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Skeletal muscle development in normal and double-muscled cattle.

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THE ANATOMICAL RECORD PART A 281A:1363–1371 (2004)
Skeletal Muscle Development in
Normal and Double-Muscled Cattle
Growth Physiology, Animal Genomics, AgResearch, Hamilton, New Zealand
This study examined the effect of genotype on prenatal muscle development in both normal-muscled (NM) animals and in double-muscled (DM)
animals harboring a mutation in the gene for myostatin that results in the
production of a functionally inactive protein. The following muscle development parameters were analyzed at four gestational ages: muscle weight,
fiber type, by both enzyme histochemistry and myosin heavy-chain (MHC)
immunocytochemistry, and average fiber area. The weights of both M.
vastus lateralis and M. vastus medialis were greater throughout prenatal
development in the DM animals compared to NM. The percentage of type 1
muscle fibers initially declined with gestational age and subsequently increased in both NM and DM. The percentage of type 1 fibers was consistently lower in DM than in NM. A pattern of MHC isoform localization was
shown in DM muscle that is indicative of a delay in muscle development
relative to NM. Muscle fiber size was differentially regulated in NM and
DM, depending on fiber type. Type 1 fibers were smaller in DM than NM in
late gestation, while type 2 fibers were smaller throughout gestation. This
study suggests that the inactivating myostatin mutation in DM animals
may be associated with changes in both skeletal muscle fiber type and fiber
size during bovine muscle development. © 2004 Wiley-Liss, Inc.
Key words: bovine; muscle; development; fiber type; fiber size;
myosin heavy chain; myostatin
The major determinants of skeletal muscle mass are
muscle fiber number and muscle fiber size. During development, these factors are controlled by a series of events,
including myoblast proliferation, myotube formation, and
myofiber maturation. A number of regulatory factors can
influence each of these stages of muscle development,
including the genetic background and breed of an animal.
Within double-muscled (DM) cattle breeds, there is an
overall increase in muscle mass (Boccard, 1981). The genetic basis of the DM condition in Belgian Blue animals
arises from an 11 bp deletion mutation in the gene for
myostatin in these animals, resulting in a severely truncated myostatin protein (Grobet et al., 1997; Kambadur et
al., 1997; McPherron and Lee, 1997). Myostatin is a negative regulator of muscle mass (McPherron et al., 1997),
which has been shown to inhibit both myoblast proliferation (Thomas et al., 2000; Joulia et al., 2003) and differentiation (Langley et al., 2002; Rios et al., 2003). Each of
these effects is mediated through differential regulation of
a key component of cell cycle progression, the cyclin-dependent kinase inhibitor, p21. In addition to regulation of
cell cycle progression, myostatin also has a direct effect on
myogenesis through its action in regulating levels of the
myogenic regulatory factors (Langley et al., 2002; Joulia et
al., 2003). This dysregulation of myogenic proliferation
and differentiation leads to muscle hyperplasia and hypertrophy as seen in myostatin-null animals (Langley et
al., 2002).
The extent of the muscular hypertrophy exhibited by
DM animals has been reported to vary among different
muscles in a number of DM breeds (Butterfield, 1966;
Rollins et al., 1969; Boccard, 1981). Muscles with a large
surface area tend to be the most enlarged, while deeper
muscles tend to be reduced in size relative to NM. As all of
Grant sponsor: the New Zealand Foundation for Research,
Science and Technology.
*Correspondence to: Jenny M. Oldham, Animal Genomics,
AgResearch, PB3123, Hamilton, New Zealand, Fax: 64-7-8385536. E-mail:
Received 18 September 2003; Accepted 22 March 2004
DOI 10.1002/ar.a.20140
Published online 5 November 2004 in Wiley InterScience
these muscles have increased muscle fiber numbers, it
follows that the reduced muscles must have a smaller fiber
size (Ouhayon and Beaumont, 1968). No studies have
been carried out to determine if these differences in muscle mass and fiber size are present in prenatal animals, so
we examined the development of the M. vastus lateralis,
which is 15% heavier in adult DM than NM, and M. vastus
medialis, which is 38% lighter in mature animals (Boccard, 1981).
