Effect of Myostatin Depletion on Weight Gain,
Hyperglycemia, and Hepatic Steatosis during Five
Months of High-Fat Feeding in Mice
Kerri Burgess1, Tianshun Xu2, Roger Brown2, Bajin Han2, Stephen Welle1*
1Endocrinology and Metabolism Division, Department of Medicine, University of Rochester, Rochester, New York, United States of America, 2Muscle Metabolism DPU
and Platform Technology and Science, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, United States of America
The marked hypermuscularity in mice with constitutive myostatin deficiency reduces fat accumulation and hyperglycemia
induced by high-fat feeding, but it is unclear whether the smaller increase in muscle mass caused by postdevelopmental
loss of myostatin activity has beneficial metabolic effects during high-fat feeding. We therefore examined how
postdevelopmental myostatin knockout influenced effects of high-fat feeding. Male mice with ubiquitous expression of
tamoxifen-inducible Cre recombinase were fed tamoxifen for 2 weeks at 4 months of age. This depleted myostatin in mice
with floxed myostatin genes, but not in control mice with normal myostatin genes. Some mice were fed a high-fat diet (60%
of energy) for 22 weeks, starting 2 weeks after cessation of tamoxifen feeding. Myostatin depletion increased skeletal
muscle mass ,30%. Hypermuscular mice had ,50% less weight gain than control mice over the first 8 weeks of high-fat
feeding. During the subsequent 3 months of high-fat feeding, additional weight gain was similar in control and myostatin-
deficient mice. After 5 months of high-fat feeding, the mass of epididymal and retroperitoneal fat pads was similar in control
and myostatin-deficient mice even though myostatin depletion reduced the weight gain attributable to the high-fat diet
(mean weight with high-fat diet minus mean weight with low-fat diet: 19.9 g in control mice, 14.1 g in myostatin-deficient
mice). Myostatin depletion did not alter fasting blood glucose levels after 3 or 5 months of high-fat feeding, but reduced
glucose levels measured 90 min after intraperitoneal glucose injection. Myostatin depletion also attenuated hepatic
steatosis and accumulation of fat in muscle tissue. We conclude that blocking myostatin signaling after maturity can
attenuate some of the adverse effects of a high-fat diet.
Citation: Burgess K, Xu T, Brown R, Han B, Welle S (2011) Effect of Myostatin Depletion on Weight Gain, Hyperglycemia, and Hepatic Steatosis during Five Months
of High-Fat Feeding in Mice. PLoS ONE 6(2): e17090. doi:10.1371/journal.pone.0017090
Editor: Maria Castro, University of California, Los Angeles, and Cedars-Sinai Medical Center, United States of America
Received November 12, 2010; Accepted January 18, 2011; Published February 24, 2011
Copyright: ? 2011 Burgess et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This research was supported by the National Institutes of Health (grant number AR054366) and GlaxoSmithKline. GlaxoSmithKline scientists listed as
coauthors contributed to study design, data collection, and manuscript preparation.
Competing Interests: GlaxoSmithKline has a potential commercial interest in the metabolic effects of reducing myostatin activity. This does not alter the
authors’ adherence to all the PLoS ONE policies on sharing data and materials.
* E-mail: firstname.lastname@example.org
When laboratory mice are fed a high-fat diet, they become
obese and have hyperglycemia and hepatic steatosis as often
observed in obese humans. This diet-induced obesity is attenuated
in mice in which there is marked hypermuscularity caused by
constitutive absence of functional myostatin or constitutive expre-
ssion of a protein that inhibits myostatin activity [1–5]. Even on a
low-fat diet, mice with constitutive myostatin deficiency are leaner
than normal mice [3,4,6–8]. Mice with obesity-inducing genetic
mutations also are leaner when myostatin is absent . Because
muscle is a significant glucose consumer when insulin levels are
high, and because leanness improves sensitivity to insulin, it is not
surprising that constitutive myostatin deficiency reduces hypergly-
cemia after a glucose challenge in mice with obesity-inducing
mutations  and in mice fed a high-fat diet [1,3,4]. A constitutive
myostatin gene mutation attenuated the hepatic steatosis induced
by a high-fat diet .
