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Exercise Training and Work Task Induced Metabolic and
Stress-Related mRNA and Protein Responses in Myalgic Muscles
Gisela Sjøgaard,
1
Mette K. Zebis,
1
Kristian Kiilerich,
2
Bengt Saltin,
3
and Henriette Pilegaard
2
∼
1. Introduction
Hindawi Publishing Corporation
BioMed Research International
Volume 2013, Article ID 984523, 12 pages
http://dx.doi.org/10.1155/2013/984523
2. Subjects and Methods
2.1. Study Design.
± 44 ± 9.8
1.65 ± 0.061 72 ± 15.0
44± 9.1 1.68±0.055 70±10.6
2.2. Repetitive and Stressful Work Day.
∼
∼
per se
2.3. Interventions.
∼%
∼%
%
2
%
2
%
2.4. Biopsies.
∼
−
∘
2.5. Outcome Measures.
2.5.1. Muscle Lysate. ∼
%
%
3
4
∘
∘
2.5.2. SDS-PAGE and Western Blotting.
⋅
%
4 BioMed Research International
T 1: Primer and TaqMan probe sequences for real-time PCR.
Gene Forward primer Reverse primer Taqman probe
GLUT4 5
�
CCTGCCAGAAAGAGTCTGAAGC 3
�
5
�
ATCCTTCAGCTCAGCCAGCA 3
�
5
�
CAGAAACATCGGCCCAGCCTGTCA 3
�
GS 5
�
GCTCAGAGCAAGGCTCGAAT 3
�
5
�
CGGCCGGCGATAAAGAA 3
�
5
�
TTATGGGCATCTGGACTTCAACTTGGACA 3
�
HIF-15
�
GCCCCAGATTCAGGATCAGA 3
�
5
�
TGGGACTATTAGGCTCAGGTGAAC 3
�
5
�
ACCTAGTCCTTCCGATGGAAGCACTAGACAA 3
�
HO-1 5
�
GCCAGCAACAAAGTGCAAGAT 3
�
5
�
AGTGTAAGGACCCATCGGAGAA 3
�
5
�
AGAGGGAAGCCCCCACTCAACACC 3
�
Hsc70 5
�
GCAGACACAGACCTTCACTACCTATT 3
�
5
�
GGCACGCTCGCCTTCAT 3
�
5
�
AACCTGAATAAGCACACCAGGCTGGTTG 3
�
HSP72 5
�
GCGTGATGACTGCCCTGAT 3
�
5
�
CGCCCTCGTACACCTGGAT 3
�
5
�
TCCCCACCAAGCAGACGCAGATCT 3
�
IGF-IEa 5
�
CAGCGCCACACCGACAT 3
�
5
�
TTGTTTCCTGCACTCCCTCTACT 3
�
5
�
AAGACCCAGAAGGAAGTACATTTGAAGAACGC 3
�
IL-6 5
�
TCTCAGCCCTGAGAAAGGAGACA 3
�
5
�
CATCTTTGGAAGGTTCAGGTTGT 3
�
5
�
ACATGTGTGAAAGCAGCAAAGAGGCACTG 3
�
LDH-A 5
�
ACAACAGGATTCTAGGTGGAGGTT 3
�
5
�
GAGTTGATGTTTTTCCCAGTCCAT 3
�
5
�
TGCATGTTGTCCTTTTTATCTGATCTGTGATTAAAGC 3
�
LDH-B 5
�
GCTAAAGGATGATGAGGTTGCTC 3
�
5
�
TCACTAGTCACAGGTCTTTTAGGTCC 3
�
5
�
CTCAAGAAAAGTGCAGATACCCTGTGGGAC 3
�
Myostatin 5
�
ACCAGGAGAAGATGGGCTGAA 3
�
5
�
GTCAAGACCAAAATCCCTTCTGGA 3
�
5
�
CCGTTTTTAGAGGTCAAGGTAACAGACACACCA 3
�
PGC-15
�
CAAGCCAAACCAACAACTTTATCTCT 3
�
5
�
CACACTTAAGGTGCGTTCAATAGTC 3
�
5
�
AGTCACCAAATGACCCCAAGGGTTCC 3
�
TNF5
�
TCTGGCCCAGGCAGTCAGAT 3
�
5
�
AGCTGCCCCTCAGCTTGA 3
�
5
�
CAAGCCTGTAGCCCATGTTGTAGCAAACC 3
�
GS: glycogen synthase; HIF-1: hypoxia inducible factor-1; HO-1: heme oxygenase-1; HSP72 and HSc70: heat shock protein 70 and 72; IGF-1Ea: insulin-like growth factor-1Ea; IL-6: interleukin-6; LDH: lactate
dehydrogenase; PGC-1: peroxisome proliferator activated receptor gamma coactivator 1; TNF-: tumor necrosis factor alpha.
n n
0,118 0,094
0,886 0,801
0,132 0,111
0,127 0,086
0,230 0,263
0,239 0,175
0,182 0,207
0,016 0,010
0,152 0,148
0,150 0,140
0,269 0,406
0,122 0,166
0,105 0,124
2.5.3. RNA Isolation and Reverse Transcription.
2.5.4. PCR.
2.5.5. Determination of Single-Stranded cDNA Content.
2.6. Statistical Analysis.
6 BioMed Research International
T 3: Content of key metabolic proteins in for MYA and CON at baseline. isthenumberofsubjectsforwhomthekeyproteinwas
analyzed. Median, minimum, and maximum values are presented. No signi�cant differences were found, except for PDH-E protein being
signi�cantly lower in MYA than in CON in one-sided test ( ).
