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in frail elderly humans
Departments of Medicine and Cell Biology and Physiology, Claude D. Pepper Older Americans Independence Center, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA
2Correspondence: Washington University School of Medicine, Box 8046, 660 S. Euclid Ave., St. Louis, MO 63110, USA. E-mail semenkov{at}im.wustl.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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)
contributes to this process, we studied the effects of aging and
resistance exercise on TNF- expression in human muscle. Using
in situ hybridization, TNF- message was localized to
myocytes in sections of skeletal muscle from elderly humans. Both
TNF- mRNA and protein levels were elevated in skeletal muscle from
frail elderly (81±1 year) as compared to healthy young (23±1 year)
men and women. To determine whether resistance exercise affects TNF-
expression, frail elderly men and women were randomly assigned to a
training group or to a nonexercising control group. Muscle biopsies
were performed before and after 3 months. Muscle TNF- mRNA and
protein levels decreased in the exercise group but did not change in
the control group. Muscle protein synthesis rate in the exercise group
was inversely related to levels of TNF- protein. These data suggest
that TNF- contributes to age-associated muscle wasting and that
resistance exercise may attenuate this process by suppressing skeletal
muscle TNF- expression.—Greiwe, J. S., Cheng, B., Rubin,
D. C., Yarasheski, K. E., Semenkovich, C. F. Resistance
exercise decreases skeletal muscle tumor necrosis factor in frail
elderly humans.
Key Words: cytokines • sarcopenia • aging • lipoprotein lipase
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(TNF-),
originally part of a group of peptides named cachectin because of their
catabolic effect (1)
, is thought to play a role in the
skeletal muscle wasting that occurs with chronic infections, rheumatoid
arthritis, cancer, and other chronic diseases (2)
. In
experimental animals, disease processes such as sepsis (3)
and cancer (4)
, which raise TNF- concentrations, cause
loss of muscle mass. Infusion of TNF- decreases muscle protein
(5)
. In cultured human myoblasts, TNF- inhibits the
increase in protein synthesis rate mediated by growth factors
(6)
. In vivo, TNF- suppresses protein
synthesis rate in dogs (7)
and induces skeletal muscle
protein breakdown in rats (8)
.
Sarcopenia, the loss of skeletal muscle mass and contractile function,
is a consequence of aging that causes considerable morbidity
(9)
. Since skeletal muscle is the primary site for glucose
(10)
and triglyceride (11)
disposal and the
predominant determinant of resting metabolic rate (12)
,
age-associated muscle loss may also contribute to peripheral insulin
resistance, dyslipidemia, and increased adiposity. There is no simple
mechanism to explain age-associated muscle loss. Skeletal muscle
mitochondrial and contractile protein synthetic rates decline with age
(13
, 14)
, accounting for some of the muscle loss and
decreased functional capacity. Plasma levels of TNF- and other
proinflammatory cytokines (such as interleukin 6) and markers of
inflammation (such as C-reactive protein) increase with advancing age
(15
16
17
18
19)
. It is not clear whether the increase in TNF-
is mediated by aging per se or by chronic disease associated
with aging. Regardless, an increase in TNF-, especially if it were
to occur in skeletal muscle, could play a role in the progressive
muscle loss of advancing age.
TNF- mRNA and protein have been detected in biopsy samples from
human skeletal muscle (20)
, but the effects of age and
exercise on skeletal muscle TNF- expression are unknown. In this
paper, we test the hypothesis that TNF- produced by skeletal muscle
contributes to muscle loss with age. We compared skeletal muscle
TNF- expression in young and frail elderly subjects, and determined
the effects of resistance training on skeletal muscle TNF-
expression in the frail elderly. Resistance training increases mixed
muscle protein synthesis (21)
but the mechanisms are
unknown. Since TNF- has inhibitory effects on protein synthesis,
protein synthesis rate was also determined before and after exercise.
TNF- was originally purified (1)
on the basis of its
capacity to suppress expression of the enzyme lipoprotein lipase (LPL),
suggesting that skeletal muscle TNF- would be inversely related to
LPL. Therefore, LPL content was also determined in muscle before and
after exercise.