The studies cited above raise the possibility that an anti-
myostatin therapy, if one can be developed, would reduce fat mass,
glucose levels, and hepatic steatosis in obese humans. However, at
least in mice, the increase in muscle mass that can be achieved by
blocking myostatin activity after muscle development is only about
one-fourth to one-third of the increase in muscle mass caused by
constitutive myostatin deficiency [9–12]. In old mice, systemic
administration of an anti-myostatin antibody for four weeks did
not affect fat mass or glucose levels, but muscle mass increased
only ,15% and the mice were not challenged with a high-fat
diet . In very young ob/ob mice, administration of an anti-
myostatin antibody for 6 weeks increased muscle mass by about
one-third but did not attenuate the rapid increase in adiposity
during this period . Nevertheless, the myostatin antibody
reduced blood glucose levels. In normal young mice, systemic
administration of a soluble activin receptor type IIB (RAP-031,
which blocks the activity of myostatin and other ligands that bind
to this receptor) increased muscle mass by about one-third and
markedly reduced the increase in fat mass that occurred between 4
and 10 weeks of high-fat feeding . Serum glucose levels after 10
weeks of high-fat feeding also were reduced by RAP-031
administration. Because myostatin was inhibited by a nonspecific
mechanism in that study, it is unclear to what extent the reduction
of myostatin activity was responsible for these effects. In the
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present study, we used a genetic approach to specifically eliminate
myostatin activity after normal development, and we examined
how this affected weight gain, muscle mass, fat mass, glucose levels
and hepatic steatosis after a prolonged period of high-fat feeding.
All procedures were approved by the University of Rochester
animal research committee and were consistent with all regula-
tions on humane use of animals for research (PHS Assurance
Number A–3292–01, Protocol Number 100624/2007–029).
Mice in which exon 3 of the myostatin gene is flanked by loxP
sequences (Mstn[f/f]) have been described previously [11,15].
These mice, and Mstn[w/w] controls (normal myostatin genes),
were bred with mice hemizygous for the CAGG-CreER transgene
. Cre+male mice (both Mstn[f/f] and Mstn[w/w]) were used in
this research. Genotyping was carried out as described previously
. The background strain for all mice was C57BL/6. Mice
received food and water ad libitum and were kept in MicroVENT
cages (Allentown Caging), 2–3 mice per cage, in a room with
controlled lighting (12 light cycle starting 0600 h) and temperature
When the mice were 4 months old, their usual low-fat chow
(LabDiet 5010, 12.7% of energy from fat, 58.5% from carbohy-
drates, 28.7% from protein) was withdrawn and replaced with
low-fat chow containing tamoxifen (250 mg/kg) for a two week
period to activate the CreER protein. This procedure knocks out
myostatin exon 3 in Mstn[f/f]/CreER+mice [11,17]. Loss of
myostatin was confirmed by immunoblotting . Mstn[w/w]
control mice also received tamoxifen chow to control for any
nonspecific effects of the drug or the presence of activated CreER.
After tamoxifen-containing chow was withdrawn, all mice were
fed LabDiet 5010 for two weeks.
Two weeks after the completion of tamoxifen administration,
some of the mice were switched to a high-fat diet (Research Diets
D12462, 60% of energy from fat, 20% from carbohydrates, 20%
from protein). Other mice continued to consume the low-fat
LabDiet 5010. The mice stayed on the assigned diets for 22 weeks.
