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HIGHLIGHTED TOPICS
Physiology of Aging
1Davis Heart and Lung Research Institute and College of Pharmacy and 3College of Dentistry, The Ohio State University, Columbus, Ohio 43210; and 2Department of Physiology, Kirksville College of Osteopathic Medicine, Kirksville, Missouri 63501
Submitted 1 May 2003 ; accepted in final form 4 March 2004
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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- and 
-isoforms of myosin heavy chain (MHC- and MHC-, respectively) in multiple, specific regions of the adult rat heart and to determine whether age-dependent changes in isoform levels in different regions are uniform. Relative amounts of MHC- and MHC- were determined in right and left atria and left ventricular (LV) Purkinje fibers (PF), papillary muscles, trabeculae, and endo-, mid-, and epicardial regions at 2, 5, 10, 16, and 21 mo. PFs contained substantial amounts of myosin and were striated and capable of generating force and shortening on activation. Levels of MHC- increased in all LV compartments with age, especially between 2 and 5 mo. There was more MHC- in PFs than other LV sites. There were regional differences in the level of MHC- throughout the LV at all ages, and the rates of change within regions differed. Ca2+-activated tension in PFs and trabeculae was compared at 2 and 22 mo. PF tension was less than trabecula tension, and this difference may be explained by differences in MHC content. Vmax and tension-generating ability in PFs decreased with age. Maximal tension generated by trabeculae did not change during aging. A large proportion of the increase in the level of MHC- that is normally associated with aging occurs at a relatively early age in rat LV. PFs, with their small diameters and short diffusion distance, should be considered for skinned multicellular myocardial studies. force; velocity; Purkinje fiber; contractile proteins
-isoform of myosin heavy chain (MHC) has higher ATPase activity than the slower, more efficient -isoform of MHC. In young adult rodents, MHC- is the predominant isoform throughout the myocardium. The ventricular expression of MHC- has been reported to decrease with age, whereas MCH- increases in a reciprocal fashion (6, 23, 25). This change is associated with a slowing of contraction kinetics (10, 13, 29). Several cardiac proteins have regional distribution patterns, in addition to temporal changes associated with aging. In mammals, transmural differences in the expression and/or activity of the calcium regulatory proteins, sarcoplasmic reticulum calcium ATPase, and sarcolemmal sodium-calcium exchange current have been reported (15, 32).
The transmural distribution of myosin isoforms has been studied in rats (5, 8, 18, 28). The V3 myosin isoform (MHC- homodimer) did not differ between endocardial and epicardial regions in Wistar rats. Of note, the endocardial and epicardial samples were obtained by dividing the left ventricular (LV) sample, such that midmyocardium was included in each sample (8). In young male rats, the percentage of V3 myosin was increased in the subendocardium relative to the subepicardium (5). In addition, the distribution of V1 (MHC- homodimer) and V3 isoforms was found to be highly variable in the ventricles (5).
