1Department of Medicine, Baylor College of Medicine, Houston, Texas; and 2Wellcome Trust Center for Cell-Matrix Research, Manchester, United Kingdom
Submitted 26 August 2003 ; accepted in final form 20 August 2004
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ABSTRACT |
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muscular dystrophy; respiratory muscles; transmembrane proteins
The diaphragm muscle functions in a three-dimensional mechanical environment in which muscle contractile force can be transmitted across the lateral surfaces of the muscle cell, in the transverse plane of the cell, and at the MTJ at the ends of the muscle cell parallel to the axial direction of the cell (4). Most materials of two-dimensional sheets require a larger tensile force to hold a sample at a given stretched length when there is an additional tensile force acting perpendicular to it, in the plane of the sheet, than under uniaxial conditions, where the perpendicular direction is unrestrained (15). The diaphragm is mechanically loaded with pressure in vivo and therefore is subjected to a biaxial stress. That is, the muscle sheet of the diaphragm is subjected to stresses not only in the longitudinal direction but also in the transverse direction of the muscle fibers. Therefore, measuring the length-tension relationship in response to mechanical forces only in the direction of the diaphragm muscle fibers is not sufficient to fully characterize the mechanical properties of the diaphragm. The effect of transverse passive mechanical stress on contractile force production in the diaphragm muscles of normal mice and in those of mice lacking the key transmembrane protein integrin could be important to the understanding of the mechanisms of force transmission. We therefore wondered whether the 7-integrin plays any role in mediating the transmission of contractile force, possibly through the transverse direction of the muscle fibers of the diaphragm.
We hypothesized that the absence of 7-integrin might alter diaphragm muscle compliance and viscoelasticity as well as disrupt contractile force transmission between the longitudinal and transverse axes of the diaphragm muscle. To test this hypothesis, we used diaphragm muscles from
7-integrin-null mice and measured their passive length-tension relationships. Furthermore, we measured the stress-relaxation curves and muscle contractile properties of the diaphragm in the presence and absence of passive transverse mechanical stress. We found that the diaphragm muscles of the
7-integrin-null mutants showed 1) a significant increase in diaphragm muscle extensibility in 1-month-old mice, whereas muscle extensibility was decreased in 1-year-old mice; 2) altered muscle viscoelasticity in the transverse plane of the diaphragm in 1-month-old mice; 3) a significant increase in the force-generating capacity of the diaphragm in 1-month-old mice, whereas muscle contractility was depressed in 5-month-old mice; and 4) reduction in mechanical coupling between longitudinal and transverse properties of the diaphragm muscle sheet in 1-month-old mice.
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MATERIALS AND METHODS |
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Muscle mechanical testing. Muscle was placed into an in vitro biaxial muscle mechanical testing apparatus. This apparatus had two orthogonal axes, and each axis was driven by a micrometer. Four small, identical alligator clamps, one for each side of the muscle, were used to hold the muscle during passive lengthening and passive shortening maneuvers. The diaphragm muscle was secured by fixing one clamp to the central tendon and the opposing clamp to the tendon at the chest wall insertion, with the lower three ribs intact. The muscle was mounted so that the position of the markers on the surface of the muscle sheet during stretching and shortening could be viewed using a black-and-white closed-circuit television-type camera and recorded on a videocassette tape. The recorded videotape was digitally captured with a video capture card using a frame grabber at a sampling rate of 2 Hz. The markers on the surface of the muscle were then digitized using Image Tool version 2.0 software (http://ddsdx.uthscsa.edu/dig/itdesc.html). The precise marker position on a Cartesian coordinate axis was determined, assuming that all markers were within the same plane. Two force transducers (model FORT 100, ±50 g, differential bridge type; World Precision Instruments, Sarasota, FL) were positioned on orthogonal axes. This set of force transducers was used to measure passive muscle force, and each transducer had a resolution of 0.01% full scale, a sensitivity of 3 µV/V/g, and a hysteresis of 0.1% full scale. The measured forces were then amplified and recorded using LabVIEW software (National Instruments, Austin, TX).