Proteins MYA, nMedian Min Max CON, nMediean Min Max
cyt c 19 0,142 0,069 0,212 16 0,171 0,089 0,282
Glut 4 19 0,437 0,280 0,984 16 0,393 0,280 0,774
GS 19 0,559 0,263 0,769 16 0,501 0,351 0,760
HKII 19 0,224 0,067 0,375 16 0,185 0,049 0,452
PDH-E119 0,114 0,066 0,229 16 0,139 0,088 0,203
T 4: mRNA content before and aer 7hrs standardized repeti-
tive stressful work.
Content of mRNA PRE POST
HIF-1(n= 7)
#
0.245
(0.075–0.4859)
0.419
(0.074–3.334)
HO-1 (n= 8)
0.180
(0.062–0.313)
2.069
(0.103–6.106)
HSP72 (n= 7)
#
0.347
(0.239–0.614)
2.465
(0.244–3.334)
IGF-1Ea (n= 6)
0.256
(0.164–0.511)
0.130
(0.108–0.208)
IL-6 (n= 7)
#
0.017
(0.005–0.072)
1.244
(0.004–4.347)
Myostatin (n= 8)
0.692
(0.049–1.218)
0.073
(0.011–0.610)
PGC-1(n= 6)
0.377
(0.092–1.082)
0.073
(0.038–0.323)
Values are presented as median (range).
#
Denotes 0.05 0.10 and
denotes 0.05 in paired test. HIF-1: hypoxia inducible factor-1;
HO-1: heme oxygenase-1; HSP72: heat shock protein 72; IGF-1Ea: insulin-
like growth factor-1Ea; IL-6: interleukin-6; PGC-1: peroxisome proliferator
activated receptor gamma coactivator 1.
were deemed signi�cant if a two-sided -value was less
than 0.10. e speci�c one-sided tests were (1) the protein
contents of PDH-E1and Cyt-c are lower in MYA compared
with CON; (2) basal mRNA levels of heat shock proteins
HSc70 and HSP72 increase with repetitive stressful work but
decrease with prolonged duration of training exercises in
MYA.
3. Results
3.1. Baseline. e PDH-E1protein level was signi�cantly
lower in the MYA group than in the CON group at baseline
( in one-sided test). No other signi�cant differences
were observed between MYA and CON, and this was true for
both the mRNA data and the protein data (Tables 2 and 3).
Representative western blot images are presented in Figure 3.
3.2. Standardized Repetitive and Stressful Work. e stan-
dardized protocol including repetitive work, stress tests, and
computer work induced signi�cant changes in the mRNA
content of different genes. Signi�cant increases were found
for mRNA content of the heat shock proteins: HO-1
( ) and HSP72 ( , one-sided), while IL-
6 and HIF-1showedatrendtoincrease(Table 4). In
contrast, PGC-1, IGF-1Ea, and myostatin mRNA contents
were signi�cantly lowered ( ) several fold aer the
standardized work day (Table 4).
3.3. Intervention. In the MYA group, the tenderness score
was 12.5 (4–28) out of the possible maximum score of 28
at baseline and which decreased signi�cantly in response to
10 wks intervention in SST and GFT by 11.0 (6–20) and 6.3
(4–13), respectively. But in REF the decrease of 3.2 (3–7)
was not signi�cant.
Biopsy data showed the basal level of HSP72 mRNA
content to decrease signi�cantly aer the SST and GFT
interventions, whereas HSc70 mRNA only decreased aer
the SST intervention period ( , one-sided) (Figures
1(a) and 1(b)). Further, GS and PDH-E1protein content
increased by 22and 21, respectively, ( ) only aer
the SST intervention (Figures 2(a) and 2(b)). Cyt c, HKII,
and GLUT4 protein content did not change in either of the
intervention groups. Representative western blot images are
shown in Figure 4.
4. Discussion
Repetitive stressful work tasks increased levels of mRNA
content for heat shock proteins and decreased mRNA levels
of growth regulating proteins and proteins related to oxida-
tive metabolism. In contrast, prolonged exercise training
decreased the basal level for heat shock protein. Speci�c
strength training but not general endurance training increas-
ed the protein content of key proteins in carbohydrate
storage and oxidation in myalgic skeletal muscle. Interest-
ingly, impairment in the capacity for carbohydrate oxidation
wasseenatbaselineinMYAcomparedwithCONbutno
differences in the basal level of mRNA contents were found.
