1 Noll Physiological Research Center, Pennsylvania State University, University Park, Pennsylvania 16802-6900; and 2 Department of Clinical Neuroscience, Karolinska Hospital, SE-17176 Stockholm, Sweden
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ABSTRACT |
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The effects of aging on
the mechanical properties of myosin were measured in 87 fibers from
muscles of humans (n = 40), rats (n = 21), and mice (n = 26) using a single fiber in vitro
motility assay. Irrespective of species, an 18-25% aging-related
slowing in the speed of actin filaments was observed from 62 single
fibers expressing the slow (type I) -myosin heavy chain isoform. The mechanisms underlying the aging-related slowing of motility speed remain unknown, but it is suggested that posttranslational
modifications of myosin by oxidative stress, glycation, or nitration
play an important role. The aging-related slowing in the speed of actin filaments propelled by the type I myosin was confirmed in three mammalian species with an ~3,400-fold difference in body size. Motility speed from human myosin was 3-fold slower than from myosin of
the ~3,400-fold smaller mouse and approximately twofold slower when
compared with the ~130-fold smaller rat, irrespective of age. A
strong correlation was observed between the log values of actin sliding
speed and body mass, suggesting that the effects of scaling is, at
least in part, due to altered functional properties of the motor
protein itself.
in vitro motility; myosin heavy chain; scaling; single muscle fiber
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INTRODUCTION |
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THE IMPAIRMENTS OF MOTOR FUNCTIONS associated with the specific aging-related changes in skeletal muscle quantity and quality, termed sarcopenia, have a significant impact on the quality of life in the increasing number of elderly citizens. The greater risk for falls and fall-related injuries in old age is coupled to an impaired ability to recover from an impending fall due to loss of muscle force and contractile speed (33). Our comprehension of the mechanisms underlying the aging-related slowing of contractile speed is, however, incomplete, and there is, accordingly, a compelling need for focused research aimed at improving our basic understanding of the molecular mechanisms underlying the aging-related motor handicap.
In skeletal muscle, the molecular motor myosin generates force and
movement, and there is a close relationship between maximum velocity of
unloaded shortening (V0), myosin ATPase
activity, and myosin heavy chain (MHC) isoform composition (3, 4, 20, 30). We have previously studied the effects of aging on contractile speed in skinned muscle fibers expressing different MHC
isoforms (6, 19, 21, 46). An aging-related decline in
V0 was observed in skeletal muscle cells from
both rats and humans. In rodents, the aging-related slowing was limited
to muscle cells expressing the slow (type I) -MHC isoform (6,
21, 46), a result recently confirmed by Thompson and Brown
(40). In humans, the aging-related slowing was observed in
muscle cells expressing both the types I and IIA MHC isoforms, albeit
more pronounced in type I fibers (19). Even though myosin
is the major regulator of shortening velocity, changes in other
myofibrillar proteins, such as thin filament proteins modulating
contractile speed may, at least in part, explain the aging-related
slowing observed at the single muscle fiber level. To address this
issue, we developed an in vitro motility assay in which myosin is
extracted and immobilized from a 2- to 4-mm single muscle fiber segment for studies of actomyosin interaction, without interference from cytoskeletal or regulatory proteins (15, 16). Using this
assay, we recently reported an aging-related slowing in the speed of actin filaments propelled by myosin from young and old rat muscle fibers expressing the type I MHC isoform (16). It was,
therefore, suggested that the slowing observed at the whole muscle and
single fiber levels were related, at least in part, to altered
functional/structural properties of the motor protein itself.
Studies of single fibers from muscles of small amphibians, avians, or laboratory mammals form the basis of our knowledge on the regulatory influence of myosin isoforms on contractility, and the rat is the most extensively characterized species with regard to studies on regulation of muscle contraction and myofibrillar protein isoform expression (32). Body size is known to affect speed of skeletal muscle shortening. Consequently, large mammals are characterized by lower stride frequencies and slower limb movements than small mammals, and speed of muscle contraction has been reported to scale with body size (see Refs. 13, 31, 34, and 45). Generalization of results from small mammals, such as the rat, to larger mammals, such as humans, constituting a 200-fold difference in body size may accordingly not be valid.