Measurements of length-tension relationship of the diaphragm.
The in vitro passive mechanics experiments were conducted using 10 normal 129/SvJ mice (weight, 20.35 ± 1.91 g; age, 37 ± 5 days) and 8 7-integrin-null 129/SvJ mice (weight, 16.51 ± 1.53 g; age, 38 ± 5 days). To investigate the effect of age on the length-tension relationship of the diaphragm muscle, we used four normal 129/SvJ mice (weight, 31.5 ± 1.8 g; age, 345.3 ± 4.6 days) and four additional
7-integrin-null 129/SvJ mice (weight, 23.1 ± 2.6 g; age, 372 ± 18 days). It is important to note that at age 30 days, the homozygous mouse was healthy and appeared essentially indistinguishable from the age-matched normal mouse. By about 1 yr of age, despite normal feeding habits, the homozygous mutant mouse had lost about half of its weight and showed abnormal posture characterized by hunching (Fig. 1).
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Computation of two-dimensional muscle strains.
Planar mechanical strains on the surface of the muscle sheet were calculated according to modified methods used in a previous in vivo mechanical strain analysis of the canine diaphragm at our laboratory (7). Briefly, the region enclosed by the markers at the center of the diaphragm muscle sheet was divided into triangles, with each set of three adjacent markers defining the apices of the triangles. Any three markers defining a triangle constitute a plane. The Cartesian coordinates of these markers in the plane at the reference position were denoted xi and yi (i = 1, 2, 3). The displacements of the markers from their reference positions to their positions at a deformed state were denoted ui and vi and were assumed to be a linear function of position. The following equation:
![]() | (1) |
with the measured displacement (ui) and position coordinates (xi and yi) provided a set of three equations for three coefficients: a1, a2, and a3. Similarly, the data provided the information required to determine the values of the coefficients (a4, a5, and a6) in the following equation:
![]() | (2) |
Shear strains were small, and therefore the values of x and
y essentially reflected strains in the directions parallel to the muscle fibers and transverse to the fibers, respectively. Mechanical strains
x and
y, which occurred during either passive lengthening or passive shortening of the muscle sheets, were calculated according to the small-strain elasticity theory (16):
![]() | (3) |
![]() | (4) |
The values u and
v denote the displacement of the markers on the surface of the diaphragm in the x (parallel to muscle fibers) and y (transverse to muscle fibers) directions, respectively. The coefficients a2, a3, a5, and a6 were substituted in Equations 3 and 4 to obtain
u/
x,
v/
y. Mechanical strains were computed relative to the unstressed length of the muscle. Unstressed length was defined as the length of the muscle sheet placed into the muscle bath and attached to the clamps in the absence of applied mechanical forces. The muscle extensibility ratio (
) was computed as follows:
= 1 +
, where
is the strain either in the muscle fiber or transverse to the fiber direction.
Measurement and modeling of viscoelastic properties.
We used eight 7-integrin-null 129/SvJ mice (weight, 20.4 ± 4.48 g; age, 47.0 ± 9.74 days) and seven normal wild-type 129/SvJ mice (weight, 21.3 ± 2.78 g; age, 40.4 ± 6.21 days). After producing the length-tension curves in either the longitudinal or the transverse direction of the muscle fibers, we measured stress-relaxation curves. The viscoelastic behavior of the living tissue was sensitive to the history of mechanical deformation. Therefore, muscles were initially preconditioned with five cycles of passive lengthening of the tissue to optimal length followed by mechanical unloading of the muscle to the unstressed length. The muscle was then stretched to optimal length and maintained at that length. Muscle force was allowed to relax asymptotically until it essentially reached a plateau. Forces were measured at 10 Hz using a force transducer (model FORT 100, ±50 g; World Precision Instruments).
