scholarly journals Phospholamban: a major determinant of the cardiac force-frequency relationship

2000 ◽  
Vol 278 (1) ◽  
pp. H249-H255 ◽  
Author(s):  
Wolfgang F. Bluhm ◽  
Evangelia G. Kranias ◽  
Wolfgang H. Dillmann ◽  
Markus Meyer
Keyword(s):  
Cyclopiazonic Acid ◽  
Left Ventricular ◽  
Major Determinant ◽  
Force Frequency ◽  
Papillary Muscles ◽  
Wild Type ◽  
Plasmic Reticulum ◽  
Frequency Potentiation ◽  
Frequency Relationship

The cardiac force-frequency relationship has been known for over a century, yet its mechanisms have eluded thorough understanding. We investigated the hypothesis that phospholamban, a potent regulator of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), determines the cardiac force-frequency relationship. Isolated left ventricular papillary muscles from wild-type (WT) and phospholamban knockout (KO) mice were stimulated at 2 to 6 Hz. The force-frequency relationship was positive in WT but negative in KO muscles, i.e., it was inverted by ablation of phospholamban ( P < 0.01, n = 6 mice). From 2 to 6 Hz, relaxation accelerated considerably (by 10 ms) in WT muscles but only minimally (by 2 ms) in KO muscles (WT vs. KO: P < 0.0001, n = 6). To show that the lack of frequency potentiation in KO muscles was not explained by the almost maximal basal contractility, twitch duration was prolonged in six KO muscles with the SERCA inhibitor cyclopiazonic acid to WT values. Relaxation still failed to accelerate with increased frequency. In conclusion, our results clearly identify phospholamban as a major determinant of the cardiac force-frequency relationship.

Increased susceptibility to fatigue of slow- and fast-twitch muscles from mice lacking the MG29 gene

2000 ◽  
Vol 4 (1) ◽  
pp. 43-49 ◽  
Author(s):  
RAMAKRISHNAN Y. NAGARAJ ◽  
CHRISTOPHER M. NOSEK ◽  
MARCO A. P. BROTTO ◽  
MIYUKI NISHI ◽  
HIROSHI TAKESHIMA ◽  
...  
Keyword(s):  
Major Protein ◽  
Force Frequency ◽  
Wild Type ◽  
Membrane Structures ◽  
Intracellular Ca ◽  
Slow Twitch Muscle ◽  
Fast Twitch Muscle ◽  
Frequency Relationship ◽  
Fast Twitch

Mitsugumin 29 (MG29), a major protein component of the triad junction in skeletal muscle, has been identified to play roles in the formation of precise junctional membrane structures important for efficient signal conversion in excitation-contraction (E-C) coupling. We carried out several experiments to not only study the role of MG29 in normal muscle contraction but also to determine its role in muscle fatigue. We compared the in vitro contractile properties of three muscles types, extensor digitorum longus (EDL) (fast-twitch muscle), soleus (SOL) (slow-twitch muscle), and diaphragm (DPH) (mixed-fiber muscle), isolated from mice lacking the MG29 gene and wild-type mice prior to and after fatigue. Our results indicate that the mutant EDL and SOL muscles, but not DPH, are more susceptible to fatigue than the wild-type muscles. The mutant muscles not only fatigued to a greater extent but also recovered significantly less than the wild-type muscles. Following fatigue, the mutant EDL and SOL muscles produced lower twitch forces than the wild-type muscles; in addition, fatiguing produced a downward shift in the force-frequency relationship in the mutant mice compared with the wild-type controls. Our results indicate that fatiguing affects the E-C components of the mutant EDL and SOL muscles, and the effect of fatigue in these mutant muscles could be primarily due to an alteration in the intracellular Ca homeostasis.

Invasive hemodynamics and force-frequency relationships in open- versus closed-chest mice

1997 ◽  
Vol 273 (5) ◽  
pp. H2528-H2533 ◽  
Author(s):  
Brian D. Hoit ◽  
Nancy Ball ◽  
Richard A. Walsh
Keyword(s):  
Heart Rate ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Force Frequency ◽  
Closed Chest ◽  
Open Chest ◽  
Systolic And Diastolic Function ◽  
Frequency Relationship ◽  
Maximal Rise ◽  
Open Versus

