HAWKE and GARRY 2001 - Myogenic Satellite Cells Physiology To Molecular Biology

J Appl Physiol
91: 534–551, 2001.
invited review
Myogenic satellite cells: physiology
to molecular biology
THOMAS J. HAWKE1 AND DANIEL J. GARRY1,2

1
Department of Internal Medicine and 2Department of Molecular Biology,
University of Texas Southwestern Medical Center, Dallas, Texas 75390
Hawke, Thomas J., and Daniel J. Garry. Myogenic satellite cells:

physiology to molecular biology. J Appl Physiol 91: 534–551,
2001.—Adult skeletal muscle has a remarkable ability to regenerate
following myotrauma. Because adult myofibers are terminally differen-
tiated, the regeneration of skeletal muscle is largely dependent on a
small population of resident cells termed satellite cells. Although this
population of cells was identified 40 years ago, little is known regarding
the molecular phenotype or regulation of the satellite cell. The use of cell
culture techniques and transgenic animal models has improved our
understanding of this unique cell population; however, the capacity and
potential of these cells remain ill-defined. This review will highlight the
origin and unique markers of the satellite cell population, the regulation
by growth factors, and the response to physiological and pathological
stimuli. We conclude by highlighting the potential therapeutic uses of
satellite cells and identifying future research goals for the study of
satellite cell biology.
skeletal muscle; stem cells; regeneration; aging; transgenic models
SKELETAL MUSCLES OF ADULT mammalian species exhibit a (satellite cells expressing myogenic markers are also
remarkable capacity to adapt to physiological demands termed myoblasts). Ultimately, these cells fuse to ex-
such as growth, training, and injury. The processes by isting muscle fibers or fuse together to form new myo-
which these adaptations occur are largely attributed to fibers during regeneration of damaged skeletal muscle
a small population of cells that are resident in adult (12, 167).
skeletal muscle and are referred to as satellite cells. Since the original description of the myogenic sat-
After their initial identification in 1961 (98), Mauro ellite cell, considerable interest and research efforts
(117) described a cell closely associated with the pe- have focused on myogenic satellite cell biology.
riphery of the frog myofiber and termed it a satellite These research efforts have enhanced our under-
cell based on its location. Quiescent satellite cells are standing of muscle growth, remodeling, and regen-
physically distinct from the adult myofiber as they eration. In addition, new paradigms have been pro-
reside in indentations between the sarcolemma and posed regarding the regenerative capacity and the
the basal lamina (130). Adult skeletal muscle fibers are plasticity of the myogenic satellite cell population
terminally differentiated such that muscle growth and (108, 119, 139, 168, 169). These paradigms suggest
regeneration are accomplished by satellite cells. In the that the satellite cell population not only has a
unperturbed state, these cells remain in a nonprolif- remarkable capacity for muscle regeneration but
erative, quiescent state. However, in response to stim- may also contribute to alternative muscle and non-
uli such as myotrauma, satellite cells become acti- muscle lineages and may have clinical applications
vated, proliferate, and express myogenic markers in the treatment of devastating and deadly diseases
such as muscular dystrophy.
The current review attempts to integrate the ana-
Address for reprint requests and other correspondence: D. J.
Garry, UT Southwestern Medical Center at Dallas, 5323 Harry tomic, physiological, biochemical, and molecular prop-
Hines Blvd., NB11.200, Dallas, TX 75390-8573 (E-mail: erties that regulate the myogenic satellite cell popula-
daniel.garry@utsouthwestern.edu). tion. We begin with a brief overview of vertebrate
534 8750-7587/01 $5.00 Copyright © 2001 the American Physiological Society http://www.jap.org
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INVITED REVIEW 535
myogenesis, highlighting the populations of myoblast BUILDING OF MUSCLE WITH WAVES OF PRECURSOR
precursor cells that contribute to muscle development, CELLS
and outline a well-described genetic hierarchy that is
important in muscle specification. We describe the lim- Anatomic and molecular mechanisms during muscle
ited gene expression profile and the distinguishing regeneration have been postulated to recapitulate
morphological characteristics of the satellite cell pop- muscle development. Although current evidence sug-
ulation. We describe the inductive signals that regu- gests the regenerative process may be more complex,
late the satellite cell in vitro and in well-described an understanding of muscle development is important
physiological models. Finally, we will review the stem to appreciate the anatomic and molecular network
cell-like features of the satellite cells with emphasis on associated with muscle regeneration.
the novel strategies that may be pursued in the future During embryogenesis, the head, trunk, and limb
for the treatment of debilitating myopathies. skeletal muscles develop as separate lineages. Of the
Importantly, myogenic satellite cell biology re- three germ layers in the early embryo, the paraxial
mains an emerging field of scientific inquiry, such mesoderm gives rise to the somite (Fig. 1A). The somite
that satisfying and complete answers to the most is subdivided into the dorsomedial (epaxial) domain,
fundamental questions are currently unavailable. In which generates the muscles of the back, and the
this review, we will provide a summary of the cur- ventrolateral (hypaxial) domain, which gives rise to the
rent knowledge in this area and highlight fertile abdominal, intercostal, and limb musculature (see
areas for future research. Refs. 123 and 140 for review).
Fig. 1. Derivation of muscle precursor

cells during mouse embryogenesis. A:
precursor cells from the epaxial region
of the somite migrate to form the back
musculature. Precursor cells from the
hypaxial region of the somite migrate
to the newly formed limb buds. Note
the migrating limb precursor cells form
dorsal and ventral masses, which will
later become the extensor and flexor
muscle groups of the limb. Surround-
ing structures such as the neural tube,
notochord, dorsal aorta, and overlying
ectoderm potentially provide signals
regulating precursor cell movements
and fate. B: members of the MyoD fam-
ily play an integral role in skeletal
muscle myogenesis. MyoD and my f 5
expression is involved in determination
of precursor cells to a myogenic fate,
whereas myogenin and MRF4 expres-
sion is associated with terminal
differentiation.
J Appl Physiol • VOL 91 • AUGUST 2001 • www.jap.org