Whereas several studies have included examinations of differences in myosin expression between myocardial sites or within specific sites during maturation (4–6, 8, 10, 20, 25), none of the previous reports provide an extensive characterization of MHC isoform expression at multiple atrial and ventricular sites and at multiple times during adult maturation and aging. The results of the previous studies have demonstrated an increase in the relative level of MHC- (V3), which has been described as being aging related and has shown a difference in the level of the slower myosin between epicardium and endocardium in the ventricles of small mammals. However, the extent of dynamic regional changes in myosin, which has a prominent role in regulating contractile function, from the outermost epicardial layer to the sites first activated during contraction [Purkinje fibers (PFs)], is unknown. The purpose of this study was to undertake a more comprehensive analysis of the regional distribution of MHC isoforms in atria and multiple LV sites, including the conductile PFs, in male Sprague-Dawley (SD) rat hearts, focusing on the effects of aging on the regional distribution of MHC isoforms. Specifically, we statistically tested whether MHC isoform levels change in a site- and/or an age-specific manner. The results show that a large proportion of the increase in MHC- in rat myocardium that has been associated with aging actually occurs within the first 5 mo and that not all regional changes are uniform. After our novel observation of MHC in rat PFs, we compared tension generation in isolated PFs and trabeculae at 2 and 22 mo.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Myosin Isoform Measurement
Myosin isoform composition was determined by using previously described methods (24). Samples, other than PFs and trabeculae, were homogenized in sample buffer, denatured by heating, and loaded onto gels. Myosin in PFs and trabeculae was extracted directly in sample buffer at room temperature for 
30 min without homogenization. The trabeculae were individually extracted with 2 µl of sample buffer per nl of trabecula volume, and the PFs were each extracted with 10 µl of sample buffer. The gel sample loads were 7 µl for each trabecula (representing 3.5 nl of trabecula volume) and 10 µl for each PF (representing the entire sample). Samples were loaded onto 7% acrylamide gels and run at 200 constant volts for 24 h at 8°C. Staining and densitometric scanning of the gels for the relative amounts of MHC- and MHC- were as described in Reiser and Kline (24), by using a straight baseline and assuming no overlap of the two MHC bands. The two MHC bands were well separated for the vast majority of the samples. However, we cannot rule out the possibility that some overlap of the MHC- band led to a small overestimation of the MHC- band in a few samples. Therefore, two methods of integration (non-Gaussian and Gaussian, the latter factoring in overlap of the peaks into the analysis) of the peak areas were compared, which assessed any potential effect of gel band overlap on the calculated peak areas. The average measurement error when comparing the two methods of analysis was 2.8%. Data are presented as the percentage of MHC- (relative to total MHC).
Tension Generation and Vmax in Isolated PFs and Trabeculae
The maximal tension-generating ability and Vmax were measured at 15°C in PFs and trabeculae from three 2-mo-old and three 22-mo-old male SD rats (six PFs and five trabeculae at both ages). The methods for preparation of skinned PFs and trabeculae and for measurements of tension generation were similar to those described in Wattanapermpool and Reiser (30). Hearts were stored at –22°C in glycerinating solution for up to 2 wk. The PFs and trabeculae isolated from these hearts were soaked in 1% Triton X-100 for 5 min before mounting in the experimental chamber. Briefly, active tension and velocity measurements were made while the PFs and trabeculae were activated in a solution with pCa 4.0, which is maximally activating (30). Resting tension was measured by rapidly introducing slack into the preparation while it was bathed in a solution with pCa 9.0. The active tension generated was calculated by subtracting resting tension from total tension during maximal activation. Peak active tension was normalized with cross-sectional area, the latter calculated from measurements of the width and depth of the mounted trabeculae and PFs, with a microscope-mounted video camera, and assuming an elliptical cross-sectional shape in those cases in which the width and depth differed. The Vmax was determined in the same PFs at both ages and trabeculae at 2 mo by using the slack-test method (9). Measurements of Vmax in trabeculae at 22 mo were not sufficiently reliable for inclusion in the analyses (i.e., the linear correlation coefficients between imposed slack and duration of shortening were <0.97). Specifically, trabeculae from the older rats tended to have a much greater resting tension, and the associated large elastic recoil interfered with accurate determination of the slack time intervals in the Vmax measurements. Also, the striation pattern in many of the older trabeculae was not sufficiently clear to reliably set the initial sarcomere length. The mean resting sarcomere length in all of the preparations for which data are reported was set to 2.07 ± 0.02 (SE) µm.
Data Analysis
PF and trabecula MHC data were averaged for each animal before statistical analysis. All data are presented as means ± SE. Statistical analyses were conducted by using SAS for Windows, version 6.12 (SAS, Cary, NC). Data were analyzed by either one-way or two-way analysis of variance with post hoc Bonferroni tests. The amplitude of Ca2+-activated tension, normalized with cross-sectional area, in isolated PFs and trabeculae was compared with Student's t-test. A P value of <0.05 was the predetermined criterion for statistical significance.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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and MHC- isoforms in each sample.
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Although the mean level of MHC- was <5% at each age, statistical differences were found in the relative amount of MHC- between the right and left atria, independent of age (Fig. 2). In addition, the level of left atrial MHC- significantly increased as a function of age, whereas that in the right atrium did not change. Post hoc testing of the left atrial MHC- data did not reveal which ages differed.