To improve our understanding on how the mechanical properties of myosin is affected by aging in species with different life spans and an ~3,400-fold difference in body size, we expanded the previous in vitro motility study on 4- to 8- and 20- to 24-mo-old rats (16), to analyses of myosin isolated from human, rat, and mouse muscle fibers. Specific interest is focused on the functional properties of the type I MHC isoform in very old rodents (28-30 mo) and humans (89-92 yr).
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MATERIALS AND METHODS |
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Muscle fiber preparation.
The study was carried out on young (2 mo, n = 2) and
old (28 mo, n = 2) mice of the C57Bl/6 strain, young (2 mo, n = 1), adult (12 mo, n = 1), and
old (30 mo, n = 2) Wistar rats, and young (25-42
yr, n = 3) and old (89-90 yr, n = 3) human subjects. The median life spans for the C57Bl/6 mouse, Wistar
rat, and human are 26.2 mo, 25.5 mo, and 75 yr, respectively (23,
26, 36). The survival rates for the old 28-mo-old mice,
30-mo-old rats, and 89- to 90-yr-old humans are 40%, 20%, and 15%,
respectively (23, 26, 36). The animals were kept in
conventional facilities at 20-22°C, with constant humidity and a
12-h light:12-h dark cycle, and fed standard laboratory food and tap
water ad libitum. The rodents were anaesthetized by intramuscular
injections of fentanyl-fluanisone (0.2-0.3 ml/kg) followed by
pentobarbitone (30 mg/kg) administered intraperitoneally. The skin over
the right and left hindlimb was removed, and the soleus muscles were
dissected free from surrounding tissue. The heart muscle was removed at the end of the dissection. In humans, biopsies were taken under local
anesthesia from the lateral portion of the left quadriceps (vastus
lateralis) muscle by means of the percutaneous conchotome method with
the understanding and consent of the subjects. None of the subjects had
a history of locomotor or neuromuscular disease. Small bundles of
~25-50 fibers were dissected free from the muscle and tied to a
glass microcapillary tube. The bundles were then placed in skinning
solution at 3°C for 24 h and treated with a cryoprotectant
(sucrose) for long-term storage at 80°C (for details, see Refs.
8, 18, and 20). The use of human and
animal material in this study was approved by the ethical committees at
Karolinska Hospital (Stockholm, Sweden), Pennsylvania State University,
and the University of Pennsylvania.
In vitro motility assay. The unregulated actin used throughout this study was purified from rabbit skeletal muscle essentially as described (27) and was fluorescently labeled with rhodamine-phalloidin (Molecular Probes). The single fiber in vitro motility system has been described in detail elsewhere (15, 16). In brief, a short muscle fiber segment was placed on a glass slide between two strips of grease, and a nitrocellulose-coated coverslip was placed on top, creating a flow cell of ~5 µl volume. Myosin was extracted from the fiber segment through addition of a high-salt buffer [0.5 M KCl, 25 mM HEPES (pH 7.6), 4 mM MgCl2, 4 mM EGTA, 2 mM ATP, and 1% 2-mercaptoethanol]. After a 30-min incubation on ice, a low-salt buffer [25 mM KCl, 25 mM HEPES (pH 7.6), 4 mM MgCl2, 1 mM EGTA, and 1% 2-mercaptoethanol] was applied, followed by BSA (1 mg/ml). Nonfunctional myosin molecules were blocked with fragmentized F-actin, and rhodamine-phalloidin-labeled actin filaments were subsequently infused into the flow cell, followed by motility buffer (2 mM ATP, 0.1 mg/ml glucose oxidase, 23 µg/ml catalase, 2.5 mg/ml glucose, and 0.4% methyl cellulose in low-salt buffer) to initiate movement. The pH of the buffers was adjusted with KOH, and the final ionic strength of the motility buffer was 71 mM. The flow cell was placed on the stage of an inverted epifluorescence microscope (Olympus IX 70; Olympus America) and thermostatically controlled at 25°C. Actin movements were filmed with an image-intensified SIT camera (SIT 66; DAGE-MIT) and recorded on tape with a video-cassette recorder.