536 INVITED REVIEW
During somitogenesis, cross talk involving growth MUSCLE PRECURSOR CELLS AND LIMB
factors (Wnt proteins, Sonic hedge hog, bone morpho- DEVELOPMENT
genic proteins, and so forth) and transcription factors
Whereas the cells associated with the epaxial region
(myf 5, MyoD, Pax-3, and so forth) occurs between the
of the somite contribute to the primary myocytes of the
developing somite and the anatomically adjacent struc-
myotome, the hypaxial region of the somite (at the level
tures, including the overlying ectoderm, the ventrome-
of the limb) contributes to the migratory limb muscle
dial neurotube and notochord, and the vascular struc- precursor cells (141). Specification, migration, and dif-
tures including the aorta (38, 113, 123, 131, 145). The ferentiation of the myogenic precursor cells to their
constellation of these positional cues (i.e., growth and distal targets are complex processes involving intrinsic
transcription factors) results in the specification of and extrinsic cues of which little is known. Recent
muscle through the regulation of a distinct molecular studies have shown that these myogenic precursor
(hierarchical) cascade. cells express the paired domain transcription factor
Since the discovery of MyoD in 1987, the role of the Pax-3 (181), the tyrosine kinase receptor c-Met (205),
myogenic basic helix-loop-helix (bHLH) transcrip- the homeodomain transcriptional repressor msx1 (11,
tion factors in skeletal myogenesis has been defined 189), and the homeodomain transcription factor Lbx 1
in elegant detail by several groups (19, 126, 137, 147, (17, 71) but lack expression of the myogenic regulatory
148, 192, 200, 207). This subset of the bHLH family factors of the MyoD family. After migration to the
includes MyoD, my f 5, myogenin, and MRF4. Each of developing limb, these precursor cells coalesce into the
these myogenic bHLH proteins forms heterodimeric dorsal and ventral premuscle masses, which will be the
DNA binding complexes that include other bHLH future flexor and extensor compartments of the fore-
proteins of the E2 gene family (E12 and E47) and limb and now express members of the MyoD family (19,
bind a canonical DNA sequence, CANNTG (E-box), 137, 141).
within enhancer elements of genes that encode ter- Targeted gene disruption studies (i.e., knockout
minal differentiation markers of the skeletal muscle mouse models) have begun to provide insight into the
lineage (41, 103). MyoD family members share the molecular regulation of limb development. In mice
ability to activate skeletal muscle differentiation lacking either Pax-3 (16, 60) or c-Met (50), limb pre-
when expressed ectopically in nonmuscle cells (115, cursor cells fail to migrate into the limb, resulting in
193). The essential role played by bHLH proteins in the complete loss of limb muscles. Combinatorial
skeletal myogenesis has been demonstrated unam- knockout experiments crossing the Pax-3 mutant
biguously by gene disruption experiments (78, 138, mouse (Splotch) into the myf 5 null background result
142, 147, 148, 157, 185). The results of these gene in a further perturbation of myogenesis and an absence
knockout experiments support a role for my f 5 and of both limb and body wall muscle (181). Additional
MyoD in the determination of the myogenic cell fate studies support a genetic hierarchy where Pax-3 medi-
and the formation of myoblasts during embryogene- ates the activation of other myogenic regulatory factors
sis (Fig. 1B). Myogenin and MRF4 appear to function (myf 5 and MyoD) and functions as a key regulator of
in activation of muscle differentiation (149, 175). somitic myogenesis (113, 181). In addition, Pax-3 func-
Although a number of biochemical and transgenic tions in the specification of the limb precursor cells and
studies support an integral role for the myogenic is upstream of both c-Met and Lbx 1 (17, 50, 60, 181).
bHLH proteins during development, it is also clear Inactivation of the Lbx 1 locus by homologous recom-
that the MyoD family members interact in a combi- bination results in an extensive loss of limb muscles,
natorial fashion with known transcription factors although residual muscle groups are still present. This
such as members of the MADS box family (i.e., myo- finding suggests that Lbx 1 is not required for the
cyte enhancer factor 2 or MEF-2; Refs. 41, 103), cell specification of limb muscles but may function in the
cycle regulatory proteins, and currently undefined determination of which migratory highway the precur-
factors to regulate myogenesis (see Refs. 126 and 175 sors should pursue (17, 71).
for review). Although the role of MyoD family mem- Proliferating limb myoblasts coalesce into the ven-
bers during embryogenesis has been defined in great tral and dorsal premuscle masses, withdraw from the
detail, the functional role of these family members in cell cycle, and form multinucleated primary myofibers
established postnatal skeletal muscle remains un- at approximately embryonic day 13 postcoitum (E13)
clear. Studies support the localization of MyoD and in the mouse embryo. In a process that is less clearly
myogenin in fast-twitch and slow-twitch adult myo- defined, secondary myofibers form parallel to the pri-
fibers, respectively, suggesting a function for these mary fibers and constitute the predominant multinu-
myogenic regulatory factors in fiber-specific contrac- cleated myofibers during the latter stages of embryo-
tile protein gene expression (84, 85, 171). Future genesis (E15–E16 in the mouse) and in postnatal
studies utilizing transgenic technologies such as skeletal muscle (56, 123). Studies suggest that two
conditional or tissue-restricted knockout strategies distinct lineages generate primary myofibers (i.e., em-
of these myogenic regulatory factors will be useful bryonic myoblasts) and the secondary myofibers (i.e.,
in the definition of their role in adult skeletal fetal myoblasts). Furthermore, primary myofibers dif-
muscle. fer from secondary myofibers in their temporal devel-

INVITED REVIEW 537
opment, size, number, and expression of myosin heavy- lation. Additional fate-mapping strategies will be
chain isoforms (123, 175). needed to further define and dissect the lineage deri-
The discovery of satellite cells in the early 1960s vation of all the satellite cells that reside in adult
demonstrated the existence of yet an additional popu- skeletal muscle. These studies will be important in
lation of proliferative cells that contributed to postna- defining whether there is a common lineage source for
tal growth, the maintenance of adult skeletal muscle, the entire satellite cell population and a common lin-
and the repair of damaged myofibers. Myogenic satel- eage source for cells that have regenerative capacities
lite cells are present in the limbs of midgestational in both muscle and nonmuscle tissues.
mouse embryos after E15 (35). After birth, the satellite
cell population accounts for ⬃30% of sublaminar mus- SATELLITE CELL IDENTIFICATION
cle nuclei in neonatal hindlimb skeletal muscle (12).
These neonatal satellite cells fuse to growing myofibers Anatomic identification. Resident within adult skel-
to contribute additional nuclei during postnatal growth etal muscle is a pool of undifferentiated mononuclear
of skeletal muscle. cells termed satellite cells because of their anatomic
location at the periphery of the mature, multinucleated
SOMITIC VS. NONSOMITIC ORIGIN OF SATELLITE
myotube. The defining characteristic of the satellite
CELLS
cell is that the basal lamina that surrounds the satel-
lite cell and the associated myofiber is continuous
Previous studies support the hypothesis that muscle (167). As shown in Fig. 2, the identification of this cell
precursor cells, including the myogenic satellite cell population has historically utilized ultrastructural
population, originate from the multipotential mesoder- techniques (66, 161). Other distinguishing morpholog-
mal cells of the somite (58, 141, 167). The support for ical features of the satellite cell population include a
this hypothesis is primarily derived from chimeric or relatively high nuclear-to-cytoplasmic ratio with few
interspecies grafting experiments that have been per- organelles, a smaller nuclear size compared with the
formed in avian models. These fate-mapping studies adjacent nucleus of the myotube, and an increase in
involved the transplantation (or exchange) of embry- the amount of nuclear heterochromatin compared with
onic somites from donor quail embryos into host chick that of the myonucleus (167). These morphological
embryos (27, 105). The transplanted quail cells have features are consistent with the finding that satellite
distinguishing morphological characteristics and were cells are relatively quiescent and transcriptionally less
observed to migrate from the somite and contribute to active. These distinguishing features are absent follow-
both the limb muscles and the satellite cell population ing activation or proliferation of the satellite cells in
in postnatal chick skeletal muscle. Satellite cells have response to growth, remodeling, or muscle injury. After
been isolated from the fetal skeletal muscle from an activation, the satellite cells are more easily identified
E15 or older mouse embryo, suggesting that satellite as they appear as a swelling on the myofiber with
cells populate the developing limb during the latter cytoplasmic processes that extend from one or both
stages of embryogenesis (34, 35, 36). Whether the sat- poles of the cell (Fig. 2; Ref. 167). Associated with the
ellite cells migrate from the somite as a distinct lineage increase in mitotic activity, there is a reduction in
or whether they originate from a preexisting lineage heterochromatin, an increase in cytoplasmic-to-nu-
(i.e., embryonic or fetal myoblasts) in the developing clear ratio, and an increase in the number of intracel-
limb is unclear. Nevertheless, the underlying concept lular organelles (167).
was that each of the myoblast precursor cells (i.e., Satellite cell markers. The profile of gene expression
embryonic myoblasts, fetal myoblasts, and satellite of the quiescent satellite cell as well as their activated
cells) was a derivative of the somite. and proliferating progeny is largely unknown. The
This paradigm has recently been challenged, as stud- quiescent satellite cells do not express myogenic regu-
ies have suggested that multipotential cells of non- latory factors of the MyoD or MEF2 families or other
somitic origin may be the precursors of the satellite cell known markers of terminal differentiation (33, 119,
(45, 139). De Angelis et al. (45) reported that cells 201). Through the identification of satellite cell mark-
isolated from the embryonic dorsal aorta had a similar ers, biologists will be able to address issues related to
morphological appearance and a similar profile of gene the developmental origin of the satellite cell, the cell
expression to that of satellite cells. Furthermore, cycle control, and the molecular regulation of this
transplantation of the aorta-derived myogenic cells unique cell population during growth and regenera-
into newborn mice revealed that this cell population tion. Several satellite cell markers have been identified
participated in postnatal muscle growth, regeneration, and are restricted to either the quiescent, activated, or
and fusion with resident satellite cells. The authors proliferative state or are expressed more broadly (Ta-
proposed that satellite cells may be derived from endo- ble 1).
thelial cells or a precursor common to both the satellite We have previously determined that myocyte nu-
cell and the endothelial cell. clear factor (MNF or Foxk1), a member of the winged
Derivation of the satellite cell from the somite or a helix transcription factor family, is localized to the
nonsomitic source need not be mutually exclusive. Con- quiescent satellite cell in adult skeletal muscle (64).
ceivably, both lineages may contribute under physio- We have identified two alternatively spliced isoforms
logical or pathological states to the satellite cell popu- for MNF and termed them MNF-␣ and MNF-␤ (64,