They were weighed at 2 week intervals. Mandibular vein glucose
concentrations were determined with a FreeStyle FreedomTMglu-
cose meter (Abbott) during the 13thand 21stweek of high-fat
feeding. Blood samples were obtained in the afternoon, 5 hr after
Figure 1. Mean (±SEM) change in total body mass. Top panel
shows cumulative weight gains after changing dietary fat from 13% to
60% of energy, and lower panel shows biweekly weight changes
independent of previous measures. IPGTT=intraperitoneal glucose
tolerance test. *P,0.05 (adjusted for multiple comparisons) for
difference between normal and myostatin-depleted.
Table 1. Effects of myostatin depletion and high-fat feeding on body and organ mass.
Low-fat dietHigh-fat diet
Normal myostatin Myostatin depletedNormal myostatin Myostatin depleted
Epididymal fat (g)0.5860.070.5260.06 2.3260.14b
Retroperitoneal fat (g)0.3060.060.2960.04 2.4760.16b
Liver (g) 1.6560.051.6460.04 2.1460.14b
Kidney (mg)19365 16964a
Heart muscle (mg)13063 12963 14964b
Gastrocnemius muscles (mg) 14664 19665a
Quadriceps muscles (mg)22364 28167a
Triceps muscles (mg)12862 17866a
Values are mean6standard error. Organ mass was determined when mice were 10 months old. Myostatin depletion was induced by tamoxifen feeding for two weeks
when mice were 4 months old. High-fat feeding started when mice were 5 months old.
aP,0.02 versus normal myostatin group on same diet.
bP,0.03 versus low-fat diet group with same myostatin status.
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chow was removed from the cage, both before and after ip
injection of glucose (1 mg/g body weight). Initially, we tested
glucose concentrations at 30, 60, and 90 min after glucose
injection. This frequent sampling protocol was stressful to the
mice and resulted in highly variable and sometimes unexpectedly
high glucose concentrations even in mice consuming normal
chow. Hence, we changed the protocol to sample blood only once
after the glucose injection, at 90 min. Mean fasting glucose levels
reported here include data from all mice, but the mean 90 min
post-injection levels are based on only those mice that had a single
post-injection blood sample.
After 22 weeks of high-fat feeding, or the same period of low-fat
feeding, mice were euthanized for determination of the mass of
skeletal muscles (gastrocnemius, quadriceps, triceps), heart, liver,
kidney, and intra-abdominal fat pads (retroperitoneal and
epididymal, bilateral). In mice fed the low-fat diet, retroperitoneal
and epididymal fat pads accounted for nearly all of the visible
adipose tissue within the abdominal cavity, except for very small
amounts adhering to intestine and pancreas. In mice fed the high-
fat diet, adipose tissue surrounding gastrointestinal organs
appeared to be continuous with the retroperitoneal adipose tissue
and was classified as such. Muscles were snap frozen in liquid
nitrogen and stored at 270uC. Livers were stored in 10% buffered
neutral formalin. Fatty acid contents of triceps muscles, which
included lipids within muscle fibers and in adipose tissue between
fascicles, were determined by gas chromatography with C17:0 as
an internal standard . Transverse sections of the liver, 2–3 mm
thick, were taken from the left lateral lobe and were transferred to
an osmium tetroxide-potassium dichromate solution for 8 hours.
The tissues were rinsed in running tap water for 2 hours and
processed overnight on a tissue processor. After embedding in
paraffin, 5 micron sections were cut and stained with Hematoxylin
Figure 2. Mean (+ +SEM) muscle and intra-abdominal adipose tissue mass. Myostatin-deficient (gray bars) and control mice (white bars) were
fed a normal low-fat diet (13% of energy from fat) or were fed a high-fat diet (60% of energy from fat) for the final 22 weeks of the experiment. Each
bar represents the mean and SEM of 12–15 mice. *P,0.001 versus mice with normal myostatin levels.