We used nonlinear least-squares routines created in MATLAB software to fit the stress-relaxation data to the classical standard linear solid model of viscoelasticity (16). This simple model describes the muscle as a parallel combination of a dashpot with coefficient of viscosity 1 and a linear spring with spring constant µ1, with a second linear spring with spring constant µ0 parallel to the first spring and the dashpot. The dashpot consists of a cylinder holding a piston immersed in viscous fluid, and the fit of the piston and cylinder is not tight. The piston moves slowly in response to mechanical applied load, and the higher the loading, the faster the piston moves. The dashpot relaxation time is the length of time necessary for the dashpot, or the shock-absorbing quality of the muscle, to essentially be relaxed, and at this point, the muscle is characterized as perfectly elastic. The relaxation function based on this model is of the following form:
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where F is the relaxation force, t is time, ER is the relaxed elastic modulus, is relaxation time for constant strain, and
is the relaxation time for constant stress (16). After obtaining the three constants ER,
, and
, we calculated the viscoelastic coefficients
1, µ1, and µo on the basis of the force-displacement relationships of the viscoelastic model. The
1/µ1 ratio is a relaxation time. We report the relaxed elastic modulus and the dashpot relaxation time (
1/µ1).
Measurement of isometric contractile properties of the diaphragm.
For these experiments, we used two age groups of mice. The first group consisted of 7 normal 129/SvJ mice (weight, 17.4 g; age, 30 ± 1.1 days) and 10 7-integrin-null 129/SvJ mice (weight, 14.8 g; age, 30 ± 0.8 days). The second group consisted of four normal 129/SvJ mice (weight, 30.1 ± 2.7 g; age, 151.5 ± 0.6 days) and five
7-integrin-null 129/SvJ mice (weight, 20.8 ± 2.9 g; age, 156.7 ± 0.6 days). After anesthetizing the mice, we excised the left hemidiaphragms and immediately placed them into a muscle bath with continuously circulating oxygenated 95% O2-5% CO2 Krebs-Ringer solution maintained at 25°C. Muscles were clamped on both the central tendon and the tendon at the chest wall insertion, with one clamp connected to a Cooper Instruments LQB 630 force transducer (Cooper Instruments, Warrenton, VA) and the other clamp attached to a force carriage. After positioning the muscle between two stainless steel mesh electrodes, we electrically stimulated the muscle using a Grass S88 stimulator (Grass-Telefactor, West Warwick, RI). Muscles were stimulated directly using supramaximal current intensity (measured characteristics: 550 mA at 12 V). Optimal length was determined by twitch responses (0.1-ms stimulus duration). We used stimulus durations that evoked maximal twitch response (0.5 ms at 25°C) and tetanic train durations that produced an unambiguous plateau of tetanic force (0.5-ms pulses, tetanic train duration of 500 ms, 120-s recovery). The muscle was then clamped in the transverse direction to the long axis of the muscle fibers, with one clamp attached to a World Precision Instruments FORT 250 force transducer and the other clamp connected to a force carriage. Tetanic stimulation sequences were repeated three times in the absence of any transverse passive forces and in the presence of either 1- or 2-g passive forces applied in the direction transverse to muscle fibers. Contractile force data were collected at a sample rate of 300 Hz using a data-acquisition board (model Lab-PC-1200/AI; National Instruments) and LabVIEW software version 4.0. The force data were stored in an ASCII file for postanalysis.
Muscle contractile stress was computed as the ratio of active muscle tension to the unstressed thickness (stress = tension/thickness), with stress expressed in Newtons per square centimeter, tension assessed in Newtons per centimeter (computed as measured force in grams divided by muscle clamp width), and muscle thickness measured in centimeters. To measure muscle thickness, a digital image of the surface of the muscle sheet was obtained. The muscle was then gently blotted dry and weighed, and the surface area of the muscle sheet was determined using Image Tool version 2.0. Muscle thickness was computed using the measured surface area, mass, and muscle density. MATLAB version 5.0 software (MathWorks, Natick, MA) was used to analyze maximal tetanic data.
Statistical analysis.
