Increase in Muscle Mitochondrial Biogenesis Does Not
Prevent Muscle Loss but Increased Tumor Size in a
Mouse Model of Acute Cancer-Induced Cachexia
Xiao Wang1, Alicia M. Pickrell2, Teresa A. Zimmers1,3¤, Carlos T. Moraes1,2,3,4*
1The Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America,
2Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, Florida, United States of America, 3Sylvester Comprehensive Cancer Center,
University of Miami Miller School of Medicine, Miami, Florida, United States of America, 4Department of Neurology, University of Miami Miller School of Medicine, Miami,
Florida, United States of America
Cancer-associated cachexia is a complex metabolic condition characterized by the progressive loss of body fat and
deterioration of muscle mass. Although the cellular and molecular mechanisms of cachexia are incompletely understood,
previous studies have suggested mitochondrial dysfunction in murine models of cancer cachexia. To better understand the
metabolic shift in cancer-induced cachexia, we studied the effects of enhanced oxidative capacity on muscle wasting using
transgenic mice over-expressing Peroxisome Proliferator-Activated Receptor gamma Co-activator-1a (PGC-1a) in skeletal
muscle in a Lewis lung carcinoma-implanted model. Increased mitochondrial biogenesis was observed in the skeletal
muscle of tumor-implanted mice. However, these increases did not prevent or reverse muscle wasting in mice harboring
tumors. Moreover, tumor size was increased in muscle PGC-1a over-expressing mice. We found similar levels of circulating
inflammatory cytokines in tumor-implanted animals, which was not affected by increased muscle expression of PGC-1a. Our
data indicated that increased mitochondrial biogenesis in skeletal muscle is not sufficient to rescue tumor-associated, acute
muscle loss, and could promote tumor growth, possibly through the release of myokines.
Citation: Wang X, Pickrell AM, Zimmers TA, Moraes CT (2012) Increase in Muscle Mitochondrial Biogenesis Does Not Prevent Muscle Loss but Increased Tumor
Size in a Mouse Model of Acute Cancer-Induced Cachexia. PLoS ONE 7(3): e33426. doi:10.1371/journal.pone.0033426
Editor: Antoni L. Andreu, Hospital Vall d’Hebron, Spain
Received November 28, 2011; Accepted February 12, 2012; Published March 12, 2012
Copyright: ? 2012 Wang 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: National Institute of Health and the Muscular Dystrophy Association. The funders had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
¤ Current address: of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
Clinically, cachexia is defined as ‘‘a complex metabolic
syndrome associated with underlying illness and characterized by
loss of muscle with or without loss of fat mass’’ . It has been
found in many chronic or end-stage diseases such as AIDS,
tuberculosis, and cancer . Up to 50% of untreated cancer
patients experience progressive loss of fat and lean body mass
without starvation, a complex syndrome referred to as cancer-
induced cachexia . The presence of wasting is usually associated
with intolerance to treatment, poor quality of life and high
mortality in patients .
Although extensive studies have been carried out during the last
decade, the underlying mechanisms causing cancer cachexia are
still not fully understood. One of the leading theories is that tumor-
derived factors are responsible for the degradation of body mass,
including the muscle . It is widely accepted that pro-
inflammatory cytokines play a key role in all pathways that lead
to hyper catabolism and weight loss associated with cancer
cachexia . The presence of systemic inflammation is usually
linked to worse prognosis in the patients .