Motility data analysis. From each single fiber preparation, 20 actin filaments moving with constant speed in an oriented motion were selected for speed analysis. Recordings and analysis were only performed from preparations in which >90% of the filaments moved bidirectionally. A filament was tracked from the center of mass, and the speed was calculated from 20 frames at an acquisition rate of five or one frame(s) per second, depending on the fiber type, using an image-analysis package (OPTIMAS 6.0; Optimas). The average speed and SD of the 20 filaments were calculated. Since the SD in this group of filaments was small (between 10 and 15% of the mean), the average speed was taken as representative for the muscle fiber.
Electrophoretic separation of myosin heavy and light chain isoforms. The MHC composition of a muscle fiber was determined by 7% SDS-PAGE. The total acrylamide and Bis concentrations were 4% (wt/vol) in the stacking gel and 7% in the running gel, and the gel matrix included 30% glycerol. Electrophoresis was performed at 120 V for 24 h with a Tris-glycine electrode buffer (pH 8.3) at 15°C (SE 600 vertical slab gel unit; Hoefer Scientific Instruments).
For determination of the myosin light chain (MLC) composition, the acrylamide in the stacking and running gels were 3.5% (wt/vol) and 12% (wt/vol), respectively, and the gel matrix contained 10% glycerol. A constant current (16 mA/gel) was used, and the gels were run for 5 h at 15°C (20) in a Tris-glycine electrode buffer (pH 8.3). The gels were silver stained (see Refs. 10, 20, and 21) and subsequently scanned in a soft laser densitometer (Molecular Dynamics, Sunnyvale, CA) with a high spatial resolution (50-µm pixel spacing) and 4,096 optical density levels. The volume integration function (ImageQuant software version 3.3, Molecular Dynamics) was used to quantify the protein amount on the 7 and 12% gels.Statistics. Means, SD of means, and correlation coefficients (r) of linear regressions were calculated from individual values by standard procedures. A two-tailed t-test was used for comparisons of two groups, and ANOVA was used for intergroup comparisons between more than two groups. Differences were considered significant at P < 0.05.
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RESULTS |
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To test the accuracy of the motility analyses process, two
investigators independently analyzed the speeds of two sets of 10 actin
filaments from two separate sequences of the same fiber preparation.
From 18 preparations in the 0.39-5.53 µm/s motility speed range,
a good agreement (r2 = 0.996) in the speed
analyses was observed between the two investigators (Fig.
1). The result supports earlier
methodological studies (15, 16) demonstrating a high
reliability and precision of motility speed measurements in this assay.
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A total of 87 muscle fibers fulfilled the criteria for acceptance of
motility speed analyses. The primary interest was focused on
aging-related changes in the slow (type I) -MHC isoform (62 fibers).
A subsample of muscle cells expressing a combination of types I and IIA
MHC isoforms (6 fibers), a combination of IIA and IIX MHCs (4 fibers),
or the IIA (13 fibers) or IIX (2 fibers) MHC isoforms were included for
comparison (Table 1).
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Irrespective of species, a significant (P < 0.05-0.01) 18-25% aging-related slowing was observed in the
speed at which actin filaments were propelled by the type I myosin
isoform (Fig. 2). Because there was no
difference in motility speeds between the 2- and 12-mo-old rats, the
animals were pooled as young. The expression of MLC isoforms,
determined by 12% SDS-PAGE, was not affected by age in muscle fibers
expressing the type I myosin isoform. All rat and mouse type I muscle
fibers expressed the slow isoforms of MLC 1 and MLC 2, and the fast
essential MLC isoform (MLC 3) was not detected in any fibers. In
humans, all type I muscle fibers contained both the slow and the fast
isoforms of MLC 2, and a small amount of MLC 3 was present in all
muscle cells, except for two old fibers. However, the relationship
between regulatory (MLC 2) and essential (MLC 1 + MLC 3) light chains,
calculated as the MLC 3/MLC 2 ratio (see Ref. 19), did not
differ between young (0.14 ± 0.06) and old (0.11 ± 0.10)
type I muscle fibers. In 12 human fibers expressing the type IIA MHC
isoform, no significant aging-related difference was observed in the
speed of actin filaments. The number of single fiber in vitro motility
preparations expressing the I/IIA, IIAX, and IIX MHC isoforms was too
low to allow a statistical comparison between young and old (Table 1).
