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Department of Physiology, University of Missouri School of Medicine, Columbia, Missouri 65212
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The purpose of this study
was to examine the role of myosin heavy chain (MHC) in determining
loaded shortening velocities and power output in cardiac myocytes.
Cardiac myocytes were obtained from euthyroid rats that expressed
-MHC or from thyroidectomized rats that expressed 
-MHC. Skinned
myocytes were attached to a force transducer and a position motor, and
isotonic shortening velocities were measured at several loads during
steady-state maximal Ca2+ activation (PpCa4.5).
MHC expression was determined after mechanical measurements using
SDS-PAGE. Both -MHC and -MHC myocytes generated similar maximal
Ca2+-activated force, but -MHC myocytes shortened faster
at all loads and generated ~170% greater peak normalized power
output. Additionally, the curvature of force-velocity
relationships was less, and therefore the relative load optimal for
power output (Fopt) was greater in -MHC myocytes.
Fopt was 0.31 ± 0.03 PpCa4.5 and
0.20 ± 0.06 PpCa4.5 for -MHC and -MHC myocytes,
respectively. These results indicate that MHC expression is a primary
determinant of the shape of force-velocity relationships, velocity of
loaded shortening, and overall power output-generating capacity of
individual cardiac myocytes.
cardiac muscle contraction; sarcomere proteins
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE AMOUNT OF
BLOOD PUMPED into the circulatory system during a heartbeat
(i.e., stroke volume) is ultimately determined by the rate of
myocardial shortening, which depends on several factors, including the
afterload against which the ventricles must work, the architecture of
the ventricles, and the contractile state of the myocardium. The
contractile state of the myocardium is regulated by factors intrinsic
to individual myocytes because all myocytes contract during each
heartbeat. An example of an intrinsic factor is myoplasmic
Ca2+ concentration, which varies on a beat-to-beat basis,
thereby modulating myocyte force (19, 10, 13), shortening
velocity (11, 10) and, thus, stroke volume. Another likely
determinant of myocardial shortening and stroke volume is the isoform
of myosin heavy chain (MHC) expressed in individual myocytes. In
vertebrates, two MHC isoforms are expressed in the myocardium, -MHC,
and -MHC (20). These two MHC isoforms show considerable
homology, having 93% identical amino acids (12), but they
are functionally quite distinct. For instance, -MHC exhibits two to
three times the actin-activated ATPase activity (9) and
actin filament sliding velocity (5) as -MHC.
Additionally, myocardial strips containing predominantly -MHC
exhibited six times faster maximum shortening velocities than
myocardial preparations containing -MHC (16). These
marked differences in ATPase rates and mechanical shortening velocities
imply that power output-generating capabilities would be significantly
lower in myocytes expressing -MHC. The purpose of this study was to
directly assess loaded shortening velocities and power output of single
rat cardiac myocytes containing either -MHC or -MHC. For these
experiments, force-velocity and power-load curves were measured in
single ventricular myocytes obtained from euthyroid adult rats that
predominantly expressed -MHC and from hypothyroid adult rats that
exclusively expressed -MHC. To obtain force-velocity and power-load
curves, we utilized a single skinned ventricular cardiac myocyte
preparation having low-end compliance, minimal passive elastic forces,
and enough myosin to assess MHC isoform composition in the same myocyte
preparation used for mechanical measurements. These preparations
allowed direct comparison of power output capabilities and MHC isoform
expressed in the same individual myocyte.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental animals. Euthyroid and thyroidectomized Sprague-Dawley rats were obtained from Harlan Tekland (Madison, WI), housed in groups of two or three, and provided access to food and water ad libitum. All thyroidectomized animals were treated with propylthiouracil (PTU) as described previously (3). Briefly, PTU (12 mg/kg) was administered daily by intraperitoneal injection to all thyroidectomized rats. The combination of thyroidectomy and PTU supplement has been shown to eliminate circulating plasma 3,5,3'-triiodothyroine and thyroxine (T4) levels (4). Thyroidectomized rats were studied between 2 and 5 wk after surgery. A group of sham-operated control rats were also studied 2-5 wk after surgery to ensure that any postoperative response did not influence myocyte function and, thus, the outcome of this study. All animal usage was performed according to guidelines established by the Animal Care and Use Committee of the University of Missouri.