538 INVITED REVIEW
Fig. 2. Satellite cells occupy a sublami-

nar position in adult skeletal muscle.
In the uninjured muscle fiber, the sat-
ellite cell is quiescent and rests in an
indentation in the adult muscle fiber.
The satellite cells can be distinguished
from the myonuclei by a surrounding
basal lamina and more abundant het-
erochromatin. When the fiber becomes
injured, the satellite cells become acti-
vated and increase their cytoplasmic
content. The cytoplasmic processes al-
low for chemotaxis of the satellite cell
along the myofiber. Bar ⫽ 1 ␮m.
203, 204). These two alternatively spliced isoforms are growth deficit, a marked impairment in muscle regen-
reciprocally expressed during myogenesis and during eration (63), and a decreased number of satellite cells
muscle regeneration, suggesting that the two isoforms in adult MNF mutant skeletal muscle (Hawke and
of MNF may exert opposing effects on target genes at Garry, unpublished observations). Additional winged
discrete steps during muscle regeneration or in re- helix family members have also been identified in stem
newal of the satellite cell population (63). Using a cells or regenerating cells including Genesis (Foxd3;
RT-PCR assay, we have shown that MNF-␤ is the Ref. 83), which is expressed selectively in embryonic
principal form expressed in quiescent satellite cells, stem cells, and a protein related to hepatocyte nuclear
whereas MNF-␣ predominates in proliferating satellite factor-3 (HNF3/forkhead homolog 11), which has been
cells following muscle injury. Disruption of the MNF identified in regenerating hepatocytes (206).
locus, mutating both isoforms, resulted in a severe Utilizing single cell RT-PCR analysis, Cornelison
and Wold (33) characterized the satellite cells as a
Table 1. Expression patterns of satellite cell markers heterogeneous population based on their profile of
in adult skeletal muscle gene expression. Additionally, they identified c-Met,
the receptor for hepatocyte growth factor (HGF), as a
Molecular Marker Expression Observed in the Adult Reference marker of quiescent satellite cells. HGF is a potent
MNF Quiescent, activated, and proliferating 64 mitogen for satellite cells and has been shown to be
satellite cells important in the migration of the myogenic precur-
Pax7 Quiescent, activated, and proliferating 169 sor cells from the somite to the developing limb (5,
satellite cells 14). Moreover, c-Met deficient embryos fail to form
c-Met Quiescent, activated, and proliferating 33
satellite cells limb skeletal muscle due to a lack of myogenic pre-
M-cadherin Quiescent, activated, and proliferating 33 cursor cells (14, 112).
satellite cells Irintchev and colleagues (87) identified M-cadherin,
NCAM Quiescent, activated, and proliferating 39 a calcium-dependent cell adhesion molecule, as a
satellite cells; synaptic junctions in
adult myofibers
unique marker of the satellite cell pool. M-cadherin is
VCAM-1 Quiescent, activated, and proliferating 89 only expressed in a subpopulation of the quiescent cell
satellite cells pool; however, its expression is increased when the
Desmin Activated and proliferating satellite 15 satellite cells become activated in response to a stim-
cells ulus (9, 33). Recent studies suggest that other cell
myf5 Activated and proliferating satellite 33
cells adhesion molecules, neural cell adhesion molecule
MyoD Activated and proliferating satellite 33, 124 (NCAM) and vascular adhesion molecule-1 (VCAM-1),
cells are also potential markers of quiescent satellite cells
BrdU Proliferating cells 163 (39, 89). The role of these adhesion molecules is unclear
PCNA Proliferating cells 90
[3H]thymidine Proliferating cells 128 but collectively (NCAM, VCAM-1, and M-cadherin)
may function in the adhesion of the satellite cell to the
Expression of selected molecular markers used to identify the basal lamina of the myofiber and may participate in
satellite cell population in adult skeletal muscle is outlined. MNF,
myocyte nuclear factor; NCAM and VCAM, neural cell and vascular
the migratory capacity of this cell population in re-
adhesion molecule; BrdU, bromodeoxyuridine; PCNA, proliferating sponse to stimuli. NCAM is expressed in both myofi-
cell nuclear antigen. bers and satellite cells, whereas VCAM-1 is broadly