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The level of MHC- in the LV free wall transmural samples increased significantly with age (P < 0.0001, Fig. 3). Myosin was detected in an average of five of the six PFs from each heart. The level of MHC- in the PFs increased in the 10-, 16-, and 21-mo age groups, compared with that in the 2-mo group (P < 0.05). The percentage of MHC- in PFs increased significantly with age (Fig. 4, P < 0.05). A consistent pattern emerged during aging in the comparison of PFs with other LV compartments. The PFs differed from all other LV sites at 2 and 5 mo (P < 0.05). The differences between the PFs and the sites proximal to the PFs (papillary and trabeculae) disappeared as age increased. At the oldest age examined, only the mid- and epicardium differed from PFs (P < 0.05).
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was found to vary significantly as a function of both age and site (P < 0.001), as described below.
Age-related differences.
Post hoc testing revealed that age-dependent changes in MHC were present. Whereas the 10- and 16-mo ages did not differ from one another, all other age groups differed significantly from each other (P < 0.05). In addition, the presence of age-dependent differences at each sampling site was evaluated. Age-dependent changes in MHC- expression were evaluated for each of the sites tested (papillary muscles, trabeculae, endocardium, midmyocardium, epicardium). All sites had significant age-dependent changes in MHC- level (P < 0.05). Post hoc testing revealed different patterns of MHC- level at different ages (Fig. 4). The 2-mo age group consistently differed from all other ages at every site (P < 0.05). Notably, at least 50% of the changes in the level of MHC- in the LV compartments (except PFs) examined occurred between 2 and 5 mo. A significant spatial gradient across the LV free wall existed at 10, 16, and 21 mo (but not at 2 and 5 mo), with a greater proportion of MHC- in the endocardial layer at each age.
Site-related differences.
When examined without regard to age, MHC- expression varied significantly as a function of site. Because age was also a significant independent variable in MHC- expression, we examined differences between sites at each of the ages tested. When examined within an age group, MHC- expression differed significantly as a function of site at each age tested. Post hoc testing revealed different patterns of MHC- distribution across the LV at each of the ages studied (Fig. 4). At 2 mo of age (Fig. 4A), the PFs differed from all other regions, whereas the papillary muscles and trabeculae differed from both midmyocardium and endocardium (P < 0.05). At 5 mo (Fig. 4B), the PFs continue to differ from all other regions, whereas the papillary muscles and trabeculae differed from the epicardium (P < 0.05) but no longer differed from the midmyocardium. At 10 mo (Fig. 4C), PFs no longer differed from the papillary muscles or trabeculae, but continued to differ from the three LV free wall sites. At this age, a difference between endocardial and epicardial MHC- level (P < 0.05) appears, which continues at the older ages. At 16 mo of age (Fig. 4D), the PFs again differed from all other sites, whereas the papillary muscles and trabeculae differed significantly from both the mid- and epicardium (P < 0.05). At 21 mo (Fig. 4E), only the mid- and epicardium differed from the PFs. Otherwise, the pattern of regional differences in the LV was similar to that observed at 16 mo. The papillary muscles had a significantly higher level of MHC-, compared with the transmural samples at all ages except 5 mo (P = 0.053 at 5 mo).
Tension Generation and Velocity of Shortening in Isolated PFs and Trabeculae
Because myosin was detected in the majority of PFs that were studied, the tension-generating ability of isolated, skinned PFs was measured and compared with that of trabeculae from the same set of additional hearts. Images of a PF and a trabecula, showing striations in both, are shown in Fig. 5A. Examples of tension records in PFs and trabeculae are shown in Fig. 5C. The resting tension did not differ between PFs and trabeculae and did not change between 2 and 22 mo [means for all groups were 1.2 ± 0.2 to 1.3 ± 0.4 (SE) kN/m2]. The mean maximal tension generated by isolated 2-mo PFs was less than that in 2-mo trabeculae (Fig. 5D, P < 0.02). The tension generated by trabeculae at 22 mo did not differ from that at 2 mo. However, the tension generated by PFs at 22 mo was significantly lower than that generated at 2 mo (P < 0.05). Generally, the intensity of the striation pattern appeared to be proportional to the tension-generating ability, especially in PFs. The absolute tension generated by PFs, however, did not differ between the two ages. The mean Vmax of trabeculae (3.69 ± 1.21 trabecula length/s) and of PFs (2.62 ± 0.58 fiber length/s) were similar at 2 mo. The mean (±SE) compliance of the 2-mo PF and trabeculae was 5.4 ± 1.4 and 5.3 ± 2.2%, respectively.