Differences between groups were assessed by performing ANOVA with the use of the SAS software program (27). The model used was a two-factor effects model for two groups of mice (7-integrin-null vs. normal) and two treatments (passive mechanics: uniaxial stretch parallel to the muscle fibers vs. uniaxial stretch transverse to fibers; muscle contractility: uniaxial loading vs. either form of the biaxial loading). Muscle samples were handled as a random effect; force, treatment, and force-by-treatment interaction were handled as fixed effects. Pairwise comparisons were performed to test a priori hypotheses using linear contrast. Data are expressed as means ± SE, where SE is the standard error unless otherwise indicated. Comparisons were considered significant at P < 0.05.
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RESULTS |
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DISCUSSION |
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Integrins are important structural and receptor proteins because they provide one of the major ways in which cells can both bind and respond to the extracellular matrix (1, 8, 29). Integrins participate in vital biological processes such as embryonic development, cell differentiation, maintenance of tissue integrity, adhesion function, and cell-extracellular matrix interaction (10, 17, 22, 24, 26). 1-Integrin is expressed throughout the body, while
7-integrin is tissue-specific for both skeletal and cardiac muscles. Different isoforms of
7-integrin appear to have distinct functions in skeletal muscles. Alternative forms of the
7-integrin (13, 36, 42) are expressed in a developmentally regulated fashion during myogenesis, and different
7
1-isoforms localize at specific sites on myofibers (28).
7-integrin was found highly concentrated in MTJ (2, 31, 38). It is known that the MTJ is the principal structure that transmits force generated by muscle contraction to the tendon (39, 40). Furthermore, Mayer et al. (30, 32) have demonstrated that histological analysis of skeletal muscles from mice lacking
7-integrin revealed typical signs of a progressive muscular dystrophic phenotype in the vicinity of their MTJ. Therefore, their findings are consistent with
7-integrin being an important linkage between the muscle fiber and the extracellular matrix (25). Furthermore, because
7-integrin was also found along the entire sarcolemma (34), it is possible that
7-integrin could contribute to longitudinal and lateral force transmission between myofibers and the extracellular matrix. Our functional data demonstrating lack of the mechanical effect of transverse passive stress on muscle contractility of the diaphragm in the young mutant mice is consistent with this possibility. Mayer et al. (30) reported that the first histopathological changes in the diaphragm of
7-integrin-null mice were detected at 60 days of age with a few foci of fiber degeneration and were obvious after 100 days. Despite strong histological abnormalities of the diaphragm,
7-integrin-null mice show no overt respiratory problems before 100 days of age, as was also reported for mdx mice (37).
Our data demonstrate that muscle compliance in the diaphragms of young mutant mice appears to increase compared with the diaphragms of normal wild-type mice. These data are consistent with the possibility of 7-integrin's being a load-bearing protein. Our data also show that diaphragm muscle compliance is significantly decreased in 1-year-old
7-integrin-null mice compared with age-matched controls. Because the onset of muscle necrosis in the
7-integrin-null diaphragm occurs at
100 days of age, the decrease in muscle compliance in these diaphragms could possibly be due to muscle necrosis and the possible upregulation of collagen. Increased collagen and fibrosis are general features of muscular dystrophy, and decreased muscle compliance has generally been linked to increased collagen content (3, 14, 18, 33, 37). Some studies, however, have shown that increased collagen is not necessarily correlated with muscle compliance. In particular, alteration in muscle compliance was not associated with increased collagen due to aging in the rat soleus muscle. Furthermore, Coirault et al. (12) demonstrated increased muscle compliance of the Syrian hamster diaphragm, while the surface area of collagen was increased. Therefore, the reduced muscle compliance that we have observed in older
7-integrin-null mouse diaphragms is not necessarily due to upregulation of collagen.