INVITED REVIEW 539
expressed during embryogenesis but limited to satel- immunohistochemical techniques have been utilized
lite cells in adult muscle (39). Furthermore, VCAM-1 for the identification of the satellite cell pool. Although
has been shown to mediate satellite cell interaction a limited number of markers for the quiescent satellite
with leukocytes following injury (89). cell population exist, proliferating satellite cells, as
Recent work from the Rudnicki laboratory (169) measured by [3H]thymidine or bromodeoxyuridine
identified the paired box transcription factor, Pax7, (BrdU) incorporation, can be identified immunohisto-
expressed selectively in quiescent and proliferating chemically for the coexpression of the MyoD family
satellite cells. Analysis of the Pax7 mutant skeletal members or the intermediate filament protein, desmin
muscle revealed a complete absence of satellite cells. (15, 104, 123). MyoD expression occurs early during
This novel finding supports the hypothesis that Pax7 is the activation of the satellite cell population (within 6 h
essential for the specification of the satellite cell pop- following muscle injury) (63, 74, 100, 119, 134). In
ulation. Future studies will be important in the defini- addition, several nonselective markers of cellular pro-
tion of Pax7 downstream target genes in the satellite liferation have been used to characterize the prolifer-
cell population and may provide insight into the regu- ating satellite cell pool. These markers of cellular pro-
lation of this cellular pool. liferation include proliferating cell nuclear antigen
Identification of other satellite cell markers is the (90), BrdU (163), and [3H]thymidine (128).
focus of current research efforts. Emerging candidates Satellite cell number is dependent on the species,
include the cell surface antigen Sca-1 (stem cell anti- age, and muscle fiber type (Table 2; see Ref. 167 for
gen-1; Refs. 88, 177), the glycoprotein Leu-19 (94, 162), review). Satellite cells constitute ⬃30% of the muscle
the anti-apoptotic factor Bcl-2 (106, 123), CD34 (9), and nuclei in the neonate and decrease with age to ⬃4% in
interferon regulatory factor-2, which is a transcription the adult and ⬃2% in the senile (29–30 mo) mouse
factor that mediates VCAM-1 expression in skeletal (176). The decrease in the percentage of satellite cells
muscle (89). with aging (i.e., senile rodent) is the result of an in-
SATELLITE CELL QUANTITATION AND DISTRIBUTION
crease in myonuclei (oxidative and glycolytic myofi-
bers) and a decrease in total number of satellite cells
Quantitation of the satellite cell population in adult (glycolytic myofibers) (12, 66, 167).
skeletal muscle has been possible primarily through The satellite cell distribution between muscle groups
the use of ultrastructural techniques. More recently, is a result of the heterogeneity in satellite cell content
Table 2. Satellite cell content in skeletal muscle

Model Muscle Age and Protocol %SC SC#/muscle Reference
Rat TA 7–9 wk 4 161

Soleus 7–9 wk 11 161
Diaphragm 7–9 wk 8 161
Rat LD adult 4.5 2
Rat Soleus 1 mo 9.6 5.2 ⫻ 105 66
Soleus 1 yr 6.6 7.3 ⫻ 105 66
Soleus 2 yr 4.7 5.4 ⫻ 105 66
EDL 1 mo 7.0 3.1 ⫻ 105 66
EDL 1 yr 2.9 2.1 ⫻ 105 66
EDL 2 yr 1.9 1.3 ⫻ 105 66
Rat EDL 4 mo 3.8 146
EDL Hypothyroid 3.8 146
EDL Hypothyroid; chronic stimulation 7.9–13.8 146
Rat Levator ani 4 mo 1.9 135
Levator ani 32 mo 1.2 135
Mouse Soleus 8 mo 4.6 176
Soleus 30 mo 2.4 176
Mouse Gastroc 7–10 days 25 169
Gastroc Pax 7⫺/⫺ 0 169
Quail LD 6 wk 15.6 198
LD Stretched 16.7 198
Human Control patients 15 190
DMD patients 25 190
Human Trapezius Control (38 yr) 3.7 94
Trapezius Resistance trained 5.4 94
Human Biceps brachii ⬍30 mo 8.4 158
Biceps brachii Werdnig-Hoffman infants 14.4 158
Pig Sartorius 64 wk 1.1 21
PL 64 wk 4.3 21
Lizard Tail Lygosoma species 7.5 95
Tail Anolis species 4.8 95
Satellite cell (SC) content in various species under varying physiological and pathological conditions. TA, tibialis anterior; LD, latissimus
dorsi; Gastroc, gastrocnemius; EDL, extensor digitorum longus; PL, peroneus longus; DMD, Duchenne muscular dystrophy.

540 INVITED REVIEW
between muscle fiber types. An increase in satellite cell Table 3. Factors affecting satellite cell activity
density has been demonstrated in association with the
Chemotactic
proximity of capillaries (161), myonuclei (18, 161), and Growth Factor Ability Proliferation Differentiation Reference
motoneuron junctions (199). The proximity of satellite
cells to these anatomic structures suggests a permis- FGF 1 79
1 2 3
sive role in the regulation of the cellular pool. In sup- 1 54
port of this hypothesis, oxidative fibers (characterized NE 13
by increased capillary and motoneuron density com- 1 152
pared with glycolytic myofibers) demonstrate a five to HGF 1 13
six times greater satellite cell content (65, 161). 1 4
1 2 124
1 182
GROWTH FACTORS AS REGULATORS OF THE
IGF-I 1 79
SATELLITE CELL POPULATION 1 1 3
1 54
The process of muscle regeneration requires the in- 1 1 26(t)
fluence of growth factors and a sequence of cellular IGF-II 1 79
events, which results in the regulation of the satellite 1 54
cell population (Table 3, Fig. 3; Refs. 73, 168). Many of TGF-␤ 1 79
the studies that have examined the effect of growth 1 1 2 152
factors on satellite cell biology have utilized satellite 2 2 3
cell cultures. These studies have defined the effect of 1 13
2 1 208
growth factors alone or in combination and have pro-
vided valuable insight into the regulation of the satel- Macrophages 1 1 152
1 121
lite cell. Admittedly, in vitro studies are limited due to NE 13
the lack of permissive and repressive factors that are 1 1 86(t)
present in vivo and may influence cellular activity. Crushed muscle/
Currently, most satellite cell cultures are derived from platelet- 1 2 79
neonatal skeletal muscle due to the abundance of sat- derived
ellite cells in these tissues compared with older ani- extract 1 1 2 13
mals (⬎30% in young animals vs. ⬃5% in older ani- LIF 1 7
1 NE 152
mals; Ref. 143). The population and age of the satellite
IL-6 1 7
cell is an important consideration in cell culture prep-
arations as the response of aged, quiescent satellite PDGFAA/AB NE NE 152
NE 54
cells to growth factor stimulation differs compared
PDGFBB 1 1 152
with young, proliferating satellite cells (182). This sec- NE 13
tion will provide a brief introduction of growth factors
EGF NE 13
that are important in the regulation of satellite cell 1* *54
proliferation, differentiation, and motility (for review,
see Table 3). A number of factors affect satellite cell proliferation, differentia-
tion, and chemotaxis. All studies were performed using cell culture
Insulin-like growth factors. Skeletal muscle secretes techniques except those denoted with a (t), which were performed
insulin-like growth factors I and II (IGF-I and IGF-II), using skeletal muscle tissue. NE, no effect. FBF, HGF, IGF, TGF,
which are known to be important in the regulation of PDGF, and EGF, fibroblast, hepatocyte, insulin-like, transforming,
insulin metabolism (3, 109, 186). In addition, these platelet-derived, and endothelial growth factor, respectively. LIF,
growth factors are important in the regulation of skel- leukemia-inhibitory factor. * Stimulation of satellite cell prolifera-
tion in the presence of serum but no effect in serum-free medium. 1
etal muscle regeneration. IGF-I and IGF-II increase and 2, Increase or decrease in effect, respectively.
satellite cell proliferation and differentiation in vitro
(Table 3). The importance of these growth factors was
demonstrated with the intramuscular administration proliferation (25, 32, 170). IGF-I-stimulated satellite
of IGF-I into older, injured animals. In this study, cell differentiation appears to be mediated through the
IGF-I administration (using an osmotic minipump) re- PI-3K pathway (32). Additional studies, utilizing ge-
sulted in enhanced satellite cell proliferation and in- netic mouse models (i.e., transgenic overexpression or
creased muscle mass (26). Moreover, skeletal muscle knockout models), may further define the regulation
overload or eccentric exercise results in elevated IGF-I and signaling pathways of the IGFs and satellite cell
levels, increased DNA content (suggesting an increase biology (8, 25, 132).
in satellite cell proliferation), and a compensatory hy- Hepatocyte growth factor. Hepatocyte growth factor
pertrophy of skeletal muscle (1, 202). (HGF) is a multifunctional cytokine initially described
IGF-I appears to utilize multiple signaling pathways as a mitogen in mature hepatocytes (122). Recently,
in the regulation of the satellite cell pool. The cal- HGF and its receptor c-Met have been localized to
cineurin/NFAT, mitogen-activated protein (MAP) ki- satellite cells and adjacent myofibers but are absent in
nase, and phosphatidylinositol-3-OH kinase (PI-3K) the adjacent fibroblasts. In addition, HGF expression is
pathways have all been implicated in satellite cell proportional to the degree of muscle injury (33, 174,