4.1. MYA versus CON at Baseline. A novel �nding of the
present study was an observed lower protein level of PDH-
E1in females with trapezius myalgia than healthy controls
(Figure 1). PDH-E1is responsible for catalyzing the decar-
boxylation of pyruvate, and regulation of this PDH com-
ponent of the enzyme complex is thought to be important
for the mitochondrial choice of substrate at rest and during
exercise [31]. Reduced capacity of the pyruvate dehydro-
genase complex could facilitate movement of glycolytically
derived pyruvate toward lactate output rather than oxidation.
BioMed Research International 7
HSc70 mRNA
0
0.2
0.4
0.6
0.8
1
CON MYA REF SST GFT
= 0.066
♦
♦
(a)
HSP72 mRNA
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
CON MYA REF SST GFT
= 0.08
= 0.041
(b)
F 1: Effect of training on mRNA content. e mRNA content
of HSc70 (a) and HSP72 (b) decreased in the strength training group
(SST, ) during the 10 wks intervention period ( ).
Similarly, a decrease in HSP72 mRNA content was observed with the
GFT ( ) intervention ( ) (B). No changes were observed
for REF ((a): ; (b): ). e �gure illustrates the 5th and
95th percentile, outliers (black dot), the group median (solid line),
and group mean (dotted line).
is may underlie our �nding of higher interstitial muscle
lactate levels and impaired muscle oxygenation in MYA
compared with CON in this same experimental series during
the pegboard task as reported previously [25]. is is also
in accordance with a previous �nding, where patients with
trapezius myalgia were found to respond to repetitive low-
forcearmworkwithalargerinterstitialmusclelactate
increase than seen in healthy controls [32]. In concert, biopsy
studies on work-related trapezius myalgia have demonstrated
a reduced capillarisation per �ber cross-sectional area [33]
implying an impaired oxidative capacity, while in the present
subject groups such differences were not found between MYA
and CON [34].
4.2. Standardized Repetitive and Stressful Work Performed by
MYA. Static and highly repetitive work tasks have been iden-
ti�ed as risk factors for work-related trapezius myalgia [35].
Patients with work-related trapezius myalgia oen report
that pain worsens considerably even when remarkably light
physical work of neck and shoulder muscles is performed
which was con�rmed in the present subject group [36]. A
main �nding of the present study was that among MYA
GS
0.4
0.6
0.8
1
Pre Post
= 0.046
(a)
0.06
0.08
0.1
0.12
0.14
0.16
0.18
0.2
Pre Post
= 0.028
PDH-E1
(b)
F 2: Effect of training on protein content. e protein content
of GS (a) and PDH-E1(b) increased in the strength training group
(SST, ) aer the 10 wks intervention period ( ). e
�gure illustrates the 5th and 95th percentile, the groupmedian (s olid
line), and group mean (dotted line).
the experimntal work day including repetitive and stressful
work tasks elicited marked changes in the mRNA abundance
of a subset of metabolic and stress-related genes as will be
discussed in more detail below.
4.2.1. Heat Shock Proteins. e upregulation of HSP72
mRNA content observed in the present study may confer
protection against ischemia and preserve the cellular func-
tions [37], while HSc70 mRNA content remained unchanged
which is in accordance with its constitutively nature. e
10-fold increase in HO-1 mRNA content indicates that the
trapezius muscle may indeed be exposed to oxidative stress
during repetitive work tasks which is in accordance with
the increased interstitial lactate level reported in this subject
group during the repetitive work [25]. A previous study
showed that HO-1 mRNA increased with repetitive muscle
contractions, and increases in HO-1 protein content in
response to metabolic stress may be important in producing
antioxidants [38]. In combination the observed increase in
Glut 4
GS
15
46
89
102
40
Cyt C
HK-II
PDH-E1
C M CMkDa
Glut 4
GS
15
46
89
102
40
Cyt C
HK-II
PDH-E1
kDa
GFT SST
Pre Post Pre Post
4.2.2. Cytokines.
per se
4.2.3. Growth Regulating Proteins.
∼%
4.2.4. Metabolic Regulators.
∼
4.3. Training Intervention for MYA.
∼%
>
4.3.1. mRNA Content.
4.3.2. Protein Content.
4.4. Limitations.
10 BioMed Research International
5. Conclusion
In conclusion, no differences were found between MYA and
CON in the content of the basal level of a broad range of
mRNA’s. However, standardized repetitive, stressful work
had great impact on the mRNA expression in MYA, indi-
cating that daily repetitive low-intensity work tasks induce
metabolic stress upon the trapezius muscle. Furthermore,
a decrease in heat shock protein mRNA content was seen
not only aer strength training but also aer general �tness
training which indicates that the cellular homeostasis of
the trapezius muscle was improved in females with work-
related trapezius myalgia, regardless of training intervention
type. However, protein content of PDH-E1was lower in
MYA than CON and only speci�c strength training increased
the capacity of the oxidative and nonoxidative carbohydrate
metabolism in the trapezius muscle of MYA as seen by an
increased protein level of both GS and PDH-E1.
Acknowledgments
e authors would like to thank Rasmus S. Biensø for excel-
lent technical assistance. is study was supported by grants
from the Danish Medical Research Council 22-03-0264 and
271-08-0469, and the Danish Rheumatism Association 233-
1149-02.02.04.
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