Cancer cachexia causes systemic changes in patients’ metabolic
profile in order to support tumor development. It has been
reported that mitochondrial dysfunction in the skeletal muscle,
including decreased oxidative phosphorylation (OXPHOS) ca-
pacity and disrupted mitochondrial dynamics, is involved with
systemic inflammation and skeletal muscle wasting . The
peroxisome proliferator-activated receptors (PPARs) transcription
factors family and their modulator PPAR-gamma co-activator-1a
(PGC-1a) are the master regulators of mitochondrial biogenesis
and energy metabolism . Mitochondrial uncoupling proteins
(UCPs) 1, 2, and 3 are upregulated in atrophying muscle; and
metabolic abnormality with increased proteolysis in the muscle has
been implied in cachectic patients [9,10]. The activation of pro-
inflammatory cytokine TNFa-induced NF-kB was shown to
decrease promoter transactivation and transcriptional activity of
regulators of mitochondrial biogenesis (PGC-1a, PPARa, and
TFAM) and affect downstream oxidative markers (citrate synthase,
and cytochrome c oxidase) .
Clinical interventions have been developed for general symptom
management of this devastating condition; however, these
measures are only palliative without specifically targeting the
causing factor of cachexia and the outcomes are not satisfactory
In this study, we investigated the potential therapeutic effect of
increasing mitochondrial biogenesis by overexpressing PGC-1a in
PLoS ONE | www.plosone.org1March 2012 | Volume 7 | Issue 3 | e33426
the skeletal muscle in a transgenic mouse model of cancer
cachexia. Our results indicate that increased mitochondrial
biogenesis in the muscle was not sufficient to alter the levels of
proinflammatory cytokines and prevent the muscle loss associated
with tumor implantation. Moreover, the increase in muscle PGC-
1a may also have the side effect of promoting tumor growth.
Tumor-inoculated transgenic MCK-PGC-1a mice maintain
increased mitochondrial biogenesis in gastrocnemius
Transgenic MCK-PGC-1a mice over-express PGC-1a in the
skeletal muscle, driven by the muscle creatine kinase (MCK)
promoter . We observed an increase of Ppargc1a mRNA levels
of 13-fold in the gastrocnemius, a muscle composed of similar
levels of Type I (oxidative) and Type II (glycolytic) fibers and 19-
fold in the quadriceps, a muscle composed mostly of Type II fibers,
in 4-month-old tumor-free transgenic MCK-PGC-1a mice
(Figure 1A). A similar increase was observed for tumor bearing
mice (Figure 1A). When we determined the steady state levels of
PGC-1a protein in gastrocnemius and quadriceps homogenates,
we observed a marked increase in transgenic mice compared to
controls, with or without tumors. The results for gastrocnemious
and quadriceps were essentially identical for both genotypes
(Figure 1B, C and not shown).
PGC-1a is a transcriptional coactivator that upregulates the
transcription of nuclear-coded mitochondrial proteins, stimulating
mitochondrial biogenesis [14,15,16]. We quantified the levels of
mitochondrial proteins in 4-month-old MCK-PGC-1amice and
found significantly higher levels of several mitochondrial markers in
mice without or with tumors (Figure 1B and 1C). The levels of
mtDNA in both gastrocnemius and quadriceps were elevated in
PGC-1a expressing mice (Figure 2A). In concordance with signs of
increased mitochondrial biogenesis, we observed significant in-
creases in citrate synthase (CS) and cytochrome c oxidase (COX)
activities both in gastrocnemius and quadriceps (Figure 2B, C).
Interestingly, we noticed a differential regulation of another
member of the PGC-1 family, PGC-1b in gastrocnemius and
quadriceps in tumor inoculated animals. While it remained
unchanged in the gastrocnemius tissue, Ppargc1b mRNA levels
were significantly decreased in quadriceps tissue of tumor-bearing
MCK-PGC-1amice (Figure 2D, E). Accordingly, the expression
levels of transcription factors Ppara and Pparg were significantly
increased in gastrocnemius but not in quadriceps muscle
(Figure 2D, E).
Over-expression of MCK-PGC-1adoes not protect against
cancer-induced muscle loss
Previously, our laboratory showed that over-expression of PGC-
1ain skeletal muscle protected and slowed down the progression of
mitochondrial myopathies and age-induced sarcopenia [17,18].
We hypothesized that with increased mitochondrial function, our
MCK-PGC-1a mice would be more resistant to muscle wasting by
reversing the metabolic changes contributing to cachexia.