Double-muscled cattle have a different composition of
histochemical fiber types compared with NM, both during
prenatal development (Ashmore et al., 1974) and in the
postnatal animal (Holmes and Ashmore, 1972), where
there are increased proportions of type 2 muscle fibers and
fewer type 1 fibers. In addition to histochemical staining,
myosin heavy-chain (MHC) immunohistochemistry has
been widely used in the investigation of muscle development in DM animals. The sequence of MHC isoform transitions which myotubes undergo as they mature is an
important determinant of skeletal muscle fiber type. The
relationship between the patterns of MHC isoforms expressed by primary myotubes and the fiber type composition of mature muscles is not yet fully understood (Whalen
et al., 1984; Dhoot, 1986; Zhang and McLennan, 1998).
Immunohistochemistry using antibodies against developmental MHC isoforms has enabled changes in MHC isoform expression to be examined during normal bovine
development (Robelin et al., 1993; Picard et al., 1994,
1995b) and in DM animals (Picard et al., 1995a). This
latter study reported developmental differences in MHC
expression between NM and DM, with DM tending to
express more immature isoforms at the same gestational
age during the first two-thirds of fetal life (Picard et al.,
In normal bovine muscle, fiber size varies according to
fiber type. Type 2B fibers have the largest cross-sectional
area, type 2A fibers are intermediate, and type 1 fibers are
the smallest. In DM cattle, muscle fiber size is altered
relative to NM, with both increases and decreases in fiber
size being reported. These variations in fiber size are
related to differences in fiber type composition and animal
age (Holmes and Ashmore, 1972; Ashmore, 1974). In postnatal animals, there is an increase in the size and frequency of type 2B fibers in DM animals (Holmes and
Ashmore, 1972) and this contributes to the overall increase in the whiteness of meat from these animals. In
muscles from adult DM animals that are decreased in size
relative to normal animals, average muscle fiber size is
smaller (Ouhayon and Beaumont, 1968).
The aims of this study were to test the hypothesis that
the relative difference in size between M. vastus lateralis
and M. vastus medialis that occurs in adult NM and DM
animals was present during prenatal development, and
that differences in fiber type composition and fiber size
during prenatal development contribute to overall differences in skeletal muscle mass between NM and DM fetuses.
of one hind limb from each animal and weighed. A 5 mm
slice was taken through the mid belly of the muscle, at
right angles to the direction of the muscle fibers. These
samples were stored at ⫺80°C for fiber typing and immunohistochemistry. There were five fetuses in each of the
age groups for the normal animals and in the 120- and
160-day groups for the DM and three in the 210- and
260-day groups for the DM. These gestational ages were
selected to cover the late stages of primary myotube formation, which is nearing completion by 120 days (Stickland, 1978; Robelin et al., 1991), a period of active secondary fiber formation at around 160 days (Stickland, 1978)
and a period when all fibers were undergoing hypertrophic
growth (210 –260 days). This study was carried out with
the approval of the Animal Ethics Committee of Ruakura
Research Center.
Animal Data
Statistical analysis of muscle weight, fiber type, and
fiber size was carried out using analysis of variance with
age and breed as the main effects. Data were log-transformed before analysis as required and back-transformed
for presentation of results. Values are presented as
means; errors are pooled or individual standard errors of
the means (SEMs). Covariate analysis was carried out
within groups using sex ratio and body weight and estab-
Normal-muscled (NM) and double-muscled calves were
generated as previously described (Oldham et al., 2001).
Fetuses at 120, 160, 210, and 260 days of gestation were
collected after slaughter of the recipient cows. The M.
vastus lateralis and M. vastus medialis were dissected out
Fiber Typing
Muscle fiber typing was carried out on the M. vastus
lateralis according to a modification of the myosin ATPase
method of Guth and Samaha (1969). After fixation, slides
were incubated in 0.1 M potassium acetate buffer at pH
5.0 for 10 min. The remainder of the procedure was identical to that of Guth and Samaha (1969). This procedure
results in a staining pattern identical to that of fixed
sections preincubated at pH 9.4, with type 1 fibers showing lighter staining and type 2 fibers darker, but with
improved histology.