Cardiac myocyte preparation. Single-skinned cardiac myocytes were obtained by mechanical disruption of hearts from Sprague-Dawley rats as described previously (11). Rats were anesthetized by inhalation of methoxyflurane, and their hearts were excised and rapidly placed in ice-cold relaxing solution. The ventricles were dissected away from the atria, cut into 2- to 3-mm pieces and further disrupted for 5 s in a Waring blender. The resulting suspension of cells was centrifuged for 105 s at 165 g, after which the supernatant was discarded. The myocytes were skinned by resuspending the pellet of cells for 5 min in 0.3% ultrapure Triton X-100 (Pierce Chemical) in relaxing solution. The skinned cells were washed twice with cold relaxing solution, resuspended in 10-15 ml of relaxing solution, and kept on ice during the day of the experiment.
Solutions.
Compositions of relaxing and activating solutions used in mechanical
measurements were (in mmol/l) 7 EGTA, 1 free Mg2+, 20 imidazole, 4 MgATP, and 14.5 creatine phosphate (pH 7.0); Ca2+ concentrations of 10
9 M (relaxing
solution); 104.5 M (maximal activating solution); and
sufficient KCl to adjust ionic strength to 180 mM. Before each
activation, myocyte preparations were immersed for 30 s in
preactivating solution (identical to relaxing solution, except that
EGTA was reduced to 0.5 mmol/l). This protocol resulted in more rapid
steady-state force development and helped preserve the striation
pattern during activation. Relaxing solution, in which the ventricles
were disrupted, skinned, and resuspended contained (in mmol/l) 2 EGTA,
5 MgCl2, 4 ATP, 10 imidazole, and 100 KCl at pH 7.0.
Experimental apparatus.
The experimental apparatus for physiological measurements of myocyte
preparations was similar to one previously described in detail
(15) and recently modified specifically for cardiac myocyte preparations (11). Briefly, myocyte preparations
were attached between a force transducer and torque motor by gently placing the ends of the myocyte into stainless steel troughs (25 gauge). The ends of the myocyte were secured by overlaying a
0.5-mm-long piece of 3-0 monofilament nylon suture (Ethicon) onto each
end of the myocyte and then tying the suture into the troughs with two
loops of 10-0 monofilament suture (Ethicon). The attachment procedure
was performed under a stereomicroscope (approximately ×100
magnification) using finely shaped forceps. Dimensions of the
myocyte preparations are provided in Table
1. Sarcomere length of these preparations
was set to ~2.25 µm, which yielded passive forces near zero.
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Force-velocity and power-load measurements. All mechanical measurements were made at 13°C. The protocol for force-velocity and power-load measurements has been previously described in detail (10). First, the myocyte preparation was transferred into preactivating solution (30 s) and then into maximal Ca2+-activating solution (PpCa4.5). Once steady-state force developed, a series of force clamps (less than steady-state force) was performed to determine isotonic shortening velocities. With the use of a servo-system, force was maintained constant for a designated period of time (150-250 ms) while the length change was continuously monitored. After the force clamp was performed, the myocyte preparation was slackened to reduce force to near zero to allow estimation of the relative load sustained during isotonic shortening; the myocyte was subsequently reextended to its initial length. Because of the small lengths of the myocyte preparations, the rapid shortening introduced after isotonic shortening did not always slacken the preparation to yield a baseline force value. This resulted in an underestimation of peak force and, thus, of relative force during loaded contractions. More accurate estimates of relative forces during isotonic shortening were obtained by interpolating peak force from isometric Ca2+ activations performed before and after the series of loaded contractions. Ten to twenty force clamps were performed on a myocyte preparation during maximal Ca2+ activation. The preparation was kept in activating solution (2-3 min) throughout the series of force clamps without significant loss of force. If maximal force fell below 75% of initial force during a series of force clamps, the data were not included in the analysis.
Data analysis.
Myocyte preparation length traces were fit to a single decaying
exponential equation
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(1) |
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(2) |
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(3) |
SDS-PAGE and Western blot analysis.
