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.

Intracellular tetanic calcium signals are reduced in fatigue of whole skeletal muscle

1993 ◽  
Vol 264 (3) ◽  
pp. C577-C582 ◽  
Author(s):  
A. J. Baker ◽  
M. C. Longuemare ◽  
R. Brandes ◽  
M. W. Weiner
Keyword(s):  
Skeletal Muscle ◽  
Intracellular Calcium ◽  
Calcium Handling ◽  
Tetanic Stimulation ◽  
Muscle Contractility ◽  
Calcium Signals ◽  
Tetanic Force ◽  
Force Relaxation ◽  
Calcium Removal ◽  
Whole Muscle

Force and intracellular calcium signals were monitored in whole bullfrog semitendinosus muscles during fatigue produced by intermittent tetanic stimulation. Intracellular calcium signals were monitored using the fluorescent calcium-sensitive indicator indo-1 from the ratio of fluorescence intensities (R) at 400 and 470 nm. Fatiguing stimulation caused 1) proportional decreases of tetanic force and R, suggesting a component of the decreased force during fatigue of whole muscle may be due to insufficient calcium to activate contraction; 2) a progressive slowing of the relaxation of both force and R, suggesting slowed force relaxation may be mediated by slowed calcium removal from the myoplasm; 3) an increase of resting level R, suggesting impaired calcium removal from, or increased leakage to the cytosol; 4) prolongation of the twitch contraction, which was paralleled by changes in R. These findings are consistent with previous single fiber studies and suggest that changes in whole muscle contractility with fatigue may be partially mediated by changes in calcium handling by the cell.

scholarly journals Sarcolipin overexpression improves muscle energetics and reduces fatigue

2015 ◽  
Vol 118 (8) ◽  
pp. 1050-1058 ◽  
Author(s):  
Danesh H. Sopariwala ◽  
Meghna Pant ◽  
Sana A. Shaikh ◽  
Sanjeewa A. Goonasekera ◽  
Jeffery D. Molkentin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Performance ◽  
Force Frequency ◽  
Frequency Curve ◽  
Muscle Energetics ◽  
Store Operated Calcium Entry ◽  
Flexor Digitorum Brevis ◽  
Flexor Digitorum ◽  
Muscle Contractile ◽  
Frequency Curves

Sarcolipin (SLN) is a regulator of sarcoendoplasmic reticulum calcium ATPase in skeletal muscle. Recent studies using SLN-null mice have identified SLN as a key player in muscle thermogenesis and metabolism. In this study, we exploited a SLN overexpression ( Sln OE) mouse model to determine whether increased SLN level affected muscle contractile properties, exercise capacity/fatigue, and metabolic rate in whole animals and isolated muscle. We found that Sln OE mice are more resistant to fatigue and can run significantly longer distances than wild-type (WT). Studies with isolated extensor digitorum longus (EDL) muscles showed that Sln OE EDL produced higher twitch force than WT. The force-frequency curves were not different between WT and Sln OE EDLs, but at lower frequencies the pyruvate-induced potentiation of force was significantly higher in Sln OE EDL. SLN overexpression did not alter the twitch and force-frequency curve in isolated soleus muscle. However, during a 10-min fatigue protocol, both EDL and soleus from Sln OE mice fatigued significantly less than WT muscles. Interestingly, Sln OE muscles showed higher carnitine palmitoyl transferase-1 protein expression, which could enhance fatty acid metabolism. In addition, lactate dehydrogenase expression was higher in Sln OE EDL, suggesting increased glycolytic capacity. We also found an increase in store-operated calcium entry (SOCE) in isolated flexor digitorum brevis fibers of Sln OE compared with WT mice. These data allow us to conclude that increased SLN expression improves skeletal muscle performance during prolonged muscle activity by increasing SOCE and muscle energetics.