In situ hybridization data show that myocytes (as opposed to
other cell types in biopsy samples) are a source of TNF- in frail
elderly muscle. The results also show that skeletal muscle TNF-
expression increases by pretranslational mechanisms with age and that
expression is decreased by resistance exercise in the frail elderly,
suggesting a role for this cytokine in age-associated muscle wasting.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Elderly humans (over the age of 75) underwent a screening protocol to exclude the presence of underlying confounding diseases including cardiovascular (such as angina or congestive heart failure), metabolic (such as diabetes), neoplastic, and neuromuscular (such as Parkinsonism) disorders. The screening protocol included a complete medical history prompted by standardized questions using common terms instead of medical jargon. Subjects were specifically queried regarding arthritis, chronic infection (such as tuberculosis or a history of endocarditis), cancer (of numerous sites), allergies, autoimmune disorders, myocardial infarction, angina, heart murmurs, congestive heart failure, pacemakers, hypertension, hyperlipidemia, diabetes, chronic lung diseases, claudication, liver disease, clotting disorders, stroke, muscle weakness, dizziness or fainting, mental health problems, difficulty with memory, and orthopedic problems. Each subject underwent a complete physical examination and a laboratory evaluation, including chest radiography, mammography and pap smear testing in women, as well as determination of serum chemistries, complete blood count, serum lipids and lipoproteins, and urinalysis. In addition to being excluded for the presence of confounding diseases, volunteers were excluded if they were taking medications known to affect muscle function such as ß-adrenergic blocking agents, ß-agonists, Ca2+ channel blockers, and corticosteroids.
Body composition was assessed in every subject using whole-body
dual-energy X-ray absorptiometry as described previously
(22)
. For elderly participants in the exercise training
study, muscle mass was determined using 24 h urinary creatinine
excretion data. Results from three collections were averaged and muscle
mass was calculated by assuming that 1 g creatinine excreted/day
reflects 20 kg muscle (21)
.
Elderly subjects were objectively classified as frail on the basis of
physical performance tests developed by Reuben and Siu
(23)
and Guralnik et al. (24)
. These tests
have been shown to correlate well with degree of disability, loss of
independence, and early mortality (24
, 25)
. They include
walking speed, stair climbing speed, lower back range of motion,
balance, and upper body strength. In addition, the classification of
physical frailty was subjectively confirmed in each subject by
assessing self-reported degrees of difficulty with activities of daily
living.
Comparisons between young and frail elderly subjects
All subjects limited activity to that required for daily living
for 3 days before the biopsies. Skeletal muscle tissue was obtained
from the vastus lateralis muscle under sterile conditions after an
overnight fast. Samples were isolated from 12 consecutive young
subjects and 12 consecutive frail elderly subjects for subsequent
determination of TNF- protein levels (see below). For every third
subject in each age group, additional tissue was obtained for
subsequent analysis of TNF- mRNA by in situ hybridization
(see below).
Exercise training program
Eight frail elderly subjects underwent skeletal muscle biopsies
before and after an exercise program that has been described previously
(21)
. For 3 months prior to beginning the resistance
exercise training program, subjects followed a supervised pretraining
program 3 days/wk. The program was designed to increase flexibility and
joint range of motion and included light stretching exercises. This
pretraining program was followed by a supervised progressive resistance
exercise training program 3 days/wk for 3 months.
The training program consisted of a 5 min warm-up of stretching, light calisthenics, and walking, followed by 50–90 min of supervised resistance exercise. Exercises were initially performed with resistance machines. Later, abdominal exercises and free weight squats were incorporated. Subjects started doing 1–2 sets of 6–8 repetitions at 65–75% of the initial one-repetition maximum and progressed to 3 sets of 8–12 repetitions at 85–100% of the one-repetition maximum.
Five frail elderly subjects served as nonexercising controls. These individuals completed the 3 month pretraining program, then continued the light stretching program for an additional 3 months. They were seen at regular intervals to provide social interaction with the staff similar to that experienced by the participants in the resistance exercise training program.
Muscle assays
Muscle samples were analyzed for TNF- by enzyme-linked
immunosorbent assay (ELISA) using an anti-human TNF- monoclonal
antibody and reagents provided in a kit from Biosource International
(Camarillo, Calif.). All assays were performed in duplicate. Each
analysis used protein concentrations within the linear response range
for this assay as determined in preliminary experiments using human
muscle tissue. Samples from the same subject obtained before and after
the 3 month period were always analyzed in the same assay. The
intra-assay coefficient of variance was 2.6%.
Muscle samples from the training study were also analyzed for LPL
protein content by quantitative Western blotting (26
, 27)
.
The primary antibody was detected using horseradish
peroxidase-conjugated donkey anti-rabbit IgG and signal was generated
using enhanced chemiluminescence (Amersham, Buckinghamshire, England).