After confirming this robust enhancement in mitochondrial
biogenesis, we examined whether over-expression of PGC-1a
could provide protection against muscle loss in our tumorigenic
model. We followed the weight of the MCK-PGC-1a and wild-
type mice, with or without tumor, as an indicator of general health
after inoculating tumor cells. We observed no significant difference
between groups until post-injection day-12 and -13, where MCK-
PGC-1a tumor mice had a significant increase in percentage body
weight as compared to all 3 other groups of mice (Figure 3A).
To understand where this increase in body weight for the
MCK-PGC-1a tumor mice came from, we examined the body
weight and extracted tumor weight. We found that tumor-free
body weight was significantly decreased in tumor-bearing mice of
both genotypes, and no major differences between the transgenic
and wild-type mice (Figure 3B). However, the tumors extracted
from MCK- PGC-1a mice were approximately 50% larger than
controls (Figure 3C). When plotting the changes of body weight
against tumor size, we noted a positive correlation in wild-type
mice, which was disrupted in MCK-PGC-1a tumor mice
(Figure 3D). With this evidence, we concluded that the total body
weight gain for tumor-bearing MCK-PGC-1a mice was caused by
the increase in tumor mass and not a gain in muscle weight.
However, despite having larger tumors, MCK-PGC-1a mice did
not lose more weight than tumor bearing controls.
The weights of both gastrocnemius and quadriceps were mildly,
but significantly decreased in wild-type tumor mice, indicating our
model induced muscle loss (Figure 3E). However, there was no
difference in either muscle group as compared between tumor-
inoculated transgenic and wild-type mice (Figure 3E). We also
quantified the concentration of pro-inflammatory cytokine IL-6 in
the serum. As expected, IL-6 levels were dramatically increased in
tumor-bearing mice of both genotypes compared to tumor-free
mice, but we did not find significant differences between the two
genotypes (Figure 3F). Thus, MCK-PGC-1a did not seem to
protect against muscle loss or to lower systemic IL-6 levels at this
In this study, we utilized MCK-PGC-1a mouse model to study
the effect of increased mitochondrial biogenesis on cancer-induced
muscle loss. We found increased mitochondrial biogenesis in the
muscle of MCK-PGC-1a tumor mice compared to WT tumor
mice. Surprisingly, we found that the increased expression of
PGC-1a in muscle did not prevent muscle loss. This was an
unexpected result, as muscle PGC-1a was shown by our group and
others to confer broad protection to different conditions associated
with muscle degeneration [17,19].
Although the causes of cachexia are still poorly understood,
increased degradation and decreased synthesis of muscle proteins
by the proteasome system appears to play a major role .
Systemic inflammation seems to mediate this mechanism in
cancer-induced cachexia . Rosenberg and colleagues proposed
that high serum levels of TNFa and IL-1b were the causes for
weight loss in rheumatoid cachexia . Systemic cytokine-driven
inflammatory response in AIDS patients with concurrent active
infections has also been associated with cachexia . The model
of subcutaneous tumor implantation also shows an increase in
circulating IL-6 levels associated with muscle and total body
weight loss. However, in our experiments the IL-6 levels were not
different between wild-type and MCK-PGC-1a mice (Figure 3F).
Therefore, we speculate that although PGC-1a can protect against
muscle loss associated with intrinsic metabolic dysfunctions
[17,19], it is less effective in precluding muscle loss caused by
extrinsic inflammatory signals.