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and Eosin. Sections were graded for hepatocellular steatosis
according to the following 4-point scale: 1) rare individual
hepatocytes containing intermediate to microvesicular lipid
droplets; 2) midzonal to centrilobular distribution of primarily
small to intermediate macro-vesicular and micro-vesicular lipid
droplets with less than 50% of the lobules affected; 3) midzonal to
centrilobular distribution of intermediate-size macrovesicular and
microvesicular lipid droplets, smaller in size than grade 4 and
involving less than 70% of the lobules; 4) midzonal to centrilobular
distribution of numerous large macrovesicular and microvesicular
lipid droplets distributed across more than 70% of the lobules.
Data are expressed as means, and where error terms are shown
these are standard errors of the mean. Factorial analysis of
variance (ANOVA; myostatin status6time, with time as a within-
subject factor) was done to assess the statistical significance of the
effect of myostatin depletion on biweekly weight changes and
biweekly cumulative weight gain. The statistical significance of the
effect of myostatin depletion at each time point was assessed by
Bonferroni t-tests to adjust P for multiple comparisons. The
denominator for computing the t values was based on the residual
variance from the ANOVA. We analyzed the high-fat and low-fat
conditions separately rather than adding dietary condition as an
additional factor in the ANOVA, because variance was greater for
the high-fat condition. Thus, using residual errors pooled across
dietary conditions would have inflated the statistical significance of
the effects of myostatin deficiency during high-fat feeding.
Variance was higher with the high-fat diet for several other
outcome measures, including fat pad mass, liver mass, glucose
levels after ip glucose injection, and intramuscular lipid content.
We therefore assessed the effects of myostatin depletion separately
Figure 3. Mean (+ +SEM) blood glucose concentrations. Bars represent means, whiskers represent SEM. Number of values included in each mean
are shown at the bottom of each bar. *P,0.01 vs. normal myostatin group represented by adjacent bar. #P,0.02 vs. low-fat group with same
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for the low-fat and high-fat conditions rather than performing
ANOVA with diet as a factor. P values for effects of myostatin
depletion within diet groups were determined with t-tests. Two-
tailed P values are reported. For simplicity and consistency, this
approach was taken for all outcome measures even when variance
was similar in low-fat and high-fat conditions. The statistical
significance of differences in outcome measures for high-fat
feeding versus low-fat feeding in both myostatin-deficient and
control mice were determined by t-tests adjusted for unequal
variance between groups. Fisher’s exact probability test (two-sided)
was used to determine whether the distribution of steatosis scores
in mice fed the high-fat diet was significantly different in control
and myostatin-deficient mice. R version 2.12.0 was used for
ANOVA and Fisher’s test, and Microsoft Excel was used for
Before tamoxifen administration, the mean body mass of
Mstn[f/f] mice was slightly greater than that of Mstn[w/w] mice,
27.6 vs. 26.1 g (P,0.01). Mice of both genotypes lost some body
mass during 2 weeks of tamoxifen feeding (mean 2.2 g in Mstn[f/f]
and 1.8 g in Mstn[w/w], P.0.3 for genotype difference). During
the first 2 weeks after tamoxifen feeding, before the mice started
consuming the high-fat diet, Mstn[f/f] mice gained more weight
than Mstn[w/w] mice (4.3 vs. 2.5 g, P,0.001), presumably
because of a rapid increase in muscle mass (in a recent
unpublished study, we determined that gastrocnemius and
quadriceps muscles were 25–30% larger in Mstn[f/f]/CreER+
mice than in Mstn[w/w]/CreER+ mice 2 weeks after the cessation
of tamoxifen feeding). Thus, body mass was greater (P,0.001) in
myostatin-depleted mice at the onset of high-fat feeding (29.1 vs.
26.5 g) and at the same time point in mice that continued on the
low-fat diet (30.1 vs. 27.0 g). After the more rapid weight gain in
Mstn[f/f] mice during the first 2 weeks post-tamoxifen, there was
no further effect of myostatin depletion on the increment in total
body mass in mice in which the low-fat diet was continued during
the final 22 weeks of the study (3.8 g in myostatin-deficient mice;
3.6 g in normal mice).