Films were scanned with an imaging densitometer (Bio-Rad GS-670,
Hercules, Calif.). As for TNF-, ‘before’ and ‘after’ training
samples from the same subject were analyzed in the same assay. The
intra-assay coefficient of variance was 6.7%.
For subjects in the training study, the rate of mixed muscle protein
synthesis was determined before and after exercise using stable isotope
techniques as described (21)
. Participants ate a
standardized meat-free diet for 3 days before the protein metabolism
studies. Whole body proteolysis (measured as the rate of appearance of
leucine) and myofibrillar proteolysis (measured as the ratio of
3-methyl histidine to creatinine) was also determined in elderly
subjects before and after the exercise program.
In situ hybridization
Muscle tissue was fixed in 4% paraformaldehyde (w/v) in
phosphate-buffered saline (PBS) for 16 h at room temperature,
washed, dehydrated through an ascending ethanol series, and embedded in
paraffin wax. Sections were then cut at 7 µM and mounted to
microscope slides (Fisher Superfrost Plus).
For probe generation, an 821 bp EcoRI fragment containing
the entire coding region of the human TNF- cDNA (GenBankTM X02910)
was subcloned into pBluescript SK. The antisense strand probe was
synthesized by in vitro transcription using a
SmaI-linearized template and T7 RNA polymerase. The control
sense strand probe was synthesized using EcoRV-linearized
plasmid and T3 RNA polymerase. Both probes were labeled with
digoxigenin (DIG; Boehringer Mannheim, Mannheim, Germany) according to
the manufacturer’s recommendation. Probes were reduced in length to
200 bp by limited alkaline hydrolysis (80 mM
NaHCO3, 120 mM Na2CO3, pH
10.2, 10 mM DTT) at 60°C for 20 min. They were then precipitated,
washed, and column purified.
In situ signal was optimized empirically using activated macrophages as a positive control before analyzing human muscle samples. Paraffin-embedded sections were dewaxed in fresh xylene, rehydrated through a descending ethanol series and fixed in fresh 4% paraformaldehyde. Sections were washed in PBS, digested with proteinase K (6 µg/ml in 100 mM Tris/HCl pH 8.0, 1 mM CaCl2) for 20 min at 37°C, washed several times with PBS, dehydrated through an ascending ethanol series and air dried. Between 50 and 100 µl of hybridization solution [1 µg DIG-cRNA/ml in 4x SSC, 50 (w/v) formamide, 1x Denhardt’s solution, 5% (w/v) dextran sulfate, 0.5 mg/ml salmon sperm DNA, and 0.25 mg/ml yeast tRNA] was spread over each section and covered with coverslips. After hybridization overnight at 55°C in a 5x SSC humidified chamber, slides were immersed in 5x SSC and the coverslips were allowed to slide off. Slides were washed with 0.2x SSC at 55°C for 60 min and 0.2x SSC at room temperature for 5 min.
For immunological detection of DIG-labeled hybrids, sections were washed in buffer A (100 mM Tri/HCl pH 7.5, 150 mM NaCl), then placed in blocking solution [buffer A with 0.3% (w/v) Triton X-100, 2% (w/v) sheep serum] for 30 min. Sections were incubated for 2 h at room temperature with alkaline phosphatase-conjugated antibody (1:200), washed twice for 15 min in buffer A and once in buffer B (100 mM Tris/HCl pH 9.5, 100 mM NaCl, 50 mM MgCl2) at room temperature, then placed in buffer B containing 220 µl of 75 mg/ml nitroblue tetrazolium chloride (NBT), 165 µl of 50 mg/ml 5-bromo-4-chloro-3-indoyl phosphate (X-phosphate), and 1 mM levamisole. After incubation for 16 h in the dark, slides were placed in 100 mM Tris/HCl (pH 8.0)/2 mM EDTA, washed in xylene (5 min), followed by 100% ethanol (1 min), and mounted.
Three different observers who were blinded to the source of the slides
(young vs. old or pre- vs. postexercise) independently identified lower
TNF- signals in young compared to old and post- compared to
pre-exercise muscle. Signals were quantified in two ways, both of which
gave the same results. First, a blinded observer counted hybridization
signals in multiple standardized areas at the same magnification within
numerous muscle sections for each biopsy sample. Second, an image
processing program (Image-Pro Plus) quantified signals in standardized
areas after using color thresholding to correct for different
background intensities. The intra-assay coefficient of variance for
measuring TNF- mRNA by image processing analysis of biopsies
analyzed by in situ hybridization was 11.5%.