INVITED REVIEW 541
Fig. 3. Factors modulate satellite cell activity.

Growth factors and hormones are released from
a number of tissues and modulate satellite cell
activity (chemotaxis, proliferation, and differen-
tiation). These factors utilize signaling path-
ways in the regulation of the satellite cell. LIF,
leukemia inhibitory factor; IL-6, interleukin-6.
EGF, FGF, HGF, IGF, PDGF, and TGF, endo-
thelial-derived, fibroblast, hepatocyte, insulin-
like, platelet-derived, and transforming growth
factors, respectively.
182). Multiple roles for HGF have been proposed for injury. In contrast, Fiore et al. (57) pursued a similar
the regulation of the satellite cell, including a role as a targeting strategy to mutate the FGF-6 locus and ob-
potent chemotactic factor, an activator of the satellite served an absence of defects in response to either a
cell, and an inhibitor of myoblast differentiation (Table crush injury or chemically induced injury (notexin).
3). HGF is capable of activating and selectively promot- Consequently, the functional role(s) of FGF-6 during
ing satellite cell proliferation (4). Furthermore, HGF muscle regeneration remains unclear. Nevertheless,
administration attenuates satellite cell differentiation these studies underscore the ability of redundant fam-
through the transcriptional inhibition of the myogenic ily members to compensate for one another and result
regulatory factors (i.e., MyoD and myogenin) (62). in preserved function under pathological conditions
Fibroblast growth factors. Fibroblast growth factor (i.e., mouse knockout models).
(FGF) has nine different isoforms (FGF-1 to FGF-9). The release of FGF-2 from the damaged myofibers,
Although many of the FGF isoforms are broadly ex- like HGF, is proportional to the degree of injury (29).
pressed, FGF-6 is restricted to skeletal muscle (59). FGF levels are coordinated with FGF receptor expres-
Sheehan and Allen (173) investigated in detail the role sion. When receptor expression is increased, satellite
of the FGF family on satellite cell proliferation in cells propagated in culture demonstrate an increased
culture. In these studies, it was demonstrated that proliferation and decreased differentiation (160). Con-
FGF-1, -2, -4, -6, and -9 stimulated cellular prolifera- versely, when receptor expression is diminished, pro-
tion, whereas FGF-5, -7, and -8 had no mitogenic ac- liferation is decreased and there is a concomitant in-
tivity. The investigators further observed that addition crease in satellite cell differentiation. Interestingly,
of HGF to either FGF-2, -4, -6, or -9 resulted in a during the period of satellite cell activation and prolif-
synergistic increase in satellite cell proliferation. In eration (0–48 h after injury), FGF receptor (FGF-R1)
addition to an increase in satellite cell proliferation, mRNA is increased fivefold, and this increase is further
the FGF family has also been observed to attenuate enhanced in the presence of HGF (173).
satellite cell differentiation to myofibers (30, 91, 173, The signaling pathway(s) that transduces the FGF
178). signal has recently been investigated with the use of
Floss et al. (59) reported that mice deficient for both transgenic techniques and pharmacological inhib-
FGF-6 (i.e., knockout mice at the FGF-6 locus) have itors (92). These studies revealed that the MAP kinase
impaired satellite cell proliferation and a subsequent pathway is important in transducing the FGF-induced
defect in muscle regeneration in response to a crush increase in satellite cell proliferation; however, the