Over the first 8 weeks of high-fat feeding, the cumulative mean
weight gain of the myostatin-deficient mice was only half that of
the mice with normal myostatin expression (Figure 1, upper
panel). Beyond 8 weeks, the rate of weight gain was similar in
myostatin-deficient and control mice, but cumulative weight gain
remained lower in the myostatin-deficient mice. By ANOVA, the
pattern of biweekly weight changes (Figure 1, lower panel) was
significantly different in control and myostatin-deficient mice
(P,0.05 for myostatin status6time interaction). The only
individual time interval with significantly lower weight gain
(P,0.05) in myostatin-deficient mice was the interval between 2
and 4 weeks after starting the high-fat diet. Myostatin-deficient
mice had a greater body mass when the high-fat diet was started
(because of increased muscle mass), so their smaller weight gains
did not result in significantly lower body mass at any time point
(P.0.1, not shown except for final weights in Table 1).
At the end of the study, the mass of fat within the abdominal
cavity was more than 5-fold greater in the high-fat groups than in
low-fat groups (Figure 2). Myostatin depletion did not significantly
affect the mass of epididymal or retroperitoneal fat at the end of
the study in either the low-fat or the high-fat groups. In mice with
normal myostatin genes, the high-fat diet increased hepatic mass
by 30% (Table 1). In myostatin-deficient mice, the high-fat diet did
not consistently increase hepatic mass (mean+5%, P=0.4).
Myocardial mass was increased by the high-fat diet, 14% in
control mice and 10% in myostatin-deficient mice. Kidney mass
was not significantly affected by the high-fat diet in either normal
or myostatin-deficient mice (P.0.1, Table 1). We did not weigh
the gastrointestinal tract or other organs, but by visual inspection
we did not notice any major effects of the high-fat diet or
myostatin depletion on the size of internal organs. Skeletal muscle
mass (gastrocnemius, quadriceps, and triceps muscles) was about
30% greater than normal in myostatin-deficient mice, as expected,
regardless of dietary condition (Table 1, Figure 2).
Of the total difference in mean body mass of 19.9 g between
low-fat and high-fat groups with normal myostatin expression
(Table 1), less than 5 g can be accounted for by the increased mass
of intra-abdominal fat, liver, and heart. Skeletal muscle mass was
not increased to any significant extent by the high-fat diet
(Figure 2), meaning that we cannot account for ,15 g of the extra
body mass. It was very clear that subcutaneous fat mass was
markedly increased after 5 months of high-fat feeding. This
compartment might explain most of the unaccounted weight gain,
but this was not quantified. The difference in body mass between
the low-fat and high-fat myostatin-deficient groups was 14.1 g,
and only ,4 g of this extra weight can be explained by the
increased mass of abdominal fat, liver, and heart. Thus, the
unexplained portion of the weight difference between myostatin-
deficient mice fed the high-fat diet versus those fed the low-fat diet
was ,10 g.
Myostatin depletion did not significantly affect blood glucose
levels in mice fed a low-fat diet (Figure 3). As expected, the high-fat
diet induced hyperglycemia, both 5 hr after food was withdrawn
and 90 min after ip glucose injection (P,0.001, Figure 3). In mice
fed the high-fat diet for 5 months, myostatin depletion did not
affect fasting glycemia but reduced glucose levels 90 min after ip
glucose (P,0.01). The same pattern of mean glucose levels was
observed after 3 months of high-fat feeding, but 90 min data were
available for only 3 myostatin-deficient mice and therefore there
was limited power to assess statistical significance.
The high-fat diet induced an increase of ,4-fold in the amount
of fat in triceps muscles in mice with normal myostatin levels
(Figure 4). In contrast, the high-fat diet increased muscle fat
content only 60% in myostatin-deficient mice. The method used
Figure 4. Mean (+ +SEM) lipid mass in triceps brachii muscles.