Statistical analyses
Comparisons between variables were made using t tests
for young vs. frail elderly samples, and paired t tests for
baseline vs. post-training samples. The Pearson product moment
correlation coefficient was calculated to assess the relationship
between variables.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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in aging
and exercise, a cross-sectional study comparing young and frail elderly
and a longitudinal study in the frail elderly. Physical characteristics
of subjects in both studies are shown in Table 1
. For the cross-sectional study, maximal oxygen uptake
(P<0.0001) and lean mass (P=0.0285) were lower,
and fat mass (P=0.0152) and percent body fat
(P=0.0005) were higher in the elderly as compared to the
young, consistent with known effects of aging (28
, 29)
. In
the longitudinal study, there were no significant differences between
the exercise and control groups.
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In addition to myocytes, muscle biopsies may contain adipose tissue,
macrophages (each a source of TNF-), and other components. To
determine whether TNF- is produced by myocytes of elderly humans,
in situ hybridization experiments were performed using human
muscle biopsies. Figure 1
shows adjacent sections of skeletal muscle from an 82-year-old frail
woman. Sections were stained with hematoxylin and eosin (Fig. 1A
), hybridized with a sense strand (control) TNF- probe
(Fig. 1B
), or hybridized with an antisense TNF- probe
(Fig. 1C
). TNF- mRNA signals were detected in myocytes
using the antisense probe (Fig. 1C
) but no signals were seen
in the sections incubated with the control probe (Fig. 1B
).
|
To determine whether TNF- expression is altered with age, we
compared TNF- mRNA content in muscle from elderly and young subjects
using in situ hybridization (Fig. 2
). There were more TNF- signals in myocytes from frail elderly
subjects (Fig. 2A
) than in sections from the young (Fig. 2B
).
|
Biopsies were obtained from a total of 12 elderly subjects (including
the subjects represented in Figs. 1
and 2
) and 12 young subjects (see
Table 1
for physical characteristics). Muscle TNF- protein was
higher in the frail elderly individuals compared to young healthy
individuals (Fig. 3A
). Muscle TNF- mRNA, quantified by analysis of in
situ hybridization signals, was also higher in the elderly than
the young (Fig. 3B
), suggesting that aging is associated
with an increase in TNF- expression mediated at a pretranslational
level.
|
To determine whether exercise can affect skeletal muscle TNF-
expression in the frail elderly, subjects (different from those
referred to in Figs. 1
2
3
) were assigned to a training group or a
control group (see Table 1
for characteristics). Maximum strength
before and after 3 months of exercise in the training group is shown in
Table 2
. Strength increased for knee extension, leg press, and seated row
exercises, indicating that muscle strength improved in the muscle
studied for TNF- expression.
|
Total body, adipose, and lean mass were unaffected by 3 months of resistance exercise (not shown). Muscle mass increased slightly but not significantly (from 22.5 kg before to 23.7 kg after, P=0.06).
Muscle TNF- protein was determined in 7 of the 8 subjects in the
training group due to insufficient material in one post-training muscle
sample. Sufficient pre- and post-training tissue was available from 5
of these subjects for quantifying muscle TNF- mRNA by in
situ hybridization. Muscle TNF- protein content decreased by
34% with training (P<0.01, Fig. 4A
). TNF- mRNA decreased by 46% with training
(P<0.01, Fig. 4B
), consistent with the notion
that regulation of this cytokine in human muscle is pretranslational.
The rate of mixed muscle protein synthesis increased by 83% after
training (P<0.01, Fig. 4C
). Resistance training
did not affect whole body or myofibrillar proteolytic rate
(21)
. There was an inverse relationship between muscle
protein synthesis rate and muscle TNF- protein content (r=-0.53,
P=0.04). Skeletal muscle LPL protein content was increased
by 91% with training in these same subjects (P=0.02, Fig. 4D
). LPL content was negatively correlated with TNF-
content (r=0.63, P=0.01). In the control group, no
significant changes were detected for TNF- protein
(P=0.87), protein synthesis rate (P=0.26), or LPL
content (P=0.60).
|
Figure 5
shows representative TNF- mRNA signals using muscle sections from
the same subject before (Fig. 5A
) and after (Fig. 5B
) the 3 month training program.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this report, we provide evidence implicating TNF- in
age-associated muscle loss. TNF- message was localized to myocytes
in skeletal muscle biopsies from frail elderly humans. In a
cross-sectional comparison of young and frail elderly subjects, both
TNF- mRNA and protein levels were higher in the elderly. In a
longitudinal exercise study involving a separate group of frail
elderly subjects, baseline TNF- protein levels were essentially
identical to those measured in the cross-sectional study. After 3
months of resistance exercise, both TNF- mRNA and protein levels
decreased in concert with increases in strength and protein
synthesis.