Immunohistochemistry was carried out on serial cryostat sections of M. vastus lateralis. Slides were fixed in
neutral buffered formaldehyde, blocked in dilute normal
serum, and incubated using primary antibodies specific
for fast MHC (MY32), slow MHC (NOQ.4.D; Sigma, St.
Louis, MO), and embryonic MHC (2B6; gift of Dr. D. A.
chman). Detection of the primary antibody was carried out
using a biotinylated secondary antibody followed by
streptavidin-biotin complex and diaminobenzidine substrate.
Image Analysis
Three sections stained for mATPase activity were analyzed from each group for fiber type proportions and average area for each fiber type. All fibers within each of five
fascicles were analyzed for each animal, giving a total of
200 –300 fibers per muscle. The rationale behind sampling
entire fascicles to enable a more accurate assessment of
fiber type proportions was based on reports suggesting
that the fiber type composition of fascicles recapitulates
that of entire muscles (Maier et al., 1992). Quantitative
image analysis was carried out using the NIH image system for the Macintosh. Digital images were captured using the ScionCorp CMS-700 image analysis system.
Statistical Analysis
TABLE 1. Muscle weights and sex ratio of normal and double muscled fetuses at four gestational ages*
Vastus lateralis
Vastus medialis
wt (g)
wt (g)
wt (g)
Sex ratio
wt (g)
*Values are least-squares means, adjusted within groups for body weight and sex ratio, ⫾ SEM (n ⫽ 3–5 per group). Data are
back-transformed after log transformation for analysis.
P ⱕ 0.001.
P ⱕ 0.01.
P ⱕ 0.05.
Not significant.
lished that these factors did not contribute to the breed
Fetal Data
Both M. vastus lateralis and M. vastus medialis weights
showed a highly significant increase with increasing gestational age (P ⱕ 0.001) and both muscles were significantly larger in the DM animals relative to NM (54% for
VL, 30% for VM; P ⱕ 0.001; Table 1).
Fiber Typing and Morphological Analysis
Muscle fiber type. Qualitative analysis of sections
stained using mATPase histochemistry showed similar
fiber morphology between NM and DM at all gestational
ages. In both breeds, however, there was a noticeable
difference between 120 and 160 days gestation in the
morphology of the presumptive primary myotubes, from
being large and vacuolated to more closely resembling
mature myofibers. The smaller size of the type 1 fibers in
the DM muscles was readily seen at 260-day gestation
(Fig. 1H).
The percentage of type 1 fibers in both DM and NM
showed a biphasic pattern of change throughout development (Fig. 2), with numbers decreasing between 120 and
160 days and then increasing again between 210 and 260
days (P ⱕ 0.001). There were consistently fewer type 1
muscle fibers in DM than in NM (P ⱕ 0.001; Fig. 2).
Immunohistochemistry. This study has shown a
similar pattern of MHC expression in both DM and NM at
120-day gestation, with both presumptive primary and
presumptive secondary fibers staining positively for embryonic MHC (Fig. 3). All primary fibers were also positive
for slow MHC and all secondary fibers were also positive
for fast MHC. At 160-day gestation, the pattern was similar, but there were a number of fibers in NM that were
negative for embryonic MHC (Fig. 3G). At 210 days, a
number of presumptive secondary fibers in the DM were
negative for embryonic MHC and others were positive for
slow MHC (Fig. 4). Some presumptive secondary fibers in
NM and DM were positive for all MHC isoforms (Fig.
4A–F). At 260 days, all fibers were negative for embryonic
MHC in NM (Fig. 4G), while immunostaining remained
quite strong in smaller presumptive secondary fibers in
DM (Fig. 4J).
Muscle fiber size. The average area of type 1 fibers in
both DM and NM decreased from 120 to 160 days of
gestation (Fig. 5a), as their morphology changed from that
of primary myotubes with a central region devoid of myofibrils to more mature muscle fibers surrounded by developing secondary fibers. By 210 days, type 1 fibers of NM
muscles markedly increased in size as they continued to
mature, while DM fibers had only very small increases in
size, failing to regain the size they had previously been at
120 days. By main-effect analysis, type 1 fibers were significantly smaller overall in DM than in NM (P ⱕ 0.001)
due to the reduced size at 210 and 260 days (Fig. 5a). The
average area of type 2 muscle fibers increased with age
(P ⱕ 0.001) and was less in DM than in NM (P ⱕ 0.05).