The MCK-PGC-1a mouse model has been extensively studied
by our group and others in various myopathies. Besides the
transgenic strategy, PGC-1a can also be induced by endurance
exercise [23,24]. Both increased muscle PGC-1a expression and
exercise have been shown to ameliorate systemic inflammation
[9,19,25]. As part of combinatory therapy, exercise concordant
with patient’s physical conditions is usually suggested during
clinical intervention . In our model of cancer-induced
Muscle PGC-1a and Cancer Cachexia
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cachexia experimental animals die within 2 weeks after tumor
inoculation. The mice developed mild muscle loss within a 13-day
time frame with the tumor appearing as early as day 5 after
inoculation. Although PGC-1a overexpression did not ameliorate
the mild muscle loss in our acute tumorigenic model, we believe
future experiments should examine the potential therapeutic effect
of increased mitochondrial biogenesis in more severe or chronic
models of cancer-induced muscle wasting.
Although the reason for this negative result is not known, we
also found that the tumors were approximately 50% larger in mice
overexpressing muscle PGC-1a. One possible explanation for this
observation is that skeletal muscle can secrete myokines, such as
IL-6, which could have growth promoting activity . This was
an expected observation that warrants further exploration with
different tumor types and models.
In summary, our work demonstrated that stimulating mito-
chondrial biogenesis was not sufficient to prevent or reverse
muscle loss during acute cancer-induced muscle wasting. More-
over, we found evidence that PGC-1a expression in muscle can
lead to the development of larger tumors.
The generation of MCK-PGC-1a transgenic mice was
previously described . Female animals for analysis were pure
C57BL/6J MCK-PGC-1a mice with age-matched littermate
controls. All mice procedures were performed according to a
protocol approved by the University of Miami: Institutional
Animal Care and Use Committee (#10-071). Mice were housed in
Figure 1. Tumor inoculated transgenic MCK-PGC-1a mice maintain upregulation of PGC-1a and mitochondrial markers. A. mRNA
levels (DDCt) of Ppargc1a in gastrocnemius and quadriceps normalized to Gapdh at 4 months-of-age in MCK-PGC-1a and controls without and with
tumor implantation (n=4/group). B, C. Left panel: Representative Western blotting analysis of steady state levels of PGC-1a and mitochondrial
proteins (complex II subunit SDHA, complex III subunit UQCRC1, and complex I subunit NDUFB8) at 4 months-of-age from muscle homogenates of
MCK-PGC-1a and controls. Right panel: Optical density (O.D.) quantification of proteins of interest normalized toa tubulin (n=3/group in B, n=4/
group in C). Error bars are mean 6 SEM.
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a virus-antigen-free facility at the University of Miami: Division of
Veterinary Resources under a 12 hr light/dark cycle at room
temperature and fed ad libitum with standard rodent diet. The
endpoint of the study was set when the physical condition for more
than 50% of remaining tumor-bearing mice was evaluated as
critical and euthanized within 24 hours.
Female wild-type mice and MCK-PGC-1a transgenic litter-
mates (n=8/group) at 4 month of age were injected subcutane-
ously with 106Lewis lung carcinoma cells in 100 mL sterile vehicle,
phosphate-buffered saline (PBS), between the shoulder blades.
Controls were injected in the same manner and location with PBS
(n=7 for wild-type mice, n=5 for MCK-PGC-1a mice). The
weights of the animals were recorded and their general health was
monitored daily after tumor inoculation. Individuals deemed in
poor condition unable to survive until the endpoint of study were
euthanized and excluded from further analysis.
OXPHOS assays were performed as previously described .
In brief, homogenates from quadriceps and gastrocnemius were
prepared using a tissue homogenizer (Omni) in PBS plus protease
inhibitor cocktail (Roche) on ice. Samples were centrifuged at
800 g for 5 minutes and the supernatant of the homogenate was
added to a buffer containing 10 mM KH2PO4, 1 mg/mL BSA,
120 mM lauryl maltoside, and 2 mM cytochrome c reduced with
sodium hydrosulfite in. The mixtures were followed at 550 nm
with the absorption reading taken every 11 seconds for 2 minutes
at 37uC. 240 mM potassium cyanide was used to inhibit the
reaction to ensure slope was specific to cytochrome c oxidase
(COX). The slopes were normalized by protein concentration
determined by Bradford assay.