Esterified + non-esterified fatty acid content (palmitic + palmitoleic +
stearic + oleic + linoleic acids, which accounted for ,90% of total fatty
acid mass) was determined by gas chromatography. *P,0.001 vs. low-
fat group with normal myostatin expression. #P,0.001 vs. high-fat
group with normal myostatin expression and P,0.05 vs. myostatin-
deficient low-fat group. Data from 6 mice per genotype/diet condition.
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to assess muscle fat content did not differentiate between fat within
the muscle fibers and fat that accumulated in adipocytes between
muscle fibers. Fat deposition in the liver also was attenuated in
myostatin-deficient mice (Figure 5). All 12 livers from control mice
fed the high-fat diet received the highest steatosis score, whereas
only 5 of 13 livers from myostatin-deficient mice received the
highest score. The difference between control and myostatin-
deficient mice in the distribution of steatosis scores was significant
by Fisher’s exact probability test (P,0.01).
Mice made hypermuscular by postdevelopmental myostatin
depletion gained less weight than normal mice during the first few
weeks of exposure to a very-high-fat diet. However, the further
increase in weight beyond the first few weeks of high-fat feeding
was not significantly affected by myostatin depletion. After 5
months of high-fat feeding, the intra-abdominal fat mass was
similar in normal and myostatin-deficient mice. The mean total
Figure 5. Hepatic steatosis scores and representative micrographs of liver sections. Distribution of steatosis scores (A) is based on
examination of 12 mice with normal myostatin expression and 13 myostatin-deficient mice, all of which received the high-fat diet. Mice fed a low-fat
diet did not have hepatic fat accumulation (B, Osmium H&E6250). Mice with normal myostatin expression had significant hepatic steatosis after 5
months of high-fat feeding (C6250; D6500). Larger lipid droplets often lift off the tissue leaving the clear spaces seen in the micrographs. Less fat
accumulation was evident in livers of myostatin-deficient mice fed a high-fat diet for 5 months (E6250; F6500).
PLoS ONE | www.plosone.org6 February 2011 | Volume 6 | Issue 2 | e17090
weight gain associated with high-fat feeding (i.e., the difference in
final body weights between mice fed high-fat and low-fat diets) was
29% less in myostatin-deficient mice, but we could not account for
this difference based on the fat depots and organs that were
weighed in this study. Subcutaneous adipose tissue has a very large
capacity to store fat and a difference in subcutaneous fat
accumulation is a potential explanation for the differential weight
gain. Unfortunately, we did not include measurements of
subcutaneous fat mass when designing the study because previous
research indicated that myostatin knockout or inhibition reduced
epididymal, retroperitoneal, and subcutaneous fat mass to the
same extent [1,6,9], and because of the consensus that central
obesity is a more important determinant of metabolic problems
than subcutaneous obesity. Future research on the potential anti-
obesity effect of inhibiting myostatin activity should evaluate the
possibility that subcutaneous adipose tissue is affected more than
intra-abdominal adipose tissue after prolonged high-fat feeding.
Previous research has demonstrated that inhibition or deficiency
of myostatin does not reduce, and may increase, intake of normal
or high-fat chow [5,6,9,14,20]. Thus it is more likely that increased
energy expenditure rather than lower energy intake explains the
initial smaller weight gain in myostatin-deficient mice during high-
fat feeding. The increased muscle mass induced by myostatin
depletion must have increased maintenance energy requirements
to some extent. Mature mice with constitutive myostatin knockout
had an increase in total oxygen consumption (an index of energy
expenditure) of 14% . Recently it was reported that energy
expenditure per mouse was increased 33% after 6 weeks of anti-
myostatin antibody administration to ob/ob mice, in which the
increment in muscle mass caused by myostatin blockade was very
similar to the increment in muscle mass induced by myostatin
depletion in the present study .