542 INVITED REVIEW
MAP kinase signaling pathway did not mediate the dosages did not appreciably affect muscle regeneration
FGF-mediated repression of satellite cell differentia- (125). Future studies that combine cell culture meth-
tion. odologies and overexpression or loss of function models
Transforming growth factors. Transforming growth using molecular technologies will be helpful in the
factor-␤ (TGF-␤) is the prototypical family member of definition of the role of growth factors in satellite cell
cytokines that includes bone morphogenic protein and biology.
growth-differentiation factors. The TGF-␤ family of
cytokines transduces their signal through the SMAD FUNCTIONAL RESPONSES OF SATELLITE CELLS
family of proteins (see Ref. 196 for review). Generally, TO PHYSIOLOGICAL STIMULI
the TGF-␤ family members function to inhibit muscle
proliferation and differentiation (3, 70, 97, 99, 208) by Hypertrophic stimuli. Load-induced hypertrophy
silencing the transcriptional activation of the MyoD (chronic stretch, agonist ablation, tenotomy) and resis-
family members (115). This inhibition of differentia- tance training are physiological challenges that pro-
tion by TGF-␤, like FGF, persists even in nonmuscle mote a hypertrophic response in both human and ani-
cell lines engineered to ectopically express members of mal models (154–156, 197). Hypertrophic growth of
the MyoD family (97, 115, 184). The combination of skeletal muscle is stimulated by short bursts of muscle
IGF-I or FGF with TGF-␤ was unable to alter the activity against high resistance. Resistance training
TGF-␤-induced attenuation of satellite cell differentia- induces muscle hypertrophy through a process of sat-
tion; however, TGF-␤ action had little effect on IGF-I- ellite cell activation, proliferation, chemotaxis, and fu-
or FGF-mediated increases in proliferation (70). Dur- sion to existing myofibers to contribute to muscle
ing muscle regeneration, TGF-␤ receptor levels (TGF-␤ growth (Fig. 4; Ref. 167). The migratory capacity (che-
RII) and TGF ligand are reciprocally expressed, result- motaxis) of satellite cells is dependent on the integrity
ing in the initial promotion of cellular proliferation of the basal lamina. After the rupture or interruption
followed by enhanced muscle differentiation (159). of the basal lamina in response to myotrauma, satellite
Interleukin-6 cytokines. Leukemia inhibitory factor cells may migrate to adjacent myofibers utilizing tissue
(LIF) and interleukin-6 (IL-6) are members of the IL-6 bridges (164, 191). In response to limited myotrauma,
family of cytokines produced by many different cells, where no rupture of the basal lamina occurs, satellite
including myoblasts and macrophages. These cyto- cells migrate from the proximal intact portion of the
kines share a common receptor component, and their myofiber, under the basal lamina, to the site of injury
actions are mediated through the same signaling path- to participate in the repair process (165, 167).
ways (81, 144). Skeletal muscle regeneration after in- Exercise-induced myotrauma initiates an immune
jury in LIF mutant mice is attenuated, whereas exog- response, resulting in the influx of macrophages into
enous administration of LIF increased the regenerative the damaged region. After the acute insult, macro-
process and produced enlarged myofibers (101). The per-
phage infiltration peaks within 48 h (186). Initially, the
missive effect of LIF was associated only with the muscle
role of these blood-borne macrophages was believed to
lineage and had no effect on nonmuscle cells in skeletal
be limited to phagocytosis and the digestion of myone-
muscle (101). IL-6 promotes the degradation of necrotic
crotic fibers. However, additional roles for macro-
tissue, synchronizes the cell cycle of satellite cells, and
phages during the early stages of muscle repair are
induces apoptosis of macrophages following muscle in-
jury (22). Unlike LIF, however, IL-6 expression in injured emerging. Macrophages are essential in the orchestra-
muscle does not increase satellite cell proliferation (96). tion of the repair process as they secrete a collection of
Collectively, this family of growth factors appears to play cytokine factors that regulate the satellite cell pool
an integral role in skeletal muscle regeneration. (133). Importantly, in the absence of a macrophage
Many other factors may be involved in the regulation response, muscle regeneration is absent; in the pres-
of the satellite cell in adult skeletal muscle. Nitric ence of an enhanced macrophage response, there is an
oxide, platelet-derived growth factor, endothelial-de- increase in satellite cell proliferation and differentia-
rived growth factor, and testosterone have been shown tion (110).
to mediate satellite cell activity (6, 93, 133). Obviously, In response to resistance training, myotrauma re-
the regulation of satellite cells is orchestrated by nu- sults in the release of growth factors that will, in part,
merous factors in a temporal and concentration-depen- regulate the satellite cell population during regenera-
dent fashion during regeneration. tion (Fig. 3 and Table 3). For example, IGF-I is upregu-
Few animal studies have examined the effect of lated in response to hypertrophic signals in skeletal
growth factors in vivo. Chakravarthy et al. (26) ob- muscle and promotes proliferation and fusion of the
served that local IGF-I administration to atrophied satellite cell pool (1, 26, 186). As outlined in the previ-
muscle increased satellite cell proliferation and muscle ous section, additional growth factors and/or cytokines
mass within 2 wk. Unlike the observations with IGF-I, including LIF and members of the TGF-␤ family may
the intramuscular injection of HGF, at specified inter- play a role in the signaling or commissioning of the
vals following skeletal muscle injury, increased satel- satellite cells to participate in the hypertrophic remod-
lite cell proliferation and either had no effect or im- eling response. Although a number of questions remain
paired the rate of regeneration (124). Similarly, regarding the role of the satellite cell in muscle remod-
administration of FGF at timed intervals and selected eling, the primary physiological consequence of the

INVITED REVIEW 543
Fig. 4. Satellite cell response to myotrauma.

*Skeletal muscle trauma or injury may be minor
(e.g., resistance training) or may be more exten-
sive (e.g., toxin injection, Duchenne muscular
dystrophy). In response to an injury, satellite
cells become activated and proliferate. Some of
the satellite cells will reestablish a quiescent
satellite cell pool through a process of self-re-
newal. Satellite cells will migrate to the damaged
region and, depending on the severity of the
injury, fuse to the existing myofiber or align and
fuse to produce a new myofiber. In the regener-
ated myofiber, the newly fused satellite cell nu-
clei will initially be centralized but will later
migrate to assume a more peripheral location.
hypertrophic response is to produce a muscle with a dition, there are an increased number of satellite cells
greater capacity for peak force generation. associated with the neuromuscular junction (199). It is
Atrophic stimuli. Atrophy of skeletal muscle results conceivable that neurotrophic factors are important in
in a reduction in myonuclei number and can be induced satellite cell homeostasis. A number of laboratories
by numerous factors including denervation, hindlimb have reported that the percentage of satellite cells
suspension, and malnutrition (73). Atrophy and re- increase (from 3 to 9%) during the initial period follow-
modeling that result from muscle disuse can be pro- ing denervation (118, 187). However, a prolonged pe-
duced in laboratory rodents physiologically by tail/ riod of denervation results in a significant decrease in
hindlimb suspension or immobilization of specific the percentage of satellite cells (3 to 1% following an
muscle groups in plaster casts or pathologically 18-mo period of denervation). Viguie et al. (187) hy-
through denervation. The response of the satellite cells pothesize that the progressive decline in the satellite
appears to be pleiotropic and dependent on the atro- cell pool may be the result of satellite cell apoptosis.
phic stimulus. Alternatively, denervation may result in a lack of neu-
In adolescent rats, hindlimb suspension results in an rotrophic input (including growth factors) that nega-
irreversible remodeling process, including decreased tively impacts satellite cell function and content.
satellite cell content and an impaired proliferative ca- Long-term denervation has considerable clinical im-
pacity within 3 days of unloading in both the oxidative plications. Denervation for periods of 6–18 mo results
slow-twitch soleus and the fast-twitch extensor digito- in the inability of skeletal muscle to reestablish a
rum longus (EDL) muscles (44, 129). Thus the atrophic preinjury functional capacity even if neuronal sprout-
stimulus in the adolescent animal may irreversibly ing and regeneration occurs (180). The mechanisms for
alter the developmental program for myofibers to ac- this phenomenon are unclear, but considerable data
crue nuclei even with the resumption of weight bear- support the conclusion that the intact neuromuscular
ing. A similar reduction in the satellite cell population junction and the denervation model mediate positive
was observed in adult rat hindlimbs using an immobi- and repressive influences, respectively, on the satellite
lization model as an alternative atrophic stimulus cell pool (187).
(188). In contrast to adolescent animals, remobilization Aging. Recent advances have allowed biologists to
of the hindlimb was accompanied by increased myofi- interrogate the proliferative history of a cellular popu-
ber regeneration, supporting the hypothesis that, fol- lation. With each cell replication, there is ⬃100 bp lost
lowing completion of the developmental program, adult from the ends of eukaryotic chromosomes (47, 48, 151,
satellite cells are capable of activation and prolifera- 172). The ends of the chromosomes contain TTAGGG
tion to repopulate atrophied muscle (129, 188). repeats termed telomeres. The length of these telo-
Unlike the other forms of atrophy, denervation is a meres reflects the number of replications of a particu-
pathological rather than physiological stimulus. De- lar cell and its proliferative capacity. Using this tech-
nervation produces a form of disuse atrophy that in- nology, investigators now have the ability to analyze
cludes myofiber degeneration and is accompanied by the proliferative history and future capacity of the
distinctive changes in the myonuclei and quiescent satellite cell, providing valuable insight into the effects
satellite cells (102, 111, 153). In the unperturbed con- of aging and disease in this cell population.