For citrate synthase (CS) activity assay, the supernatants were
added to a buffer containing 50 mM Tris-HCl pH 7.5, 20 mM
acetyl CoA, 10 mM 5, 59-dithiobis-(2-nitrobenzoic acid), and
0.1% triton X-100. The assay was performed at 30uC with 50 mM
Figure 2. Tumor injected transgenic MCK-PGC-1a mice maintain upregulation of mtDNA levels and mitochondrial enzymes activity.
A. mtDNA copy number of gastrocnemius and quadriceps of 4-months-old MCK-PGC-1a and wild-type mice, without and with tumor implantation
(n=5/group). B–C. COX and CS enzymatic activity of gastrocnemius (B) and quadriceps (C) muscle homogenates normalized to protein from tumor
MCK-PGC-1a and age-matched controls (n=5/group). D–E. mRNA levels (DDCt) of Ppara, Pparg, Ppard, and Ppargc1b in gastrocnemius (D) and
quadriceps (E) normalized to Gapdh at 4-months-old tumor MCK-PGC1–a and aged-matched controls (n=4/group). Error bars are mean 6 SEM.
Muscle PGC-1a and Cancer Cachexia
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oxaloacetate (OXA) to start the reaction. Readings were obtained
every 11 seconds for 3 minutes. The slopes taken before adding
OXA were extracted from the slope with OXA. Normalization
was as above.
mRNA Isolation and Reverse Transcriptase PCR
Dissected quadriceps and gastrocnemius muscle tissues were
submerged in TRIzolH (Sigma/Invitrogen). Tissues were homog-
enized with a hand-held rotor homogenizer (VWR), and RNA was
extracted by chloroform phase separation. We used 1 mg of RNA
for reverse-transcription reaction using the iScript cDNA synthesis
kit according to the manufacturer’s protocol (BioRad).
Maxima SYBR Green/ROX qPCR master mix (Fermentas)
was used according to manufacturer’s directions to perform real-
time PCR. Primers used for the cDNA quantification were:
Ppargc1a (59- CTGCGGGATGATGGAGACA, 59- AGCAGC-
GAAAGCGTCACA), Ppargc1b (59- TGGCCCAGATACACT-
GACTATG, 59- TGGGCCTCTTTCAGTAAGCT), Ppara (59-
TTCCCTGTTTGTGGCTGCTAT, 59- CCCTCCTGCAAC-
TTCTCAATGTAG), Pparg (59- CGGAAGCCCTTTGGTGA-
CTTTA, 59- GCGGTCTCCACTGAGAATAATGAC), Ppard
(59- ACCGCAACAAGTGTCAGTAC, 59- CTCCGGCATCC-
GTCCAAAG), and Gapdh (59- TGCACCACCAACTGCTTAG,
The following primer pairs were used for the quantification of
mtDNA copy number in total DNA (extracted with phenol:
chloroform phase separation): Nd1 (59- CAGCCTGACCCA-
TAGCCATA, 59- ATTCTCCTTCTGTCAGGTCGAA), Actb
(59- TCACCCACACTGTGCCCATCTACGA, 59- CAGCG-
GAACCGCTCATTGCCAATGG). Comparative Ct method
was used to determine the relative abundance of genes of interest
or mtDNA .