After mechanical measurements, MHC isoform expression was determined
for each myocyte preparation. The single myocyte was removed from the
experimental apparatus, suspended in 8 µl of SDS sample buffer, and
stored at 
80°C for subsequent SDS-PAGE analysis. The gel
electrophoresis procedure was similar to one previously described
(13). The gels for SDS-PAGE were prepared with 3.5%
acrylamide in the stacking gel and 12% acrylamide in the resolving
gel. Samples were separated by SDS-PAGE at constant voltage (250 V) for
6.5 h. Gels were initially fixed in an acid-alcohol solution,
followed by glutaraldehyde fixing. MHC isoforms were visualized by
ultrasensitive silver staining, and gels were subsequently dried
between mylar sheets.
Statistics. One-way ANOVA was used to test for differences among myocyte dimensions, force velocity, and power output characteristics among myocytes from euthyroid, sham-operated euthyroid, and hypothyroid rats. The Student-Newman-Keuls test was used post hoc to assess differences among means. P < 0.05 was chosen as indicating significance. All values are expressed as means ± SD.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of thyroid deficiency on contractile protein expression and
myocyte dimensions.
Consistent with recent findings (3, 13), thyroidectomy
followed by 2-5 wk of PTU treatment yielded a complete shift from predominantly -MHC to -MHC as assessed by SDS-PAGE/silver
staining, whereas the pattern of expression of other key myofilament
proteins was not altered by this treatment as assessed by Western
blots. Western blot analysis showed no differences in isoform
expression pattern of TnT, Tm, TnI, and RMLC in adult cardiac myocytes
from euthyroid, sham-operated euthyroid, and hypothyroid rats (Fig. 1). MHC isoform expression was determined
for each individual cardiac myocyte preparation after mechanical
measurements by SDS-PAGE and silver staining to provide a definitive
relationship between MHC and power output. -MHC and -MHC myocyte
preparations were similar in size, sarcomere length, and production of
passive and maximal Ca2+-activated force (Table 1).
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Effect of MHC isoform expression on force-velocity and
power-load curves.
Force-velocity and power-load curves were characterized in single
cardiac myocyte preparations containing either -MHC or -MHC, as
determined by SDS-PAGE/silver staining after functional measurements.
Figure 2 shows force-velocity curves,
power-load curves, and SDS-PAGE/silver stain analysis of two myocyte
preparations, one that expressed -MHC and the other that expressed
-MHC myocyte. Peak normalized power output was 217% greater
in the -MHC myocyte compared with the -MHC myocyte [0.111
vs. 0.035 (P/Po · ML/s), where ML is muscle
length]. Figure 3 shows cumulative
force-velocity and power-load curves for 10 -MHC myocytes from
euthyroid rats and 11 -MHC myocytes from hypothyroid rats. There
were several clear differences in the curves between -MHC and
-MHC myocytes. First, expression of -MHC significantly increased
the curvature of the force-velocity relationship, which shifted the
relative force that power was optimal (i.e., Fopt) to
significantly lower values (0.31 ± 0.03 to 0.20 ± 0.06 PpCa4.5, Table 2). Second, shortening velocities were slower, and, thus, power output was lower in
-MHC myocytes at all relative loads less than isometric (1.0 PpCa4.5). Peak normalized power output was on average 174% greater in -MHC myocytes versus -MHC (Table 2). Interestingly, the difference in shortening velocity between -MHC and -MHC myocytes progressively increased from zero load to higher loads until
finally converging at isometric force where there was no shortening.
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-MHC and, as expected, produced peak
normalized power outputs similar to those observed in myocytes from
euthyroid rats and significantly greater than power produced by -MHC
myocytes. Peak normalized power output in sham-operated -MHC
myocytes was 0.073 ± 0.009 ML/s (n = 5) compared
with 0.085 ± 0.019 ML/s in euthyroid -MHC myocytes
(P = 0.21) and 0.031 ± 0.010 in -MHC myocytes
(P < 0.001). These results are consistent with the
conclusion that reported differences in loaded shortening velocities
and power output result from altered MHC isoform expression.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study directly related force-velocity and power-load curves
with MHC composition of single skinned cardiac myocyte preparations. Single myocyte preparations were incorporated to more accurately define
force-velocity and power-load relationships of -MHC and -MHCs in
preparations that lack gross mechanical artifacts, which are often
present in multi-cellular preparations and tend to obscure isotonic
shortening traces. The main findings of this study are as follows:
1) maximal Ca2+-activated isometric force
production was similar in -MHC and -MHC skinned myocyte
preparations; 2) force-velocity relationships were
significantly more curved in -MHC myocytes; and 3) loaded shortening velocities and power generation were markedly less at all
loads in -MHC myocytes. Thus we conclude that MHC isoform expression
is a primary determinant of the shape of force-velocity relationships,
velocities of loaded shortening, and power output-generating capacity
of individual cardiac myocytes.