This effect was consistent across age groups from 160 to
260 days (Fig. 5b).
One of the most sensitive measures of overall fiber type
composition is total % area of a specific fiber type, which is
the product of average fiber area and average numerical
percentage of each fiber type. The total % area of type 1
fibers declined between 120 and 160 days of gestation in
both NM and DM, then remained relatively constant
throughout the remainder of the period studied. The net
effect of the changes in size and proportions of type 1 fibers
in the DM animals was that the muscle overall had a
significantly lower proportion of total area given over to
type 1 fibers at all gestational ages (P ⱕ 0.001; Fig. 6).
This study describes the quantitative and qualitative
analysis of bovine muscle development in normal animals
and in animals harboring a mutation in the gene for
myostatin. Skeletal muscle mass was increased in DM
fetuses relative to NM in both the M. vastus medialis and
the M. vastus lateralis. This contrasts with observations
from postnatal DM animals in which the M. vastus medialis is 38% smaller in size relative to NM animals, while
the M. vastus lateralis is 15% larger (Boccard, 1981). This
suggests that the difference in muscle mass between DM
and NM is not due to a direct effect of the myostatin
mutation on muscle development. The atrophy may occur
as a result of an effect that is not expressed until the
postnatal period, or it may also be a consequence of postnatal environmental effects. In humans, injury to or diseases of the knee joint may be associated with atrophy of
the M. vastus medialis and hypertrophy of the M. vastus
Fig. 1. Myosin ATPase staining in M. vastus lateralis at four gestational ages: 120 days (A and B), 160 days (C and D), 210 days (E and F),
and 260 days (G and H) of gestation. NM in panels on left (A, C, E, and
G); DM in panels on right (B, D, F, and H). A and B stained after
preincubation at pH 4.2; C-G stained after preincubation at pH 5.0
according to modified histochemical staining procedure. Dotted lines
indicate primary myotubes; open arrows indicate type 1 fibers. Scale
bar ⫽ 50 ␮m.
Fig. 2. Average percentages of type 1 muscle fibers in M. vastus
lateralis from NM (filled circle) and DM (open circle) fetuses at four
gestational ages (n ⫽ 3 per group). Values are mean ⫾ pooled SEM.
Triple asterisk, P ⱕ 0.001; asterisk, P ⱕ 0.05.
lateralis (Speakman and Weisberg, 1977). Animals exhibiting extreme muscular hypertrophy have some abnormalities in stance and in the anatomy of the front limbs and
hocks (Kieffer et al., 1972). This postural abnormality may
therefore result in atrophy of the M. vastus medialis in
DM animals during postnatal life.
Quantitative analysis of histochemical fiber type
showed the percentage of type 1 muscle fibers initially
declines with gestational age and then increases again. In
developing human muscle, a proportion of primary myotubes degenerate between 16 and 20 weeks of gestation
(Fidzianska and Goebel, 1991), a time period that coincides with the decrease in the percentage of type 1 fibers
seen in the current study. This would have the net effect of
decreasing the percentage of type 1 fibers, as seen in this
study. An alternative mechanism for the reduction in the
percentage of type 1 fibers may be that a proportion of
fibers underwent transformation from type 1 to type 2
fibers (Whalen et al., 1984). This possibility was not directly tested in this study, as individual fibers could not be
followed throughout gestation.
During late gestation, the percentage of type 1 fibers
increases in both NM and DM. A similar observation to
this has been previously made in developing ovine muscle
(Maier et al., 1992). Maier et al. (1992) suggested that the
majority of the fibers transforming to slow MHC initially
expressed an adult fast MHC isoform. This was not, however, supported by other investigators, who suggested that
in predominantly fast twitch muscles, all the slow fibers
originated from primary generation myotubes (Picard et
al., 1994). Although the current study did not investigate
temporal changes in MHC isoforms in individual fibers,
this remains an area for future investigation in order to
determine whether those fibers that express slow MHC
isoforms in late gestation are indeed the original population of primary myofibers.