Western Blotting Analysis
Protein extracts were prepared from the quadriceps and
gastrocnemius muscles that were homogenized with a hand-held
rotor (VWR) in PBS containing protease inhibitor cocktail
(Roche). Samples were then snap frozen in liquid nitrogen and
stored in 280uC until used. Upon use, homogenates were diluted
1:10 with RIPA buffer (62.5 mM Tris-HCl pH 7.4, 150 mM
NaCl, 1% NP-40, 0.25% SDS, 1 mM EDTA, with protease
inhibitors and phosphatase inhibitors added freshly) and sonicated
briefly. Homogenates were then centrifuged at 15,0006g and the
supernatant was collected. Proteins were quantified using Bradford
Figure 3. Over-expression of MCK-PGC–1a does not protect against cancer-induced cachexia. A. Percentage body weight over two
weeks after tumor cell or saline injection for MCK-PGC-1a or controls at 4 months-of-age, numbers of animals as labeled. B. Percentage tumor-free
body weight at 2 weeks after tumor inoculation of MCK-PGC-1a and age-matched controls, numbers of animals as in panel A. C. Weight of tumor
(grams) extracted from site of injection 2 weeks after tumor inoculation (n=5 for wild-type, n=7 for MCK-PGC-1a). D. Linear regression modeling
relationship between changes in percentage body weight and the weight of tumor of MCK-PGC-1a and age-matched tumor-bearing controls,
numbers of animals as in panel C. E. Weight of gastrocnemius and quadriceps (grams) of saline-injected and tumor-inoculated groups of MCK-PGC-1a
or age-matched wild-type mice, numbers of animals as in panel A. F. Concentrations of serum IL-6 in control and tumor-bearing wild-type and MCK-
PGC-1a mice (n=5/group). Error bars are mean 6 SEM.
Muscle PGC-1a and Cancer Cachexia
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assay. Equal amount of protein were loaded onto a 4–20% SDS- Download full-text
polyacrylamide gradient gel (BioRad). The gel was blotted on
Polyvinylidene Fluoride (PVDF) membrane (BioRad).
Membranes were blocked in Odyssey blocking solution (LI-
COR Biosciences) diluted 1:1 with PBS for 1 hour at room
temperature. Primary antibodies used were OXPHOS rodent
cocktail (Mitosciences), a-tubulin (Sigma), PGC1-a (Santa Cruz),
SDHA (Mitosciences), b-actin (Sigma), cytochrome c (Mitos-
ciences), porin (Mitosciences), and UQCRC1 (Mitosciences).
Primary antibody was incubated overnight at 4uC. Secondary
antibodies used were either infrared conjugated antibodies anti-
rabbit-700 or anti-mouse-800 (Rockland) at manufacturer-sug-
gested concentrations. Secondary antibodies were incubated for
1 hour at room temperature. Blots with infrared secondary
antibodies were visualized with Odyssey Infrared Imaging System
(LI-COR Biosciences). Optical density measurements were taken
using the Gel-Pro Analyzer software.
Endurance was evaluated using a six lane treadmill with
motivation grid designed for rodents (Columbus Instruments).
Animals were given one training day to adapt to the equipment
and motivation grid. On the test day, mice were required to run at
a speed of 8 m/min for 5 minutes and the number of falls onto the
motivation grid was recorded for each mouse.
Serum IL-6 Quantifications
Blood was taken from the left ventricle of deeply anesthetized
mice before euthanized. Blood was allowed to clot on ice, and
serum was isolated at 1,0006 g in a bench top centrifuge
(Eppendorf 5424) for 15 minutes at 4uC. An additional centrifu-
gation step of the serum at 10,0006g for 10 minutes at 4uC was
performed for complete platelet removal. Serum was used in BD
cytometric bead array mouse inflammation cytokine kit according
to the manufacturer’s instructions (BD Biosciences). Samples were
analyzed on a BD LSRFortessa cell analyzer (BD Biosciences).
All results were expressed as means 6 STDEV. Significance of
the differences was evaluated by 2-way ANOVA followed by
Bonferroni post-test for experiments with more than 2 groups or
by unpaired Student t-test between 2 groups. Differences were
considered significant when p,0.05 (*), 0.001,p,0.01 (**),
We thank Dr. Bruce M. Spiegelman for providing the transgenic MCK-
PGC-1a mice used in this study.
Conceived and designed the experiments: XW AMP TAZ CTM.
Performed the experiments: XW AMP. Analyzed the data: XW AMP
TAZ CTM. Wrote the paper: XW AMP TAZ CTM.
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