In mice with constitutive expression of a protein that inhibits
myostatin activity, a high-fat diet fed during development (4–23
weeks of age) increased body mass and muscle mass more in
myostatin-deficient than in mice with normal myostatin activity
. In the present study, the high-fat diet did not enhance the
muscle hypertrophy and total weight gain induced by myostatin
depletion. Thus, the effect of high energy intake on muscle growth
and the influence of myostatin on pathways that regulate this
process might be different in immature and mature mice.
Presumably, most of the increase in liver mass associated with
high-fat feeding was caused by steatosis, which was evident in the
histological examinations of liver sections. The mean increase in
liver mass in the obese myostatin-deficient mice (,0.1 g) was
markedly attenuated compared with that of the obese mice with
normal myostatin expression (0.5 g), and histology indicated that
steatosis was not as severe in the myostatin-deficient mice. A
constitutive myostatin gene mutation also attenuated the hepatic
steatosis induced by a high-fat diet . Blocking myostatin in mice
with a soluble activin receptor type IIB reduced hepatic steatosis
induced by androgen deprivation . The fact that hypermus-
cularity induced by elevated Akt1 activity reduced hepatic steatosis
in mice fed a high-fat diet  suggests that this is an indirect
consequence of hypermuscularity rather than a direct effect of
reduced activin receptor activity in liver. Myostatin knockout also
reduced lipid accumulation in skeletal muscle, an effect that has
not been reported previously. The mechanism for reduced fat
accumulation in liver and muscles of myostatin-deficient mice is
not known and was not examined in the present study.
consumes fat rather than glucose as its primary fuel source. Thus, it is
not surprising that the hypermuscularity in myostatin-deficient mice
did not reduce glucose levels after a 5 hr fast. When insulin levels are
elevated, muscle becomes a major glucose consumer. The lower
glucose levels in myostatin-deficient mice 90 min after glucose
administration could simply reflect the increased mass of an insulin
sensitive tissue. It also is possible that loss of myostatin increased
sensitivity to insulin. Although insulin resistance has been induced by
injecting myostatin into mice [4,23], this does not prove that the
normal basal level of myostatin is a significant determinant of insulin
sensitivity. Insulin sensitivity typically is defined as the rate of fall of
glucose levels after insulin administration, or the amount of glucose
that must be infused to maintain constant glucose levels during
continuous insulin infusion. Thus, even if the rate of glucose uptake
per gram of muscleisnot affected by myostatin deficiency, the whole-
body insulin sensitivity would appear to be increased because of the
larger muscle mass. When the activity of myostatin and other activin
receptor type IIB ligands was reduced by systemicadministration of a
insulin-stimulated glucose uptake per g muscle when mice were on a
normal diet, but not when they were on a high-fat diet .
Nevertheless, the treated mice had lower blood glucose levels on the
high-fat diet, perhaps because their leaner body composition
improved hepatic insulin sensitivity and thereby reduced endogenous
glucose production. Obese ob/ob mice treated with an anti-myostatin
antibody had reduced glucose levels when consuming normal low-fat
food, but this occurred without a change in the glucose-lowering
effect of exogenous insulin . More research is needed to clarify to
mechanism whereby loss of myostatin activity reduces glucose levels.
All research in this area, including the present study, has
examined whether lack of myostatin activity attenuates the
development of obesity or hyperglycemia when myostatin activity
was knocked out or inhibited before the mice became obese.
Future studies should be designed to determine whether inhibition
of myostatin signaling can help to reverse established obesity,
hepatic steatosis and glucose intolerance.
We thank Christopher Storey for assistance with animal care, Sangeeta
Mehta for performing the fatty acid assays, and Teresa Wylie for staining
the liver samples.
Conceived and designed the experiments: TX RB BH SW. Performed the
experiments: KB SW. Analyzed the data: KB RB SW. Contributed
reagents/materials/analysis tools: TX RB BH SW. Wrote the paper: RB
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PLoS ONE | www.plosone.org8 February 2011 | Volume 6 | Issue 2 | e17090