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The influence of scaling on the mechanical properties of the type I MHC
isoform was assessed in 62 human, rat, and mouse muscle fibers. The
speed of myosin-driven actin filaments varied significantly (P < 0.001) with body weight for both young and old
myosin. In young individuals, the motility speed from human single
muscle fiber myosin (0.68 ± 0.15 µm/s) was threefold slower
than from myosin of the ~3,400-fold smaller mouse (1.97 ± 0.29 µm/s) and approximately twofold slower compared with the ~130-fold
smaller rat (1.34 ± 0.41 µm/s). Motility speed and body weight
was inversely correlated (r2 = 0.998) when
displayed in a double log plot (Fig. 3).
The slope of the regression line, i.e., the scaling effect, was
0.128. Furthermore, motility data yielded from the aged myosin showed an almost identical relationship with body weight (
0.132) as for
myosin extract from muscle fibers of young rodents and humans (see Fig.
3).
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DISCUSSION |
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The major findings from this study are as follows. 1)
The aging-related slowing previously observed in single muscle cells expressing the slow (type I) -MHC isoform was paralleled by a similar slowing at the molecular level, indicating specific kinetic changes in the molecular motor myosin with aging; 2) the
aging-associated decline in myosin function was of similar magnitude in
all species studied, i.e., in human, rat, and mouse; and 3)
the motility speed from type I myosin displayed a linear and inverse
correlation with body mass in a log-log plot, along with a scaling
effect of
0.13 for both young and old myosin.
Effects of aging. One of the major observations from this study was the aging related, interspecies slowing of the speed of myosin-driven actin filaments assayed from single muscle cells expressing the type I MHC isoform. The results indicate a common, aging-related effect on the enzymatic/functional properties of myosin. The 18-25% decrease in motility speed was less dramatic, however, compared with the ~50% decline in V0 from previous studies on single membrane permeabilized type I fibers from humans and rats (6, 19, 21, 40, 46). This difference may be reflected by paralleled aging-related changes in structural and thin filament proteins modulating shortening velocity at the cellular level. This is supported by the observation of posttranslational alterations in myofibrillar proteins with increasing age (39). Another explanation could originate from methodological differences, but this appears to be less likely because we have shown, in both rat and human single fiber preparations, that the speed of actin filaments in the in vitro motility assay is a good molecular analog to V0 (15, 18).
In our previous study on in vitro myosin extracted from muscle fibers of 4- to 8-mo-old and 20- to 24-mo-old rats (16), motility speed from aged myosin was reduced by 11%, which is less than half of the 25% in slowing obtained from the 30-mo-old rats in the current study. The accelerated decline in myosin function at an advanced age gains support from a study by Thompson and Brown (40) in which unloaded shortening velocity in rat type I fibers remained unchanged until the age of 24 mo, but then decreased dramatically by ~50% at 30 mo of age.Posttranslational modification of myosin. The production of reactive oxygen species has been recognized as a source of increased, aging-related posttranslational change in proteins, with effects on enzymatic activity, stability, and digestibility (see Ref. 24). One such change in skeletal muscle is nitration of tyrosine in sarcoplasmic reticulum (SR) Ca2+-ATPase, which preferentially affects slow-twitch muscle (25, 42, 43). In accordance with the aging-related dysfunction of the slow-twitch muscle SR, the aging-related slowing of contractile speed at the molecular and cellular levels indicates that rodent slow-twitch muscles and muscle fibers are preferentially targeted by aging-associated posttranslational modifications (6, 16, 21, 40, 46). In humans, on the other hand, we have observed a parallel slowing of contractile speed at the cellular level in both types I and IIA fibers (19), although the reduction in V0 was less pronounced in fast (~30%) than in slow muscle fibers (~46%).