A KATP channel deficiency affects resting tension, not contractile force, during fatigue in skeletal muscle

2000 ◽  
Vol 279 (5) ◽  
pp. C1351-C1358 ◽  
Author(s):  
B. Gong ◽  
T. Miki ◽  
S. Seino ◽  
J. M. Renaud
Keyword(s):  
Soleus Muscle ◽  
Force Frequency ◽  
Wild Type ◽  
Tetanic Force ◽  
Major Function ◽  
Resting Tension ◽  
Force Recovery ◽  
Fatigue Characteristics ◽  
Old Mice ◽  
Deficient Mice

The objective of this study was to determine how an ATP-sensitive K+ (KATP) channel deficiency affects the contractile and fatigue characteristics of extensor digitorum longus (EDL) and soleus muscle of 2- to 3-mo-old and 1-yr-old mice. KATP channel-deficient mice were obtained by disrupting the Kir6.2 gene that encodes for the protein forming the pore of the channel. At 2–3 mo of age, the force-frequency curve, the twitch, and the tetanic force of EDL and soleus muscle of KATPchannel-deficient mice were not significantly different from those in wild-type mice. However, the tetanic force and maximum rate of force development decreased with aging to a greater extent in EDL and soleus muscle of KATP channel-deficient mice (24–40%) than in muscle of wild-type mice (7–17%). During fatigue, the KATP channel deficiency had no effect on the decrease in tetanic force in EDL and soleus muscle, whereas it caused a significantly greater increase in resting tension when compared with muscle of wild-type mice. The recovery of tetanic force after fatigue was not affected by the deficiency in 2- to 3-mo-old mice, whereas in 1-yr-old mice, force recovery was significantly less in muscle of KATP channel-deficient than wild-type mice. It is suggested that the major function of the KATP channel during fatigue is to reduce the development of a resting tension and not to contribute to the decrease in force. It is also suggested that the KATP channel plays an important role in protecting muscle function in older mice.

scholarly journals Na+-K+-ATPase and Ca2+ clearance proteins in smooth muscle: a functional unit

2010 ◽  
Vol 299 (2) ◽  
pp. H548-H556 ◽  
Author(s):  
Tracy J. Pritchard ◽  
Peggy Sue Bowman ◽  
Andrew Jefferson ◽  
Metiner Tosun ◽  
Ronald M. Lynch ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Myosin Light Chain ◽  
Functional Unit ◽  
Mrna Levels ◽  
Relaxation Rates ◽  
Wild Type ◽  
Plasmic Reticulum ◽  
Smooth Muscle Function ◽  
Intracellular Ca ◽  
Percent Contribution

The Na+-K+-ATPase (NKA) can affect intracellular Ca2+ concentration regulation via coupling to the Na+-Ca2+ exchanger and may be important in myogenic tone. We previously reported that in mice carrying a transgene for the NKA α2-isoform in smooth muscle (α2sm+), the α2-isoform protein as well as the α1-isoform (not contained in the transgene) increased to similar degrees (2–7-fold). Aortas from α2sm+ mice relaxed faster from a KCl-induced contraction, hypothesized to be related to more rapid Ca2+ clearance. To elucidate the mechanisms underlying this faster relaxation, we therefore measured the expression and distribution of proteins involved in Ca2+ clearance. Na+-Ca2+ exchanger, sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), and plasma membrane Ca2+-ATPase (PMCA) proteins were all elevated up to approximately fivefold, whereas actin, myosin light chain, and calponin proteins were not changed in smooth muscle from α2sm+ mice. Interestingly, the corresponding Ca2+ clearance mRNA levels were unchanged. Immunocytochemical data indicate that the Ca2+ clearance proteins are distributed similarly in wild-type and α2sm+ aorta cells. In studies measuring relaxation half-times from a KCl-induced contraction in the presence of pharmacological inhibitors of SERCA and PMCA, we estimated that together these proteins were responsible for ∼60–70% of relaxation in aorta. Moreover, the percent contribution of SERCA and PMCA to relaxation rates in α2sm+ aorta was not significantly different from that in wild-type aorta. The coordinate expressions of NKA and Ca2+ clearance proteins without change in the relative contributions of each individual protein to smooth muscle function suggest that NKA may be but one component of a larger functional Ca2+ clearance system.