544 INVITED REVIEW
As age progresses, there is an impairment of skeletal This question is applicable to the young population as
muscle regeneration following injury (see Ref. 72 for well. If satellite cells have a limited proliferative ca-
review). A decrease in satellite cell number and/or pacity (⬃60 doublings), does a lifetime of intense exer-
proliferative capacity has been used to explain this cise have a negative influence on their ability to regen-
phenomena. Support for this hypothesis is observed in erate skeletal muscle as aging progresses?
rodent models, as increasing age is associated with a
decrease in satellite cell number and a reduced prolif- FUNCTIONAL RESPONSES TO DISEASE STATES
erative capacity (52, 66, 166). In contrast to the rodent
Most myopathies have a molecular mutation that
model, a decrease in human satellite cell population
affects the structural or cytoskeletal proteins in skele-
and proliferative ability is observed only during the
tal muscle. Duchenne muscular dystrophy (DMD) is
childhood years. For example, neonatal (5-day-old) and
the most common and the most devastating of the
infant (5-mo-old) satellite cells are capable of ⬃60 and
muscular dystrophies (20, 55, 76, 82, 127). Disease
45 replications, respectively, whereas 9-yr-old and
progression and death are ultimately due to a failure of
ⱖ60-yr-old humans are both capable of 20–30 replica-
the myogenic satellite cells to maintain muscle regen-
tions (151). However, as aging progresses, satellite
eration (36, 80). DMD is a recessive X-linked disease
cells (ⱖ60-yr-old skeletal muscle) fuse to form thinner,
that results in a null mutation at the dystrophin locus
more fragile myotubes (151). Thus, despite a normal
(20, 82, 127). The absence of this cytoskeletal protein
ability to proliferate, the satellite cells of older humans
renders the muscle fiber extremely fragile. In response
have a reduced capacity to repopulate the myofiber
to mechanical stress associated with repeated contrac-
population.
tion, there is widespread degeneration. The satellite
The impaired regenerative response that is observed
cells respond to the injury by repopulating the injured
with aging in humans thus appears to be much more
skeletal muscle with defective myofibers lacking dys-
complex than satellite cell senescence alone. Results
trophin. This process results in continuous degenera-
from cross-transplantation experiments suggest that
tion-regeneration cycles and ultimately exhausts the
the host environment is a critical factor in the ability of
satellite cell pool (36, 80).
older skeletal muscle to regenerate (23, 24). Cross
Clinical symptoms are apparent by 4–5 yr of age in
transplantation of EDL muscles between 4-mo-old and
boys with DMD (10, 20, 127). DMD patients (4–5 yr of
24-mo-old rats demonstrated that mature skeletal
age) have been shown to undergo more skeletal muscle
muscle was as capable as young skeletal muscle in
regeneration than that measured in a total of six nor-
recovering from transplant and from toxin-induced in-
mal patients over 60 yr of age (46). These results were
jury. However, young (4-mo-old) nerve-muscle au-
confirmed by Renault et al. (151), who demonstrated
tografts functioned significantly better than old (24-
that the proliferative life span of satellite cells derived
mo-old) nerve-muscle autografts, as determined by the
from a 9-yr-old DMD patient was approximately one-
measurement of mass and maximum isometric force,
third of an age-matched control. Proliferative fatigue
suggesting that the ability for neuronal regeneration
or senescence of the satellite cell population and the
may be a critical factor in activating the satellite cell
milieu of the DMD skeletal muscle may collectively
response and, ultimately, regenerating the damaged
impair the proliferative or regenerative capacity of this
muscle (23, 24).
cell population. In the DMD patient, increased levels of
Other factors within the host environment affect the
IGF binding proteins (IGFBP) are released by fibro-
efficiency of skeletal muscle regeneration as aging
blasts. The elevated IGFBP sequesters IGF-I, limiting
progresses. A thickening of the basal lamina (176),
its bioavailability for satellite cells and ultimately re-
increased fibrosis within skeletal muscle (114), and
sulting in increased skeletal muscle fibrosis (120). The
reduced capillary density (31) may also contribute to
evidence to date demonstrates the tremendous strain
impaired regeneration. Inflammatory factors (macro-
and ultimate failure of the satellite cell population to
phages and associated cytokines) are essential for the
adequately compensate for the persistent degenera-
normal satellite cell response to injury. Aging nega-
tion-regeneration process that is occurring in the DMD
tively impacts the immune response, resulting in a
skeletal muscle.
decrease of the inflammatory factors and macrophages
(43). In association with an impaired immune re- GENETIC MOUSE MODELS OF MYOPATHY
sponse, there are reduced serum levels of growth fac-
tors including IGF-I in aged rats and humans (150, A number of gene knockout mouse models and ex-
183). After multiple cycles of atrophy, there is no res- perimental methods are available for studies of muscle
toration of muscle mass or satellite cell proliferation in regeneration and satellite cell biology. Although the
aged rats even after 9 wk of recovery. However, local mdx mouse, which lacks dystrophin, has provided im-
IGF-I administration to the atrophied muscle resulted portant insights into the pathophysiology of DMD, the
in significant increases in mass and satellite cell pro- myopathy in these animals does not represent the
liferation within 2 wk (26). myopathic process of DMD in humans (75). The mdx
An unresolved question with regard to satellite cells mice have a normal life span, a temporally restricted
and the aging process is whether repeated exhaustive myofiber degeneration, and adapt to muscle degenera-
and/or resistance training exercise programs have a tion with an expansion of the satellite cell pool and
negative impact on the long-term satellite cell content? muscle hypertrophy, thereby avoiding the compro-

INVITED REVIEW 545
mised muscle function that afflicts humans who lack to study satellite cell biology. Perhaps the most exten-
dystrophin (51, 69, 116, 179). In addition to the spon- sive and reproducible muscle injury is the delivery of
taneous dystrophin mutation in the mdx mouse, myo- cardiotoxin (purified from the venom of the Naja ni-
pathic mouse models include genetically engineered gricollis snake) into the hindlimb skeletal muscle of the
mouse strains with knockouts of utrophin (49, 69), mouse (53, 63, 134). The intramuscular injection of 100
MyoD (119), or MNF (63) crossed into the mdx back- ␮l of 10 ␮M cardiotoxin into the gastrocnemius muscle
ground. Each of these double mutant mouse models results in 80–90% muscle degeneration (Fig. 5). After
exhibit features that more closely resemble DMD in cardiotoxin-induced injury, satellite cells become acti-
humans, including a severe myopathy, an impaired vated within 6 h of injury (Garry, unpublished obser-
regenerative capacity, and a decreased life span. vations). In response to locally released growth factors
from injured myotubes and macrophages, the satellite
MUSCLE REGENERATION MODELS
cells proliferate extensively within 2–3 days of injury
An alternative strategy that has been successfully (63, 64). Approximately 5 days after injury, the satel-
used for the study of satellite cell activation, prolifer- lite cells withdraw from the cell cycle and either self-
ation, regeneration, and self-renewal is to experimen- renew or form differentiated myotubes that contain a
tally produce a controlled skeletal muscle injury. Strat- central nucleus (63, 64). With the use of this cardio-
egies including crush (101), freeze (40), or chemically toxin-induced injury protocol, the architecture of the
induced injury (42, 63) have all been successfully used injured muscle is largely restored within 10 days after
Fig. 5. Skeletal muscle response to tox-