We compared hemodynamics, ventricular function, and force-frequency relationships in six open-chest and six closed-chest anesthetized mice (FVB/N strain). Left ventricular (LV) pressure was measured with a 1.8- or 1.4-Fr Millar catheter placed via the right carotid artery and the LV apex in the closed- and open-chest state, respectively. Pacing was performed with electrodes placed either directly on atrial appendages (open chest) or with a 1-Fr bipolar catheter via the jugular vein (closed chest). Closed-chest animals had greater spontaneous heart rate (267 ± 106 vs. 147 ± 27 beats/min), LV systolic (81 ± 14 vs. 48 ± 9 mmHg) and diastolic pressures (11.2 ± 4.8 vs. 5.6 ± 2.4 mmHg), and maximal rise (+dP/d t max: 6,208 ± 2,519 vs. 3,682 ± 671 mmHg/s) and fall in pressure development (−dP/d t max: −6,094 ± 2,386 vs. −3,001 ± 399 mmHg/s). LV systolic pressure (98 ± 18 vs. 52 ± 11 mmHg), +dP/d t max (9,240 ± 2,459 vs. 5,777 ± 2,473 mmHg/s), and −dP/d t max(−8,375 ± 2,551 vs. −3,753 ± 1,170 mmHg/s) were significantly higher when animals were matched at a heart rate of 420 beats/min in closed-chest vs. open-chest animals. Biphasic force-frequency relationships were seen in all animals, but the critical heart rate was greater in the closed- than open-chest animals (432 ± 42 vs. 318 ± 42 beats/min). We conclude that 1) there are significant differences between invasive indexes of systolic and diastolic function between the closed- and open-chest preparations, 2) there is a biphasic force-frequency relationship in the anesthetized mouse, and 3) dP/d t max can be used to assess the cardiovascular phenotype.

Phospholamban-to-SERCA2 ratio controls the force-frequency relationship

1999 ◽  
Vol 276 (3) ◽  
pp. H779-H785 ◽  
Author(s):  
Markus Meyer ◽  
Wolfgang F. Bluhm ◽  
Huaping He ◽  
Steven R. Post ◽  
Frank J. Giordano ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Transgenic Mice ◽  
Cardiac Myocytes ◽  
Cardiac Contractility ◽  
Adult Rabbit ◽  
Force Frequency ◽  
Papillary Muscles ◽  
Inhibitory Protein ◽  
Frequency Relationship ◽  
Myocyte Contractility

The force-frequency relationship (FFR) describes the frequency-dependent potentiation of cardiac contractility. The interaction of the sarcoplasmic reticulum Ca2+-adenosinetriphosphatase (SERCA2) with its inhibitory protein phospholamban (PLB) might be involved in the control of the FFR. The FFR was analyzed in two systems in which the PLB-to-SERCA2 ratio was modulated. Adult rabbit cardiac myocytes were transduced with adenovirus encoding for SERCA2, PLB, and β-galactosidase (control). After 3 days, the relative PLB/SERCA2 values were significantly different between groups (SERCA2, 0.5; control, 1.0; PLB, 4.5). SERCA2 overexpression shortened relaxation by 23% relative to control, whereas PLB prolonged relaxation by 39% and reduced contractility by 47% (0.1 Hz). When the stimulation frequency was increased to 1.5 Hz, myocyte contractility was increased by 30% in control myocytes. PLB-overexpressing myocytes showed an augmented positive FFR (+78%), whereas SERCA2-transduced myocytes displayed a negative FFR (−15%). A more negative FFR was also found in papillary muscles from SERCA2 transgenic mice. These findings demonstrate that the ratio of phospholamban to SERCA2 is an important component in the control of the FFR.

scholarly journals Enhanced Ca2+ transport and muscle relaxation in skeletal muscle from sarcolipin-null mice

2011 ◽  
Vol 301 (4) ◽  
pp. C841-C849 ◽  
Author(s):  
A. Russell Tupling ◽  
Eric Bombardier ◽  
Subash C. Gupta ◽  
Dawar Hussain ◽  
Chris Vigna ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Relaxation ◽  
Force Frequency ◽  
Relaxation Rates ◽  
Wild Type ◽  
Inhibitory Effects ◽  
Tetanic Force ◽  
Plasmic Reticulum ◽  
Force Relaxation ◽  
Frequency Curves

Sarcolipin (SLN) inhibits sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pumps. To evaluate the physiological significance of SLN in skeletal muscle, we compared muscle contractility and SERCA activity between Sln-null and wild-type mice. SLN protein expression in wild-type mice was abundant in soleus and red gastrocnemius (RG), low in extensor digitorum longus (EDL), and absent from white gastrocnemius (WG). SERCA activity rates were increased in soleus and RG, but not in EDL or WG, from Sln-null muscles, compared with wild type. No differences were seen between wild-type and Sln-null EDL muscles in force-frequency curves or maximum rates of force development (+dF/d t). Maximum relaxation rates (−dF/d t) of EDL were higher in Sln-null than wild type across a range of submaximal stimulation frequencies, but not during a twitch or peak tetanic contraction. For soleus, no differences were seen between wild type and Sln-null in peak tetanic force or +dF/d t; however, force-frequency curves showed that peak force during a twitch and 10-Hz contraction was lower in Sln-null. Changes in the soleus force-frequency curve corresponded with faster rates of force relaxation at nearly all stimulation frequencies in Sln-null compared with wild type. Repeated tetanic stimulation of soleus caused increased (−dF/d t) in wild type, but not in Sln-null. No compensatory responses were detected in analysis of other Ca2+ regulatory proteins using Western blotting and immunohistochemistry or myosin heavy chain expression using immunofluorescence. These results show that 1) SLN regulates Ca2+-ATPase activity thereby regulating contractile kinetics in at least some skeletal muscles, 2) the functional significance of SLN is graded to the endogenous SLN expression level, and 3) SLN inhibitory effects on SERCA function are relieved in response to repeated contractions thus enhancing relaxation rates.

