trials.
Recently, Kawahara et al. (252) used a zebra
fish model of DMD to screen a small-molecule
library to identify compounds that ameliorate
dystrophic pathology in newborn fish. The
most potent chemical identified in this study
was aminophylline, reported to be a nonselective phosphodiesterase (PDE) inhibitor (253).
Interestingly, the skeletal muscle structure of
affected dystrophin-null fish was restored after treatment with aminophylline for 26 days,
although no dystrophin expression was detected in the muscle. The mechanism underlying this compound’s activity is not understood,
but it may relate to elevation of intracellular
cyclic AMP (cAMP) levels and activation of
cAMP-dependent protein kinase (252). These
authors also reported that sildenafil citrate, a
PDE5 inhibitor, influences muscle pathology in
dystrophin-null zebra fish. Sildenafil citrate was
previously shown to reverse cardiomyopathy in
mdx mice, possibly via activation of cyclic GMP
(cGMP)-dependent pathways (254). Tadalafil,
another PDE5 inhibitor, reportedly improves
the histopathology of dystrophic muscle in
mdx mice when administrated prenatally (255);
however, existing studies on the effects of PDE5
inhibitors on dystrophic muscle have evaluated compound administration only in the early
stages of life, and it remains unclear whether
these molecules can reverse disease phenotype if animals are treated after disease onset. Both sildenafil citrate and tadalafil are in
clinical trials for DMD and BMD patients
(clinicaltrials.gov identifiers: NCT01350154,
NCT01070511, and NCT01359670).
Small-molecule approaches for the treatment of myotonic dystrophy have focused primarily on either disrupting RNA-MBNL interactions or addressing symptoms of DM.
Several compounds displace MBNL from expanded CUG repeats or suppress CUG repeat–
dependent pathology (256–259), and some have
proven efficacious in animal models (257, 259).
Approaches to identify these compounds include the use of high-throughput screening
methods, such as fluorescence resonance energy transfer and fluorescence anisotropy. A
modular approach also has been pioneered
in which molecules that target short RNA
motifs with moderate affinity are assembled
onto a peptoid-like backbone to increase affinity and specificity (260). Mexiletine, a US
Food and Drug Administration–approved antiarrhythmic sodium channel blocker, has been
used to treat myotonia and other DM symptoms (261); a clinical trial is under way to
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formally investigate mexiletine’s potentially
positive effects in this context.
CONCLUSIONS AND
PERSPECTIVES
The great variation in the etiology and pathology of skeletal muscle diseases presents many
challenges to their efficient diagnosis and treatment; however, recent advances show promise
for applying both patient-specific and generic
therapies to ameliorate symptoms and, potentially, to reverse disease course. Further understanding of the molecular and biochemical bases for myofiber loss in these genetically diverse degenerative diseases will certainly
help uncover new strategies for effective intervention to promote healthy muscle function
throughout life.
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SUMMARY POINTS
1. Damage to skeletal muscle may occur throughout life due to exercise and contraction,
acute physical and chemical insult, abnormalities in the immune system, or muscle degenerative diseases.
2. Skeletal muscle has significant endogenous repair capacity, including the abilities to
repair small disruptions in muscle fiber membranes and to produce new myofibers from
resident muscle stem cells following injury.
3. Muscular dystrophies include a wide range of genetic muscle degenerative diseases caused
by deficiencies in stability, repair, or gene-expression regulation in muscle fibers.
4. Some muscular dystrophies arise from mutations in ubiquitously expressed genes; the
reasons for the muscle specificity of these genetic disruptions remain mysterious.
5. Although most muscular dystrophies are caused by mutations in protein-coding genes,
myotonic dystrophy arises from expanded nucleotide repeats in noncoding RNAs, which
cause pathological sequestration of proteins involved in mRNA splicing.
6. Current therapeutic approaches for muscular dystrophies are based on ectopic introduction of the normal gene, endogenous repair of the mutated gene, or amelioration of
symptoms achieved by triggering alternative or redundant pathways.