in-induced injury. A: transverse section
of the adult gastrocnemius muscle
stained with hematoxylin and eosin at
defined intervals following cardiotoxin-
induced injury. After cardiotoxin deliv-
ery, there is evidence of extensive myo-
necrosis and edema of the myofibers
(12 h; denoted by a). A hypercellular
response (proliferating satellite cells
and inflammatory cells) is observed
within 2 days of injury. Muscle regen-
eration is evident within 5 days of in-
jury. At this time, newly regenerated
myofibers are evident as small, baso-
philic, central-nucleated myofibers (de-
noted by b). The architecture of the
muscle is largely restored within ⬃10
days following injury. The newly regen-
erated myofiber displays numerous
centrally aligned nuclei, demonstrat-
ing the fusion of many satellite cells to
form a single myofiber (hyperplasia) as
denoted by the myofiber designated c.
B: schematic diagram emphasizing the
temporal pattern of satellite cell prolif-
eration and muscle differentiation fol-
lowing a chemically induced injury of
adult mouse skeletal muscle. Bar ⫽
100 ␮m.

546 INVITED REVIEW
injury (Fig. 5). The complete profile of intrinsic and can be purified based on the exclusion of Hoechst dye
extrinsic cues that regulate the satellite cell population and can adopt alternative fates. Further studies are
during muscle regeneration remains unclear. There- necessary to determine whether the SP cells are satel-
fore, the use of reproducible experimental injuries such lite cell progenitors, a subpopulation of the satellite
as cardiotoxin-induced injury will be important to eval- cells, or an independent progenitor cell population that
uate and define the regulation of the satellite cell are resident in skeletal muscle.
population in molecular and physiological myopathic Alternative sources of proliferating myoblasts have
models. Additional myonecrotic agents such as notexin recently been described. Odelberg et al. (136) recently
have been used with similar success (107), resulting in reported that terminally differentiated myotubes are
a well-characterized regenerative response in skeletal capable of dedifferentiation to form myoblasts when
muscle. exposed to the homeobox-containing transcriptional re-
pressor, msx1. Furthermore, in response to appropri-
SATELLITE CELLS AS MUSCLE PRECURSOR CELLS OR ate cues (i.e., conditioned media), these dedifferenti-
STEM CELLS ated myoblasts have the capacity to adopt alternative
phenotypes. Collectively, these studies are challenging
Myogenic satellite cells have a tremendous prolifer-
the established developmental paradigms regarding
ative capacity and are capable of self-renewal. These
satellite cell biology and the plasticity or the potential
tissue-specific progenitor cells or satellite cells are im-
of the terminally differentiated myotube for dediffer-
portant in the maintenance and regeneration of skele-
entiation. Further studies are necessary to define the
tal muscle. Progenitor cells that are resident in other
molecular regulation of this dedifferentiation process
adult tissues have stem cell characteristics, as they are
but clearly have applications for the treatment of my-
capable of self-renewal and multilineage differentia-
opathies including DMD.
tion along a specified molecular pathway (61, 194, 195).
For example, Clarke et al. (28) revealed that neural FUTURE PROSPECTS
stem cells isolated from the adult mouse brain had a
very broad developmental capacity and could contrib- Since the initial description of the satellite cell ap-
ute to virtually all tissues when delivered into the proximately 40 years ago, a number of anatomic and
developing embryo. These results suggest that adult physiological studies have established the importance
stem cells or progenitor cells are capable of dedetermi- of this cellular pool in the growth, remodeling, and
nation and/or transdifferentiation to adopt alternative regeneration of adult skeletal muscle. The profile of
lineages in a permissive environment. Unlike the neu- gene expression that regulates the cell cycle progres-
ral stem cell population, the potential of the satellite sion of the satellite cell from a quiescent to an activated
cell pool in adult skeletal muscle remains incompletely and proliferating state remains ill-defined. Despite its
defined. Further definition of the gene expression pro- complexity, future challenges for this field will include
file of the satellite cell population and an enhanced the definition of the development, maintenance, self-
understanding of the molecular events responsible for renewal, and potentiality of the satellite cell popula-
satellite cell development, activation, proliferation, tion. These challenges will require an integration of
and self-renewal will define the stem cell characteris- each of the biological disciplines, including the use of
tics of the satellite cell. increasingly powerful molecular biological tools.
The authors recognize the research efforts of those included and
SIDE POPULATION CELLS
those omitted (due only to space considerations) who have contrib-
uted to this field of study. Special thanks to Drs. M. I. Lindinger, P.
Recent studies have identified a population of pluri- Mammen, and R. S. Williams for critical review of this manuscript.
potent stem cells from adult skeletal muscle termed The authors’ work is supported by grants from the Muscular
side population (SP) cells. Skeletal muscle- and bone Dystrophy Association, March of Dimes, Doris Duke Charitable
marrow-derived SP cells are isolated using a DNA- Foundation, Texas Advanced Research (Technology) Program, and
binding dye (Hoechst 33342) and dual-wavelength flow the Donald W. Reynolds Foundation.
cytometric analysis (67, 68, 77). This method, which REFERENCES
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HAWKE and GARRY 2001 - Myogenic Satellite Cells Physiology To Molecular Biology

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J Appl Physiol

91: 534–551, 2001.

THOMAS J. HAWKE1 AND DANIEL J. GARRY1,2

Hawke, Thomas J., and Daniel J. Garry. Myogenic satellite cells:

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Fig. 1. Derivation of muscle precursor

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Fig. 2. Satellite cells occupy a sublami-

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Table 2. Satellite cell content in skeletal muscle

Rat TA 7–9 wk 4 161

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Fig. 3. Factors modulate satellite cell activity.

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Fig. 4. Satellite cell response to myotrauma.

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Fig. 5. Skeletal muscle response to tox-

J Appl Physiol • VOL 91 • AUGUST 2001 • www.jap.org

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J Appl Physiol • VOL 91 • AUGUST 2001 • www.jap.org

Downloaded from www.physiology.org/journal/jappl (189.120.075.241) on July 11, 2019.

J Appl Physiol • VOL 91 • AUGUST 2001 • www.jap.org

Downloaded from www.physiology.org/journal/jappl (189.120.075.241) on July 11, 2019.

J Appl Physiol • VOL 91 • AUGUST 2001 • www.jap.org

Downloaded from www.physiology.org/journal/jappl (189.120.075.241) on July 11, 2019.

J Appl Physiol • VOL 91 • AUGUST 2001 • www.jap.org

Downloaded from www.physiology.org/journal/jappl (189.120.075.241) on July 11, 2019.

J Appl Physiol • VOL 91 • AUGUST 2001 • www.jap.org

Downloaded from www.physiology.org/journal/jappl (189.120.075.241) on July 11, 2019.

J Appl Physiol • VOL 91 • AUGUST 2001 • www.jap.org

Downloaded from www.physiology.org/journal/jappl (189.120.075.241) on July 11, 2019.

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