In an earlier study, we (4) investigated the mechanical role of desmin, a cytoskeletal protein, in muscles. In that study, it was demonstrated that desmin integrated the three-dimensional properties of skeletal muscles by coupling the longitudinal and transverse mechanical properties of the diaphragm. The present study and the previous study conducted by Boriek et al. (4) have demonstrated that transverse loads increase maximal muscle contractile force production in the normal diaphragm, the presence of structures that couple the diaphragm muscle's longitudinal and transverse properties of the diaphragm muscle. Our mechanical data obtained in 1-month-old mice suggest that desmin may not be the only structural protein that integrates the longitudinal and transverse elements in skeletal muscles. The integrin complex may be another structural element that could transmit muscle force between the longitudinal and transverse elements. This hypothesis is consistent with recent data demonstrating that 7-integrin is expressed along the entire sarcolemma and at myomyonal junctions in series-fibered muscles (34).
With regard to viscoelastic behavior, the force needed to maintain a particular constant extension once that extension has been produced (or the stress needed to maintain a particular constant strain) decreases over time. Using the standard linear viscoelastic model, we started by only extending the series spring. As time passed, that spring relaxed while the parallel spring extended to share the load. The reduction of stress at constant strain is known as stress relaxation, and the ratio of stress to strain is known as the relaxation modulus, which decreases over time. Stress relaxation is a characteristic of an elastic sheet that displays a viscous response. Previous studies of the diaphragm have shown that this muscle displays a viscous response (4). Measurements of the viscoelastic properties include ER values, which provide a quantitative value for the degree of relaxed stiffness in muscle; an ER of 1.0 signifies a perfectly elastic material. The results of the present study show that ER values are greater in the direction transverse to the fibers than those in the longitudinal direction. This finding is consistent with the diaphragm muscle being stiffer in the direction transverse to the muscle fibers than along the muscle fibers. These data are consistent with passive mechanical data found in the diaphragms of the dog (5) and the rat (6).
In 1-month-old mice, maximal muscle tetanic stress was enhanced in the 7-integrin-null diaphragm compared with the normal diaphragm only under the uniaxial loading condition. Biaxial loading increased muscle stress only in the normal diaphragm. The increase in muscle force in the
7-integrin-null mice is consistent with a possible role for
7-integrin in dissipating mechanical energy of the diaphragm during normal breathing. However, in young mice, the increase in tetanic stresses that resulted from biaxial mechanical loading of diaphragm appeared to require, at least in part, the contribution of
7-integrin.
Cohn et al. (11) provided a quantitative assessment of the sarcolemmal immunoreactivity of muscle proteins in 7-integrin mutant mice. They found that other transmembrane proteins of the dystroglycan complex and the sarcoglycan complex were unaffected by the absence of
7-integrin. In addition, normal levels of
2-laminin appear to be expressed in the mutant mouse. Therefore, our experimentsat least those in young miceprovide data directly pertinent to the mechanical role of
7-integrin in skeletal muscle function.
7
1-Integrin is related to several neuromuscular diseases. Hodges et al. (20) suggested that the expression of
7-integrin is upregulated in skeletal muscles from either patients with Duchenne muscular dystrophy or an animal model, the mdx mouse. Downregulation of expression of the integrin contributes to muscle pathology in congenital laminin deficiencies. Furthermore, mutations in the
7-integrin gene have been found to be responsible for a form of congenital neuromuscular disease (19). Burkin and Kaufman (8) overexpressed the
7-integrin chain in mice that were null in both dystrophin and utrophin, and they found that the transgenic expression of the
7-integrin chain in these mice ameliorated the development of disease and maintained longevity in mice that otherwise would have developed severe myopathy and died. These investigators suggested that bolstering the integrin-mediated association of muscle with the extracellular matrix could possibly prevent Duchenne muscular dystrophy.
In summary, our data demonstrate that 7-integrin may contribute to muscle compliance. In addition, the absence of
7-integrin in 1-month-old mice increased maximal tetanic force production, whereas in 5-month-old mice, force production was compromised in the mutant mice. Our data confirm that passive transverse force alters the production of maximal contractile properties in normal diaphragm and provide new evidence that this effect is absent in
7-integrin-null diaphragm. Our mechanical data are consistent with a mechanism of force transmission in the diaphragm that is altered by the loss of the
7-integrin.
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FOOTNOTES |
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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.
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