Nonenzymatic glycosylation, or glycation, is another posttranslational modification of proteins, which plays an important role in the aging process. Proteins with a long turnover rate, such as myosin, are more susceptible to the slow glycation process, and glycation of myosin has been reported to increase in old rats (38). This observation is in agreement with the longer turnover rate of myosin in old age, secondary to a decrease in the rate of synthesis and degradation (2). The catalytic ATPase site of myosin is rich in lysine, an amino acid whoseEffects of scaling on young and old myosin.
In 1950, A. V. Hill observed that animals of similar body shape
and gait characteristics were able to move at similar velocities, independent of body size (13). For a smaller animal to
move at a similar speed as that for a larger animal, Hill suggested a
body size-dependent and inversely correlated increase in skeletal muscle shortening velocity. Later, cell physiological experiments on
V0 in single muscle fibers (31, 34,
45) have proven this hypothesis to be accurate by demonstrating
the presence of scaling at a cellular level. The strong linear
correlation (r2 = 0.998) in the present
study between motility speed of type I myosin from species with a
~3,400-fold range in body mass further suggests that the body
size-related changes in mammalian muscle performance is, at least in
part, attained by corresponding alterations in the functional
properties of the myosin molecule. Furthermore, the identical scaling
effect of 0.13 from young and old myosin indicates that the
aging-related changes in the functional properties of type I myosin are
not species specific.
A molecular base for myosin function diversity. Changes in the MLC isoform composition is an unlikely explanation for the species-related difference underlying the scaling effect, because the observed 1.5-fold difference (P < 0.01) in motility speed between rat and mouse myosin in the present study was accompanied by an identical MLC isoform composition. More likely, the explanation is to be found in the function of the actin binding and catalytic sites located in the MHC head domain. On the basis of available data, the homology in amino acid sequence between identical MHC isoforms in human, rat, and mouse is 90-98%, with the least conserved amino acids found in two loop structures located in the myosin head subunit (44). These loops, one positioned close to the ATPase catalytic site (loop 1) and the other in the actin-binding domain (loop 2), have attracted specific attention due to their potential role in regulation of muscle contraction.
Chimerical engineered studies using loop 1 fragments of various types of myosin tested in an in vitro motility assay showed that alterations in the loop 1 sequence had an impact on ADP release from myosin, and as a consequence, on actin filament motility speed (35, 37). Uyeda and coworkers (41) used a similar technique to show that changes in the loop 2 sequence did not affect motility speed, but was well correlated with an alteration in actin-activated ATPase activity. These observations, that loop 1 is a major determinant of motility speed and that loop 2 controls the ATPase activity through its interaction with actin, indicates that the noted differences in actomyosin velocity in the present study could be related to species-specific variations in loop 1 sequence. Recent studies, however, have indicated a less clear correlation between loop sequences and actomyosin kinetics. Using chimeric constructs of myosin from 10°C- and 30°C-acclimated carp, Hirayama et al. (14) showed that the previously reported difference in actin filament motility speed between the two groups of myosin was not due to differences in the loop 1 sequence. Furthermore, a study on four myosin isoforms from frog skeletal muscle failed to report a relationship between the wide range in functional characteristics of the different myosin isoforms and the overall structure of loops 1 and 2 (22). Given this, it remains to be determined through combined amino acid sequencing and kinetic/function analyses, to what extent the differences in function of skeletal muscle type I myosin from species with various body mass are due to divergence in the MHC loops, or to changes in other parts of the myosin molecule. ![]() |
ACKNOWLEDGEMENTS |
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We are grateful to Parinaz Pircher for performing the SDS-PAGE and to Dr. E. Barton-Davis for the mouse muscle samples.
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FOOTNOTES |
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This study was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR-45627-01 and grants from the Muscular Dystrophy Association, Pennsylvania State University, the European Commission, and the Swedish Medical Research Council.
Address for reprint requests and other correspondence: L. Larsson, Noll Physiological Research Center, Pennsylvania State Univ., University Park, PA 16802-6900 (E-mail: lgl5{at}psu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8 September 2000; accepted in final form 20 October 2000.
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