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The relative levels of MHC- measured in these PFs and trabeculae were 58 and 30% at 2 mo and 72 and 58% at 22 mo, respectively. These values are similar to the mean values at 2 and 21 mo that were obtained from the larger sample size presented above. The mean total amount of MHC (MHC- and MHC- isoforms combined), normalized for PF and trabecula length, was approximately proportional to the maximal tension generated by the PFs and trabeculae (7,421 and 26,747 at 2 mo and 3,525 and 29,471 at 22 mo, in arbitrary densitometric scan units, respectively). The amount of MHC cannot be compared between the two ages because the PFs and trabeculae at each age were analyzed on separate gels, and there is no assurance that the gels were stained identically.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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increases in the rat left atrium and all examined regions of the rat LV during aging. The increases continue through at least 21 mo, a senescent age at which the expected survival of male SD rats is 80% (12a) and falls markedly thereafter. An aging-related increase in MHC- has been reported in several rat strains (4, 11, 22), but the present study examined right and left atria separately and specific ventricular sites individually. Unexpectedly, the results show that at least one-half of the aging-related increases in the proportion of MHC- in each of the LV compartments examined (other than the PFs) occurs between relatively young ages (2–5 mo), a period of maturation that has not been well characterized previously. The magnitude of change in the level of MHC- during the transition from 2 to 5 mo ranged from 3- to 13-fold in different ventricular regions. These increases are more robust than suggested by earlier studies, which were based on measurements of MHC protein levels at fewer ages (10) or on MHC mRNA levels (20). Our results, therefore, emphasize the need to rigorously control for age in studies utilizing young adult rats.
The increase in the level of MHC- in the rat myocardium is usually regarded as an aging-related phenomenon, whereas our results show that much of the increase occurs during maturation of young adult rats. Therefore, slowing of SD rat LV contractions at later ages is likely due primarily to mechanisms other than an increase in the level of MHC-, such as reduced Ca2+ cycling (e.g., Ref. 12). The mechanisms that are responsible for the aging-related increase in the proportion of MHC- observed in this study are not known, and whether the increase in the proportion of MHC- in rat myocardium during aging is adaptative or maladaptive is not clear. Regardless, the increase in MHC- is likely associated with an increase in contraction economy, with an accompanying decrease in power output (13). Heart rate, systolic ventricular and arterial pressures, and diastolic ventricular and arterial pressures do not increase between 3 and 19–21 mo in SD rats (3). Therefore, the changes that we observed are unlikely to result from age-dependent alterations in rate or pressure.
Given that MHC- is associated with greater economy of contraction, compared with that of MHC-, our results suggest that there is an increase in the economy of contraction in all regions of the rat ventricle during normal maturation and subsequently with aging. Our results further suggest that a large increase in economy occurs within the young adult stage (2–5 mo) and does not initially occur in response to aging-related changes in the cardiovascular system (e.g., increased mean arterial pressure). This greater economy is directly linked to a decrease in shortening velocity and, therefore, decreased power output as MHC- is associated with slower contraction rates. Therefore, the young adult rat ventricle appears to undergo a marked transition from relatively high-contraction rates and power output to slower, more economical contractions during a relatively brief time in the absence of changes in afterload.