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.

scholarly journals Overexpression of HSP10 in skeletal muscle of transgenic mice prevents the age-related fall in maximum tetanic force generation and muscle cross-sectional area

2010 ◽  
Vol 299 (1) ◽  
pp. R268-R276 ◽  
Author(s):  
Anna C. Kayani ◽  
Graeme L. Close ◽  
Wolfgang H. Dillmann ◽  
Ruben Mestril ◽  
Malcolm J. Jackson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Cross Sectional Area ◽  
Force Generation ◽  
Sectional Area ◽  
Wild Type ◽  
Cross Sectional ◽  
Tetanic Force ◽  
Age Related ◽  
Muscle Cross Sectional Area

Skeletal muscle atrophy and weakness are major contributors to frailty and impact significantly on quality of life of older people. Muscle aging is characterized by a loss of maximum tetanic force (Po) generation, primarily due to muscle atrophy, to which mitochondrial dysfunction is hypothesized to contribute. We hypothesized that lifelong overexpression of the mitochondrial heat shock protein (HSP) HSP10 in muscle of mice would protect against development of these deficits. Po generation by extensor digitorum longus muscles of adult and old wild-type and HSP10-overexpressing mice was determined in situ. Muscles were subjected to damaging lengthening contractions, and force generation was remeasured at 3 h or 28 days to examine susceptibility to, and recovery from, damage, respectively. Muscles of old wild-type mice had a 23% deficit in Po generation and a 10% deficit in muscle cross-sectional area compared with muscles of adult wild-type mice. Overexpression of HSP10 prevented this age-related fall in Po generation and reduction in cross-sectional area observed in muscles of old wild-type mice. Additionally, overexpression of HSP10 protected against contraction-induced damage independent of age but did not improve recovery if damage occurred. Preservation of muscle force generation and CSA by HSP10 overexpression was associated with protection against the age-related accumulation of protein carbonyls. Data demonstrate that development of age-related muscle weakness may not be inevitable and show, for the first time, that lifelong overexpression of an HSP prevents the age-related loss of Po generation. These findings support the hypothesis that mitochondrial dysfunction is involved in the development of age-related muscle deficits.

The decay phase of Ca2+ transients in skeletal muscle: regulation and physiologyThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 373-376 ◽  
Author(s):  
A. Russell Tupling
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Muscle Contraction ◽  
Peer Review Process ◽  
Muscle Relaxation ◽  
Dependent Protein Kinase ◽  
Plasmic Reticulum ◽  
Dependent Protein ◽  
Contraction And Relaxation ◽  
Signalling Systems

Cytosolic Ca2+ transients associated with contraction and relaxation cycles in skeletal muscle are primarily dependent on the kinetics of Ca2+ release and Ca2+ uptake by the sarcoplasmic reticulum (SR). In humans, sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs) are solely responsible for the removal of Ca2+ from the cytosol following muscle contraction. There are several signalling systems involved in the acute regulation of SERCAs required to achieve a given Ca2+ transient during muscle contraction–relaxation cycles. Cyclic-AMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase signalling activate SERCAs through the regulation of the endogenous SERCA-regulatory proteins, phospholamban and sarcolipin, both of which are highly expressed in human skeletal muscle. Recent studies on the regulation of SERCA2b in arterial smooth muscle and work from my laboratory on the interaction between SERCAs and the inducible 70-kDa heat shock protein suggests a novel role for redox signalling in regulating SERCA activity. In the absence of fatigue, activation of these signalling systems in response to repeated muscle activity serves to increase the rate of cytosolic free Ca2+ ([Ca2+]f) decay (i.e., SR Ca2+ uptake) and the speed of muscle relaxation.

Effects of intracellular acidosis on Ca2+ activation, contraction, and relaxation of frog skeletal muscle

1995 ◽  
Vol 268 (1) ◽  
pp. C55-C63 ◽  
Author(s):  
A. J. Baker ◽  
R. Brandes ◽  
M. W. Weiner
Keyword(s):  
Skeletal Muscle ◽  
Thin Filament ◽  
Frog Skeletal Muscle ◽  
Intracellular Acidosis ◽  
Tetanic Force ◽  
Force Relaxation ◽  
Cross Bridges ◽  
Contraction And Relaxation ◽  
Initial Force ◽  
Force Relationship