The pattern of change in fiber type proportions described in this study was similar in both NM and DM,
although in the DM the percentage of type 1 fibers was
consistently lower than in the NM. This result had been
previously reported both during prenatal development
(Ashmore et al., 1974) and in adult animals (Holmes and
Ashmore, 1972). On that basis, it appears that the initial
decrease in type 1 fibers and the subsequent increase
again are unrelated to the DM condition. The overall fiber
type composition is, however, affected by the mutation.
Previous studies have generally shown a positive association between myostatin expression and fast MHC isoforms. Myostatin mRNA was undetectable in the slow
MHC expressing soleus muscle in mice (Carlson et al.,
1999), and in vitro myostatin was associated with myotubes expressing the MHC type II isoform (Artaza et al.,
2002). In rats, in which muscle atrophy was induced following dexamethazone treatment, myostatin mRNA was
elevated, and there was an increase in type 2 muscle fibers
(Ma et al., 2003). The mechanism through which myostatin mediates effects on MHC expression remains unknown.
In the earliest periods of gestation covered by this study,
differences in MHC isoform expression between NM and
DM were restricted to a population of fibers in NM that
were negative for embryonic MHC at 160 days. As this is
a developmental isoform, expression of which is lost as
fibers mature, this suggests a relatively more advanced
stage of development in the NM at this gestational age.
Ninety and 130 days of gestation have been identified as
the ages during which developmental differences were
most marked between NM and DM (Picard et al., 1995a).
The current study extended the period of gestation a further 50 days beyond that of Picard et al. (1995a) and has
demonstrated that at 260 days of gestation NM no longer
expresses embryonic MHC, although it is still relatively
abundant in DM. These results suggest that later muscle
development in DM fetuses is delayed relative to NM with
respect to the expression of MHC isoforms.
An alternative explanation for the prolonged period of
expression of immature MHC isoforms is that the period
of secondary fiber formation is extended in DM. This is
consistent with the observation of an overall increase in
muscle fiber number in DM animals. An elevation in satellite cell numbers in muscle fibers from mstn⫺/⫺ mice
also suggests that myostatin deficiency may be a mechanism through which muscle fiber number may be increased in DM animals (McCroskery et al., 2003). A number of in vitro studies have identified a role for myostatin
in blocking cell cycle progression and differentiation (Langley et al., 2002; Rios et al., 2003), with inhibition of
myostatin synthesis leading to enhanced cell cycle withdrawal and the stimulation of myoblast differentiation
(Joulia et al., 2003). One proposed mechanism for the
mediation of cell cycle progression may be a heightened
response to MyoD in DM animals (Oldham et al., 2001;
Spiller et al., 2002). A C313Y mutation in the myostatin
gene results in hyperplasia but not hypertrophy in both
cattle (Berry et al., 2002) and mice (Nishi et al., 2002),
suggesting that different dominant negative mutations in
the myostatin gene can have different effects on muscle
fiber number and fiber size.
The average size of primary myotubes initially decreased from 120 to 160 days of gestation as they developed into mature myofibers. A similar result has been
previously reported in bovine muscle (Stickland, 1978).
After the initial decrease in fiber size that occurred in both
breeds, type 1 fibers in muscles from NM fetuses began to
enlarge, but fibers from DM fetuses did not. This result
Fig. 3. Photomicrographs showing MHC immunohistochemistry in M. vastus lateralis at 120 (A–F) and
160 days (G–L) of gestation. NM in rows A–C and G–I, and DM in rows D–F and J–L. Embryonic MHC is
shown in left column, slow MHC in central column, and fast MHC in right column. Dotted lines indicate type
1 fibers. Scale bar ⫽ 50 ␮m.
suggests that during late gestation, some hypertrophic
stimulus induces growth in type 1 fibers of NM only, while
in DM, either this stimulus is not present or the muscle
fibers are unable to respond. The time period during which
a difference develops in the average area of type 1 fibers
between NM and DM is from 160 to 210 days of gestation.