Two observations suggest that the TNF- findings are physiologically
relevant. First, TNF- content was inversely related to the rate of
mixed muscle protein synthesis. TNF- decreases protein synthesis
(6
, 7)
. The finding that exercise coordinately decreases
skeletal muscle TNF- and increases protein synthesis suggests that
resistance training reduces the inhibitory effect of TNF- on the
production of new protein in the elderly. Second, TNF- content was
also inversely related to the content of LPL in skeletal muscle.
TNF- was originally purified on the basis of its capacity to
suppress LPL expression (1)
. LPL and TNF- expression
are inversely related in human adipose tissue (30)
. LPL is
abundantly expressed in human muscle and regulated by exercise
(26
, 27)
. In the elderly, skeletal muscle TNF- may
control several metabolic processes. Resistance training, by relieving
the inhibitory effect of TNF- on both LPL expression and protein
synthesis, may allow the synthesis of new protein and provide a
preferred source of energy (fatty acids from the action of LPL on
circulating triglycerides) to support protein synthesis.
There are several mechanisms by which TNF- might lead to muscle loss
and dysfunction. First, TNF- decreases protein synthesis in animals
and cultured cells and appears to interfere with the assembly of the
translational complex (6
, 7
, 31)
. Elevated TNF- in the
skeletal muscle of the elderly may be partly responsible for the
decrease in muscle protein synthesis that occurs in this age group
(13
, 14
, 32)
.
Second, TNF- directly induces the loss of muscle protein. In
muscle-like C2C12 cells and rat skeletal muscle, the cytokine increases
ubiquitin conjugation of proteins (33)
, targeting those
proteins for proteasome-mediated degradation. Oxidative damage leading
to muscle loss may also be involved. TNF- activates the
transcription factor NF-
B in multiple tissues (34)
,
increasing iNOS expression (35)
and leading to the
production of highly reactive free radicals such as peroxynitrite. iNOS
is implicated in the skeletal muscle weakness associated with
congestive heart failure in humans (36)
.
Third, TNF- can induce cell death. There are two ubiquitously
expressed cell surface receptors for TNF-: TNFR-I and TNFR-II.
TNFR-I contains an 80 amino acid intracellular ‘death domain’ that
interacts with a series of adapter proteins capable of triggering
either apoptosis or necrosis (34)
. Proving a role for
apoptosis in muscle dysfunction has been complicated by the presence of
apoptosis-prone nonmyocyte cells within muscle tissue. However,
apoptosis occurs in C2C12 cells (37)
, and programmed cell
death with features distinct from classic apoptosis occurs in skeletal
muscle (38
, 39)
, suggesting that TNF- produced by
myocytes could act in a paracrine fashion to induce cell death.
It is clear that TNF- may contribute to muscle loss with aging but
not so obvious why this cytokine is elevated in aging muscle. Increased
skeletal muscle TNF- may reflect a decreased ability to control
oxidative stress with age. NF-B is activated by reactive oxygen
species. Active NF-B is present in the lymphoid tissues of aging
mice and correlates with TNF- expression (40)
.
Age-related oxidative stress may have the same effects on TNF-
expression in muscle.
Our study has limitations. We did not evaluate the effects of different
exercise intensities on TNF- expression in healthy young people or
in healthy elderly people who were not frail. Future studies involving
these groups will help discriminate between physical deconditioning and
aging as contributors to elevated levels of TNF- in skeletal muscle.
In addition, the number of TNF- mRNA samples for the cross-sectional
study was small (4 per group). However, the difference was
statistically significant (P<0.01) and paralleled the
change measured for TNF- protein in skeletal muscle.
Successful aging probably cannot occur without exercise, skeletal
muscle’s raison d’etre. Our data show that TNF- is transcribed by
human myocytes, elevated in the muscle of the frail elderly, and
decreased by exercise. Exercise may thus contribute to successful aging
by altering the concentration of a potentially detrimental cytokine in
skeletal muscle. Antagonizing the effects of TNF-, either through
exercise or pharmacologic inhibitors capable of acting on a chronic
basis in muscle, might delay some of the inevitable decline in skeletal
muscle function faced by an aging population.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication June 1, 2000.
Revision received July 19, 2000.
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