The goal of this study was to determine the effects of intracellular acidosis (pH approximately 6.3) of frog skeletal muscle on force and on intracellular Ca2+ concentration ([Ca2+]i; measured at 20 degrees C using indo 1 fluorescence). Acidosis reduced tetanic force by only 11 +/- 2% (mean +/- SE, n = 8) but increased tetanic [Ca2+]i by 33 +/- 6%, suggesting that acidosis reduced the maximum Ca(2+)-activated force. During relaxation, the [Ca2+]i at half-maximal force was doubled with acidosis, suggesting that acidosis altered the Ca(2+)-force relationship. Acidosis markedly slowed force relaxation and [Ca2+]i decline (time constants fitted to force and [Ca2+]i during relaxation increased by 133 +/- 20 and 68 +/- 13%, respectively, with acidosis), suggesting that slowed force relaxation with acidosis may arise from slowed Ca2+ clearance from the cytosol. Late in relaxation, at approximately 30% of initial force, there was a transient phase of [Ca2+]i increase that was delayed with acidosis in proportion to the slowing of force relaxation. This is consistent with previous suggestions that dissociation of cross-bridges from the thin filament during relaxation promotes Ca2+ release to the cytosol from troponin. This study concludes that in skeletal muscle acidosis has little effect on tetanic force and that the major effects are decreased Ca2+ sensitivity and slower relaxation.

Divergent abnormal muscle relaxation by hypertrophic cardiomyopathy and nemaline myopathy mutant tropomyosins

2002 ◽  
Vol 9 (2) ◽  
pp. 103-111 ◽  
Author(s):  
Daniel E. Michele ◽  
Pierre Coutu ◽  
Joseph M. Metzger
Keyword(s):  
Skeletal Muscle ◽  
Hypertrophic Cardiomyopathy ◽  
Muscle Contraction ◽  
Cardiac Muscle ◽  
Muscle Weakness ◽  
Contractile Function ◽  
Muscle Relaxation ◽  
Nemaline Myopathy ◽  
Force Frequency ◽  
Cardiac Muscle Cells

Mutations in tropomyosin (Tm) have been linked to distinct inherited diseases of cardiac and skeletal muscle, hypertrophic cardiomyopathy (HCM), and nemaline myopathy (NM). How HCM and NM mutations in nearly identical Tm proteins produce the vastly divergent clinical phenotypes of heightened, prolonged cardiac muscle contraction in HCM and skeletal muscle weakness in NM is currently unknown. We report here a direct comparison of the effects of HCM (A63V) and NM (M9R) mutant Tm on membrane-intact myocyte contractile function as assessed by adenoviral gene transfer to fully differentiated cardiac muscle cells. Wild-type, and mutant HCM, and mutant NM proteins were expressed at similar levels in myocytes and incorporated into sarcomeres. Interestingly, HCM mutant Tm produced significantly longer contractions by slowing relaxation, whereas NM mutant Tm produced the opposite effect of accelerated muscle relaxation. We propose slowed relaxation caused by HCM mutant Tm can directly contribute to diastolic dysfunction seen in HCM even without secondary cardiac remodeling. Conversely, hastening of relaxation by NM mutant Tm may shift the force-frequency relationship in skeletal muscle and contribute to muscle weakness seen in NM. Together, these results implicate divergent, abnormal “turning off” of muscle contraction as a cellular basis for the differential pathogenesis of mutant Tm-associated HCM and NM.

Skeletal muscle relaxation rate after fasting or hypocaloric feeding

1991 ◽  
Vol 71 (1) ◽  
pp. 204-209 ◽  
Author(s):  
M. L. Nishio ◽  
K. N. Jeejeebhoy
Keyword(s):  
Skeletal Muscle ◽  
Relaxation Rate ◽  
Muscle Fiber ◽  
Fiber Type ◽  
Muscle Relaxation ◽  
Relaxation Times ◽  
Exponential Phase ◽  
Relaxation Rates ◽  
Type Composition ◽  
Hypocaloric Feeding

The effect of malnutrition on skeletal muscle relaxation is not entirely clear; some studies indicate no change and others a slowing of the relaxation rate. We investigated whether these different results were due to type of malnutrition, muscle fiber type composition, or the index used to express relaxation rate. The effect of a 2-day fast (16% body wt loss) or 1 wk of hypocaloric feeding (22.6% wt loss) on relaxation rates of soleus and extensor digitorum longus (EDL) muscles was studied in situ with the use of anesthetized adult Wistar rats. Relaxation rates were assessed for twitch contractions using half-relaxation times and exponential phase half-times and for tetanic contractions using exponential phase half-times. The rate of relaxation was unaffected by fasting, whereas hypocaloric feeding reduced relaxation rates after twitch and tetanic contractions in both soleus and EDL muscles. We conclude that slowing of skeletal muscle relaxation rate occurs after 1 wk of hypocaloric feeding but not after 2 days of fasting. The slowing is independent of muscle fiber composition, type of contraction, or the index used to express relaxation rate.

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