7. High-throughput screening for therapeutically beneficial compounds has identified some
small molecules with potential clinical applicability in muscular dystrophy patients.
8. Skipping of mutated exons in DMD has been promising, and results from clinical trials
hold promise for improved therapies for many patients with relevant genetic lesions.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
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Contents
Annual Review of
Pathology:
Mechanisms of
Disease
Volume 8, 2013
Pathogenesis of Langerhans Cell Histiocytosis
Gayane Badalian-Very, Jo-Anne Vergilio, Mark Fleming,
and Barrett J. Rollins p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Molecular Pathophysiology of Myelodysplastic Syndromes
R. Coleman Lindsley and Benjamin L. Ebert p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p21
The Role of Telomere Biology in Cancer
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Chromosome Translocation, B Cell Lymphoma,
and Activation-Induced Cytidine Deaminase
Davide F. Robbiani and Michel C. Nussenzweig p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p79
Autophagy as a Stress-Response and Quality-Control Mechanism:
Implications for Cell Injury and Human Disease
Lyndsay Murrow and Jayanta Debnath p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 105
Pathogenesis of Antineutrophil Cytoplasmic Autoantibody–Associated
Small-Vessel Vasculitis
J. Charles Jennette, Ronald J. Falk, Peiqi Hu, and Hong Xiao p p p p p p p p p p p p p p p p p p p p p p p p p 139
Molecular Basis of Asbestos-Induced Lung Disease
Gang Liu, Paul Cheresh, and David W. Kamp p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 161
Progressive Multifocal Leukoencephalopathy: Why Gray
and White Matter
Sarah Gheuens, Christian Wüthrich, and Igor J. Koralnik p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 189
IgA Nephropathy: Molecular Mechanisms of the Disease
Jiri Mestecky, Milan Raska, Bruce A. Julian, Ali G. Gharavi,
Matthew B. Renfrow, Zina Moldoveanu, Lea Novak, Karel Matousovic,
and Jan Novak p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 217
Host Responses in Tissue Repair and Fibrosis
Jeremy S. Duffield, Mark Lupher, Victor J. Thannickal,
and Thomas A. Wynn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 241
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Cellular Heterogeneity and Molecular Evolution in Cancer
Vanessa Almendro, Andriy Marusyk, and Kornelia Polyak p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 277
The Immunobiology and Pathophysiology of Primary Biliary Cirrhosis
Gideon M. Hirschfield and M. Eric Gershwin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 303
Digital Imaging in Pathology: Whole-Slide Imaging and Beyond
Farzad Ghaznavi, Andrew Evans, Anant Madabhushi,
and Michael Feldman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 331
Annu. Rev. Pathol. Mech. Dis. 2013.8:441-475. Downloaded from www.annualreviews.org
by Harvard University on 02/02/13. For personal use only.
Pathological and Molecular Advances in Pediatric
Low-Grade Astrocytoma
Fausto J. Rodriguez, Kah Suan Lim, Daniel Bowers,
and Charles G. Eberhart p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 361
Diagnostic Applications of High-Throughput DNA Sequencing
Scott D. Boyd p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 381
Pathogenesis of the Viral Hemorrhagic Fevers
Slobodan Paessler and David H. Walker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 411
Skeletal Muscle Degenerative Diseases and Strategies for Therapeutic
Muscle Repair
Mohammadsharif Tabebordbar, Eric T. Wang, and Amy J. Wagers p p p p p p p p p p p p p p p p p p p 441
The Th17 Pathway and Inflammatory Diseases of the Intestines,
Lungs, and Skin
Casey T. Weaver, Charles O. Elson, Lynette A. Fouser, and Jay K. Kolls p p p p p p p p p p p p p p 477
Indexes
Cumulative Index of Contributing Authors, Volumes 1–8 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 513
Cumulative Index of Article Titles, Volumes 1–8 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 517
Errata
An online log of corrections to Annual Review of Pathology: Mechanisms of Disease articles
may be found at http://pathol.annualreviews.org
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