MHC as a determinant of force-velocity relationships and power
output in cardiac myocytes.
Although -MHC and -MHC molecules exhibit nearly 93% amino acid
identity (12), there appear to be several important sites of difference within regions of the rod, tail-hinge, lever arm, nucleotide binding site, and actin binding domains (12,
23). In accordance with previous studies, our results suggest
that these differences manifest different cross-bridge cycling rates between -MHC and -MHC. Previous work has found that myosin
composed of -MHC exhibits two to three times more actin-activated
ATPase activity (17, 24) and actin filament sliding
velocity (5, 23) as -MHC. Additionally, myocardial
strips and single cardiac myocytes containing predominantly -MHC
exhibited five to six times faster maximum shortening velocities than
myocardial preparations containing -MHC (3, 16). These
previous studies assessed the cross-bridge cycling rates in the absence
of external loads, which the myocardium actually works against during
systole. In this study, we assessed the role that cardiac MHC isoform
plays in determining force-velocity relationships and power output. Force-velocity relationships were much more curved in -MHC myocyte preparations, which is consistent with the greater curvature reported for slow-twitch skeletal muscle fibers that also express -MHC (8). Thus it appears that MHC is a key determinant of
force-velocity curvature as opposed to, for instance, alterations in
cross-bridge number or cross-bridge cycling rates as determined by thin
filament proteins.
-MHC and -MHC myocytes (Fig. 3) also provides some insight into
chemomechanical transitions that may be most important in limiting
loaded shortening rates and, thus, power output. From Fig. 3,
shortening velocities at or near zero load were ~45% faster in
-MHC myocytes. Maximum velocity of shortening (i.e.,
Vmax) is postulated to be limited by the rate of
detachment of negatively strained cross-bridges (7), which
has been shown to be highly correlated with the ADP release step in the
cross-bridge cycle (18). Interestingly, because curvature
of the force-velocity curve was greater in -MHC myocytes, the
difference in loaded shortening velocities progressively increased
between -MHC and -MHC myocytes as relative load increased from
zero until finally converging at isometric force where there is no
shortening. For example, at 90% of isometric force, loaded shortening
velocity was ~225% faster in the -MHC myocytes compared with 45%
faster at zero load. If ADP release limits myocyte shortening velocity over the entire range of loads, this result implies that ADP release varies as a function of load much differently between -MHC and -MHC myocytes. Alternatively, the divergence of the two curves may
imply that an entirely different step in the cross-bridge cycle is most
important in limiting shortening rates over much of the load range. For
instance, the transition from weak-binding to strong-binding
cross-bridge states, which is thought to be associated with inorganic
phosphate release, may limit loaded shortening velocities. Identifying
the steps of the cross-bridge cycle that actually limit loaded
shortening velocities requires further experiments that probe specific
cross-bridge state transitions in -MHC and -MHC myocytes during
both isometric and isotonic contractions.
Absolute peak power output was more than two times greater in -MHC
myocytes compared with -MHC myocytes. Because power output is a
function of both (shortening) velocity and force, we also normalized
power output to isometric force (PpCa4.5). Normalized power
output was also more than twice as great in -MHC myocytes than
-MHC myocytes, which implies that MHC isoform determines power
output independent of isometric force development. However, this was
not entirely the case because Fopt was significantly lower
in -MHC myocytes. Thus greater peak power output (both absolute and
normalized) in -MHC myocytes resulted for two reasons: 1)
faster shortening velocities at Fopt, and 2)
greater Fopt values due to less curvature associated with
-MHC. Overall, the mechanisms whereby peak power output varies with
MHC isoform involves both differences in loaded cross-bridge cycling
rates and differences in relative loads where myocytes generate peak
power (i.e., Fopt), which is likely the loads where
myocytes work in vivo and are most efficient.
Possible implications to impaired cardiac function.