Type 2 fibers grew at a relatively constant rate throughout the time period studied and were consistently smaller
in DM than NM. The smaller fiber size in DM may be
explained by the apparent developmental delay in these
animals with myofiber hypertrophy lagging behind that of
NM, in the same way as expression of more mature MHC
Fig. 4. Photomicrographs showing MHC immunohistochemistry in M. vastus lateralis at 210 (A–F) and
260 days (G–L) of gestation. NM in rows A–C and G–I, and DM in rows D–F and J–L. Embryonic MHC is
shown in left column, slow MHC in central column, and fast MHC in right column. Solid arrows indicate type
1 fibers, open arrows indicate fibers positive for all MHC isoforms. Scale bar ⫽ 50 ␮m.
isoforms was delayed. In postnatal animals, type 2 fibers
have been shown to be larger in myostatin-deficient DM
animals than in NM (Holmes and Ashmore, 1972). This is
consistent with studies in humans, in which chronic disuse atrophy of the vastus muscles, resulting in a reduction
in the area of type 2A and 2B muscle fibers, was associated
with an increase in myostatin expression (Reardon et al.,
2001). It is well established that fiber type composition
between DM and NM changes from prenatal to postnatal
life (Holmes and Ashmore, 1972; Ashmore et al., 1974).
Fiber size differences between DM and NM also appear to
vary with developmental age.
The total area of muscle classified as type 1 or type 2
fibers is a more accurate measure of overall fiber type
Fig. 6. Total percentage of area of type 1 fibers calculated from
average fiber number per fascicle multiplied by average fiber area in M.
vastus lateralis from NM (filled circle) and DM (open circle) fetuses at four
gestational ages (n ⫽ 3 per group). Values are least-squares mean ⫾
SEM. Data was log-transformed for analysis. Triple asterisk, P ⱕ 0.001;
double asterisk, P ⱕ 0.01.
Fig. 5. Average cross-sectional area of (a) type 1 and (b) type 2
muscle fibers in M. vastus lateralis NM (filled circle) and DM (open circle)
fetuses at four gestational ages (n ⫽ 3 per group). Values are mean ⫾
pooled SEM. A t-test was used for the calculation of significant differences within time periods. Triple asterisk, P ⱕ 0.001; asterisk, P ⱕ 0.05.
composition than measurement of either fiber type percentage or average fiber area in isolation (Holmes and
Ashmore, 1972; West, 1974). The total area of type 1
muscle fibers in NM and DM declines between 120 and
160 days, largely because of the remodeling of the vacuolated primary myotubes, then remains essentially level.
The increase in the percentage of type 1 fibers in the DM
at 210 and 260 days of gestation is able to compensate
fully for the smaller average fiber size, with no overall
decrease in the total area occupied by type 1 fibers. Although myosin ATPase activity in developing muscle is
not necessarily a reliable indicator of contraction speed or
metabolic activity (Guth and Samaha, 1972), this decline
may represent a change in the metabolic pathway being
employed by the muscles at this stage of development.
Previous researchers proposed that a transformation toward more glycolytic fiber types in DM animals may reflect an inability of the cardiovascular system to supply
the excess musculature, resulting in a compensatory shift
toward more anaerobic metabolism (Ashmore, 1974).
In summary, in contrast to postnatal animals, the M.
vastus medialis in DM animals is not reduced in mass
relative to NM during prenatal growth. In M. vastus lateralis, type 1 muscle fibers in both NM and DM exhibited a
biphasic change in proportions with gestational age, and
proportions of type 1 fibers were consistently lower in DM,
suggesting that differences in fiber type composition are
associated with the myostatin mutation. There are patterns of MHC isoform localization in DM muscle that are
indicative of a delay in development relative to NM. There
is an increase in the proportion of type 2 muscle fibers that
may contribute to the increase in muscle mass seen in DM
animals during postnatal growth. Finally, type 1 fibers are
smaller in DM than NM in late gestation only and type 2
fibers are smaller throughout gestation. We provide evidence that in this myostatin-deficient model of muscular
hypertrophy, the increase in muscle mass in prenatal
animals is not associated with muscle fiber hypertrophy
and may therefore be largely accounted for by the increase
in muscle fiber number seen in these animals.
The authors thank N. Cox for assistance with statistical
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