Force-frequency relationship and rest potentiation in papillary muscles of Siberian ground squirrel in the period of preparation to hibernation

2006 ◽  
Vol 407 (1) ◽  
pp. 74-76 ◽  
Author(s):  
O. V. Nakipova ◽  
L. A. Andreeva ◽  
N. A. Chumaeva ◽  
N. M. Zakharova ◽  
N. I. Kukushkin ◽  
...  
Keyword(s):  
Ground Squirrel ◽  
Force Frequency ◽  
Papillary Muscles ◽  
Frequency Relationship

scholarly journals Induced overexpression of phospholemman S68E mutant improves cardiac contractility and mortality after ischemia-reperfusion

2014 ◽  
Vol 306 (7) ◽  
pp. H1066-H1077 ◽  
Author(s):  
JuFang Wang ◽  
Jianliang Song ◽  
Erhe Gao ◽  
Xue-Qian Zhang ◽  
Tongda Gu ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ischemia Reperfusion ◽  
Cardiac Contractility ◽  
Left Ventricular ◽  
Wild Type ◽  
Protein Levels ◽  
Plasmic Reticulum ◽  
Intracellular Ca ◽  
Similar Survival

Phospholemman (PLM), when phosphorylated at Ser68, inhibits cardiac Na+/Ca2+ exchanger 1 (NCX1) and relieves its inhibition on Na+-K+-ATPase. We have engineered mice in which expression of the phosphomimetic PLM S68E mutant was induced when dietary doxycycline was removed at 5 wk. At 8–10 wk, compared with noninduced or wild-type hearts, S68E expression in induced hearts was ∼35–75% that of endogenous PLM, but protein levels of sarco(endo)plasmic reticulum Ca2+-ATPase, α1- and α2-subunits of Na+-K+-ATPase, α1c-subunit of L-type Ca2+ channel, and phosphorylated ryanodine receptor were unchanged. The NCX1 protein level was increased by ∼47% but the NCX1 current was depressed by ∼34% in induced hearts. Isoproterenol had no effect on NCX1 currents but stimulated Na+-K+-ATPase currents equally in induced and noninduced myocytes. At baseline, systolic intracellular Ca2+ concentrations ([Ca2+]i), sarcoplasmic reticulum Ca2+ contents, and [Ca2+]i transient and contraction amplitudes were similar between induced and noninduced myocytes. Isoproterenol stimulation resulted in much higher systolic [Ca2+]i, sarcoplasmic reticulum Ca2+ content, and [Ca2+]i transient and contraction amplitudes in induced myocytes. Echocardiography and in vivo close-chest catheterization demonstrated similar baseline myocardial function, but isoproterenol induced a significantly higher +dP/d t in induced compared with noninduced hearts. In contrast to the 50% mortality observed in mice constitutively overexpressing the S68E mutant, induced mice had similar survival as wild-type and noninduced mice. After ischemia-reperfusion, despite similar areas at risk and left ventricular infarct sizes, induced mice had significantly higher +dP/d t and −dP/d t and lower perioperative mortality compared with noninduced mice. We propose that phosphorylated PLM may be a novel therapeutic target in ischemic heart disease.

Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity

2004 ◽  
Vol 286 (3) ◽  
pp. H1146-H1153 ◽  
Author(s):  
Jo El J. Schultz ◽  
Betty J. Glascock ◽  
Sandra A. Witt ◽  
Michelle L. Nieman ◽  
Kalpana J. Nattamai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Wild Type ◽  
Human Heart Failure ◽  
Protein Levels ◽  
Plasmic Reticulum ◽  
Lv Mass ◽  
Pump Activity

We recently developed a mouse model with a single functional allele of Serca2 ( Serca2+/–) that shows impaired cardiac contractility and relaxation without overt heart disease. The goal of this study was to test the hypothesis that chronic reduction in sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2 levels in combination with an increased hemodynamic load will result in an accelerated pathway to heart failure. Age-matched wild-type and Serca2+/– mice were subjected to 10 wk of pressure overload via transverse aortic coarctation surgery. Cardiac hypertrophy and heart failure were assessed by echocardiography, gravimetry/histology, hemodynamics, and Western blotting analyses. Our results showed that ∼64% of coarcted Serca2+/– mice were in heart failure compared with 0% of coarcted wild-type mice ( P < 0.05). Overall, morbidity and mortality were greatly increased in Serca2+/– mice under pressure overload. Echocardiography assessment revealed a significant increase in left ventricular (LV) mass, and LV hypertrophy in coarcted Serca2+/– mice converted from a concentric to an eccentric pattern, similar to that seen in human heart failure. Coarcted Serca2+/– mice had decreased contractile/systolic and relaxation/diastolic performance and/or function compared with coarcted wild-type mice ( P < 0.05), despite a similar duration and degree of pressure overload. SERCA2a protein levels were significantly reduced (>50%) in coarcted Serca2+/– mice compared with noncoarcted and coarcted wild-type mice. Our findings suggest that reduction in SERCA2 levels in combination with an increased hemodynamic load results in an accelerated pathway to heart failure.

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