A consequence of heart failure, diabetes, and hypothyroidism is
depressed cardiac function (2, 21), but the exact
molecular mechanism(s) responsible remain unknown. It is well
established in rodents that each of these disease states is associated
with a shift in MHC isoform expression from -MHC to -MHC
(1, 13) and a recent report found that only small shifts
in the myosin isoform composition (-MHC to -MHC) in rodent
myocardium disproportionately depressed cardiac contractility
(22). Interestingly, such a mechanism may also be involved
in the failing human heart. Miyata et al. (14) recently
demonstrated that -MHC protein is detectable in nonfailing human
left ventricles but is virtually undetectable in failing human left
ventricles. Our findings that power output is ~175% greater in
-MHC myocytes provides a potential molecular basis that could
contribute to the altered cardiac function associated with these
various disease states.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-57852.
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FOOTNOTES |
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Address for reprint requests and other correspondence: K. S. McDonald, Dept. of Physiology, School of Medicine, Univ. of Missouri, Columbia, MO 65212 (E-mail: mcdonaldks{at}missouri.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 13 December 2000; accepted in final form 4 May 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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C. C. Sucharov, P. D. Mariner, K. R. Nunley, C. Long, L. Leinwand, and M. R. Bristow A beta1-adrenergic receptor CaM kinase II-dependent pathway mediates cardiac myocyte fetal gene induction Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1299 - H1308. [Abstract] [Full Text] [PDF]
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 A. C. Hinken, F. S. Korte, and K. S. McDonald Porcine cardiac myocyte power output is increased after chronic exercise training J Appl Physiol, July 1, 2006; 101(1): 40 - 46. [Abstract] [Full Text] [PDF]
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M. L. Tschirgi, I. Rajapakse, and M. Chandra Functional consequence of mutation in rat cardiac troponin T is affected differently by myosin heavy chain isoforms J. Physiol., July 1, 2006; 574(1): 263 - 273. [Abstract] [Full Text] [PDF]
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A. C. Hinken and K. S. McDonald {beta}-Myosin heavy chain myocytes are more resistant to changes in power output induced by ischemic conditions Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H869 - H877. [Abstract] [Full Text] [PDF]
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C. A. Emter, S. A. McCune, G. C. Sparagna, M. J. Radin, and R. L. Moore Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2030 - H2038. [Abstract] [Full Text] [PDF]
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F. S. Korte, T. J. Herron, M. J. Rovetto, and K. S. McDonald Power output is linearly related to MyHC content in rat skinned myocytes and isolated working hearts Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H801 - H812. [Abstract] [Full Text] [PDF]
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V. L. M. Rundell, V. Manaves, A. F. Martin, and P. P. de Tombe Impact of {beta}-myosin heavy chain isoform expression on cross-bridge cycling kinetics Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H896 - H903. [Abstract] [Full Text] [PDF]
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R. S. Haworth, F. Cuello, T. J. Herron, G. Franzen, J. C. Kentish, M. Gautel, and M. Avkiran Protein Kinase D Is a Novel Mediator of Cardiac Troponin I Phosphorylation and Regulates Myofilament Function Circ. Res., November 26, 2004; 95(11): 1091 - 1099. [Abstract] [Full Text] [PDF]
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C. A. Carnes, T. P. Geisbuhler, and P. J. Reiser Age-dependent changes in contraction and regional myocardial myosin heavy chain isoform expression in rats J Appl Physiol, July 1, 2004; 97(1): 446 - 453. [Abstract] [Full Text] [PDF]
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V. L. M. Rundell, D. L. Geenen, P. M. Buttrick, and P. P. de Tombe Depressed cardiac tension cost in experimental diabetes is due to altered myosin heavy chain isoform expression Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H408 - H413. [Abstract] [Full Text] [PDF]
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G. M. Diffee and E. Chung Altered single cell force-velocity and power properties in exercise-trained rat myocardium J Appl Physiol, May 1, 2003; 94(5): 1941 - 1948. [Abstract] [Full Text] [PDF]
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K. S. McDonald and T. J. Herron It Takes "Heart" to Win: What Makes the Heart Powerful? Physiology, October 1, 2002; 17(5): 185 - 190. [Abstract] [Full Text] [PDF]
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W. |
, Data from a myocyte that expressed
100% 
, data from a
myocyte that expressed 100% 