Long et al. (20) reported that the MHC- mRNA level does not increase between 2 and 6 mo but increases significantly between 6 and 24 mo in Wistar rat LV, whereas our results from SD rats show a large, significant increase in the proportion of MHC- at the protein level between 2 and 5 mo. This difference between studies could be due to the different rat strains that were utilized, but we did not measure RNA levels, and Long et al. did not report MHC protein levels. Alternatively, the discrepancy could suggest that the regulation of MHC- protein is not strictly regulated transcriptionally in the maturing and aging rat LV. This is clearly an important area that needs to be resolved to more fully understand regulation of MHC isoform expression in the aging myocardium. It should be noted that we did not measure absolute MHC protein levels, and it is possible that the changes in the relative levels of MHC- that we measured were due to decreases in the absolute level of MHC-. However, because MHC- is the predominant isoform at early adult ages, it is unlikely that the increase in the relative level of MHC- during aging is due solely to a decrease in MHC-.
Another striking result of this study is the relatively high level of MHC- in PFs, especially at young adult ages. The regulatory mechanisms that are responsible for the relatively high proportion of MHC- in rat PFs have not been determined. Understanding these mechanisms could provide valuable insight into the regulation of the MHC- gene, especially given that the level of MHC- in PFs is approximately ninefold higher than the LV transmural samples at 2 mo. An increase in afterload is well known to result in upregulation of the MHC- in mammalian heart (1, 19). It is possible that stretch of the ventricular wall during diastole represents a preload on the PFs and, at the onset of systole, becomes a significant afterload (stress), which might promote the expression of MHC-.
Others have shown that MHC- and MHC- isoforms are expressed in bovine and human PFs (16, 17, 26). Our results show that both MHC isoforms are present in the specialized conducting fibers of rats, as well. Of note, the proportion of MHC- in PFs is the highest of all of the sites tested, especially at the younger adult ages examined. The relatively high proportion of MHC- in PFs, and presumably slower contractions, suggests that a relatively high level of MHC- in PFs is necessary for coordinated contraction with the adjoining endocardial structures. Our results show that isolated rat PFs are capable of generating tension and are, in fact, capable of shortening. It is reasonable, therefore, to assume that PFs shorten during systole in the intact heart. The results of this study also show that the mean maximal tension generated by PFs, normalized for cross-sectional area, is approximately one-third of that generated by isolated trabeculae under identical conditions, with the latter being nearly identical to that reported by Wattanaparmpool and Reiser (30). It is unlikely, however, that PFs contribute significantly to ventricular tension production during systole due to their small cross-sectional areas. The difference in mean tension-generating ability between PFs and trabeculae was similar to the difference in MHC content at both ages studied, based on the lower MHC content of PFs, compared with trabeculae, when analyzed by SDS-PAGE.
Our results indicate that the steady-state, maximal tension-generating ability of the fundamental contractile apparatus of rat myocardium, as assessed in skinned LV trabeculae, is unchanged from young adult to early senescent stages. This is in accordance with measurements of tension production in electrically stimulated (i.e., intact, not skinned) trabeculae and papillary muscles (12, 31). Our results and those of Wei et al. (31) also indicate that resting tension does not change between young adult and senescent ages. Therefore, two fundamental mechanical properties of isolated trabeculae from rat LV do not change during this age range. The basis for the decrease in tension-generating ability in PFs with increasing age is not clear, but it appears, for several reasons, that the decrease is not due to the increase in the proportion of MHC-. Wattanapermpool and Reiser (30) reported that variations in tension-generating ability and the proportion of MHC- in skinned trabeculae from normal young adult female rats were not correlated. The results of the present study show that the proportion of MHC- in trabeculae increases approximately fourfold between 2 and 21 mo without an accompanying change in tension generation. Metzger et al. (21) also reported that the maximal forces generated by skinned myocytes, isolated from SD hearts, expressing either predominantly MHC- or MHC-, did not differ from each other. The basis for the decrease in Vmax in PFs between 2 and 21 mo is also not clear but is consistent with the decrease in Vmax in rat LV papillary muscles, as reported by Capasso et al. (7). The decrease in shortening velocity could be due, at least in part, to the increase in the relative level of MHC- between these ages. However, the level of MHC- differs between PFs and trabeculae at 2 mo to a greater extent, yet they have a similar mean Vmax. Furthermore, the greater compliance of the PFs at the older age could contribute to the reduction in Vmax (9). Possible aging-related increases in noncontractile elements in PFs (e.g., collagen, cross-linking of collagen, fibroblasts), as reported in other myocardial regions (2, 27), could, if sufficiently large, result in an increase in cross-sectional area and, thereby, decrease the force-generating ability (force/cross-sectional area) and interfere with shortening and, thereby, reduce Vmax. The significance of these changes during aging and differences between trabeculae and PFs is not clear. However, it is interesting to note that the decrease in PF Vmax between young and aged rats coincides with the increase in the level of MHC- throughout the ventricle, which presumably slows contraction of the LV free wall.
Kuro-o et al. (17) showed that relatively more cells in the human LV conduction system, compared with the working myocardium, expressed MHC- and that more cells in the subepicardial layer contained MHC-, compared with the subendocardial layer, the latter being consistent with our results. They also reported that a higher proportion of cells in human papillary muscle expressed MHC- than did cells in the endocardium, which is opposite to what we observed in rat papillary muscle. Therefore, our results and those from earlier studies (16, 17) indicate that differences in regional MHC isoform expression exist between rats and several larger sized mammalian species.
Anversa et al. (3) observed a greater incidence of focal areas of interstitial and replacement fibrosis in the endocardial layer of the LV free wall, compared with other layers of the wall, in male SD rats during aging. It is generally presumed that loss of working myocytes will result in a greater workload and subsequent hypertrophy and upregulation of MHC- in the surviving myocytes. This may contribute to the spatial gradient that we observe in relative MHC- level across the LV free wall in older SD rats.
There is evidence for a transmural gradient for ventricular contraction and relaxation (15). Of note, in a normal cardiac cycle, the endocardial regions of the heart are the earliest to undergo electrical activation and the resultant contraction. Our findings support the concept that the earliest activated ventricular sites have the highest level of MHC-, resulting in the slowest contraction velocity. This could be a protective mechanism for the PFs to minimize shortening before contraction of the LV wall, which could otherwise result in detachment of the PFs from their points of attachment to the septum and free wall. Conversely, the midmyocardium and epicardium are the ventricular sites last activated and have the highest levels of MHC-, resulting in relatively more rapid contraction. Thus, having an increased fraction of the slower isoform (MHC-) at the earliest sites of activation should enhance coordinated contraction of the LV free wall. Our results suggest that there is a matching of the pattern of electrical activation with the pattern of MHC isoform expression across the LV free wall in the normal myocardium.
Our results show that the predominant isoform in the rat atria is MHC- at all ages. The relative level of this isoform changes in the left atria during maturation and aging. However, the significance of this change is unclear. The higher level of MHC- in the left atrium might reflect the fact that pressures on the left side of the heart are typically higher than those on the right side. Herron and McDonald (14) have demonstrated that even small differences in MHC isoform content are associated with significant functional differences.
Several conclusions can be drawn from the results of this study. First, the increase in the proportion of MHC- in rat myocardium is especially large during maturation at ages when heart rate or afterload are not increasing (3). The rapid increase in the proportion of MHC- during maturation in young adult rats (2–5 mo) is likely to contribute to significant changes in the kinetics and economy of contraction, even within this relatively short period of maturation and, therefore, should be considered in the design of future experiments. Second, steady-state tension-generating ability of the contractile apparatus in rat trabeculae is unchanged between young adult and early senescent stages, suggesting that changes in contractile function during this period are due to other parameters of excitation-contraction coupling. Finally, rat ventricular PFs have the ability to generate tension and to shorten when activated, and both of these properties undergo significant decrements by early senescent stages.
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ACKNOWLEDGMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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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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, Purkinje fibers (PF); 
, trabeculae (Trab); 
, Pap; 
, endocardial layer (Endo); 
, Mid; 
, Epi. Values are means ± SE. Differs from *(PF), #Pap, 
Trab, 
Endo, ^Mid, and xEpi (P < 0.05).