Role of calpain in eccentric contraction-induced proteolysis of Ca2+-regulatory proteins and force depression in rat fast-twitch skeletal muscle

2017 ◽  
Vol 122 (2) ◽  
pp. 396-405 ◽  
Author(s):  
Keita Kanzaki ◽  
Daiki Watanabe ◽  
Mai Kuratani ◽  
Takashi Yamada ◽  
Satoshi Matsunaga ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Force Production ◽  
Eccentric Contraction ◽  
Dihydropyridine Receptor ◽  
Regulatory Proteins ◽  
Calpain Inhibitor ◽  
Contributing Factors ◽  
Fast Twitch

The aim of this study was to examine the in vivo effects of eccentric contraction (ECC) on calpain-dependent proteolysis of Ca2+-regulatory proteins and force production in fast-twitch skeletal muscles. Rat extensor digitorum longus muscles were exposed to 200 repeated ECC in situ and excised immediately [recovery 0 (REC0)] or 3 days [recovery 3 (REC3)] after cessation of ECC. Calpain inhibitor (CI)-treated rats were intraperitoneally injected with MDL-28170 before ECC and during REC3. Tetanic force was markedly reduced at REC0 and remained reduced at REC3. CI treatment ameliorated the ECC-induced force decline but only at REC3. No evidence was found for proteolysis of dihydropyridine receptor (DHPR), junctophilin (JP)1, JP2, ryanodine receptor (RyR), sarcoplasmic reticulum Ca2+-ATPase (SERCA)1a, or junctional face protein-45 at REC0. At REC3, ECC resulted in decreases in DHPR, JP1, JP2, RyR, and SERCA1a. CI treatment prevented the decreases in DHPR, JP1, and JP2, whereas it had little effect on RyR and SERCA1a. These findings suggest that DHPR, JP1, and JP2, but not RyR and SERCA1a, undergo calpain-dependent proteolysis in in vivo muscles subjected to ECC and that impaired function of DHPR and/or JP might cause prolonged force deficits with ECC. NEW & NOTEWORTHY Calpain-dependent proteolysis is one of the contributing factors to muscle damage that occurs with eccentric contraction (ECC). It is unclear, however, whether calpains account for proteolysis of Ca2+-regulatory proteins in in vivo muscles subjected to ECC. Here, we provide evidence that dihydropyridine receptor and junctophilin, but not ryanodine receptor and sarcoplasmic reticulum Ca2+-ATPase, undergo calpain-dependent proteolysis.

scholarly journals Effect of Dietary Nitrate on Force Production and Sarcoplasmic Reticulum Ca<sup>2+</sup> Handling in Rat Fast-Twitch Muscles Following Eccentric Contraction

2018 ◽  
Vol 08 (12) ◽  
pp. 607-618 ◽  
Author(s):  
Satoshi Matsunaga ◽  
Chihiro Aibara ◽  
Daiki Watanabe ◽  
Keita Kanzaki ◽  
Yurie Morizaki ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Force Production ◽  
Eccentric Contraction ◽  
Dietary Nitrate ◽  
Fast Twitch

scholarly journals Calmodulin sensitivity of the sarcoplasmic reticulum ryanodine receptor from normal and malignant-hyperthermia-susceptible muscle

1996 ◽  
Vol 319 (2) ◽  
pp. 421-426 ◽  
Author(s):  
Sean O'DRISCOLL ◽  
Tommie V. McCARTHY ◽  
Hans M. EICHINGER ◽  
Wolf ERHARDT ◽  
Frank LEHMANN-HORN ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Central Region ◽  
Dependent Manner ◽  
Release Channel ◽  
Malignant Hyperthermia Susceptible ◽  
Potential Binding ◽  
Cam Regulation

Ca2+ release from sarcoplasmic reticulum (SR) of malignant-hyperthermia-susceptible (MHS) muscle is hypersensitive to Ca2+ and caffeine. To determine if an abnormal calmodulin (CaM) regulation of the SR Ca2+-release-channel-ryanodine-receptor complex (RYR1) contributes to this hypersensitivity, we investigated the effect of CaM on high-affinity [3H]ryanodine binding to isolated SR vesicles from normal and MHS pig skeletal muscle. CaM modulated [3H]ryanodine binding in a Ca2+-dependent manner. In the presence of maximally activating Ca2+ concentrations, CaM inhibited [3H]ryanodine binding with no differences between normal and MHS vesicles. In the absence of Ca2+, however, CaM activated [3H]ryanodine binding with a 2-fold-higher potency in MHS vesicles. Significant differences between normal and MHS tissue were observed for CaM concentrations between 50 nM and 10 µM. A polyclonal antibody raised against the central region of RYR1 specifically inhibited this activating effect of CaM without affecting the inhibition by CaM. This indicates that the central region of RYR1 is a potential binding domain for CaM in the absence of Ca2+. It is suggested that in vivo an enhanced CaM sensitivity of RYR1 might contribute to the abnormal high release of Ca2+ from the SR of MHS muscle.

Calcium activation of sarcoplasmic reticulum ATPase following strenuous activity

1981 ◽  
Vol 59 (12) ◽  
pp. 1214-1218 ◽  
Author(s):  
A. N. Belcastro ◽  
M. Rossiter ◽  
M. P. Low ◽  
M. M. Sopper
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Atpase Activity ◽  
Wistar Rats ◽  
Force Production ◽  
Tetraacetic Acid ◽  
Strenuous Activity ◽  
Significant Difference ◽  
Significant Depression ◽  
Gastrocnemius Muscles ◽  
Fast Twitch

The purpose of this study was to examine the effects of varying Ca2+ concentration on the Ca2+ activated sarcoplasmic reticulum (SR) ATPase activity of fast-twitch (FT) skeletal muscle at exhaustion and during recovery. Wistar rats (200 g) were assigned to control (C), exhausted (E), and three recovery groups (R) at 5, 15, and 30 min. Following exhaustion on a motor-driven treadmill, the gastrocnemius muscles from all groups were excised and frozen. Muscle samples were assayed for ATPase activity in a Ca2+ – ethyleneglycol bis (β-aminoethyl ether)-N,N′-tetraacetic acid (EGTA) buffering system. At 1.25 μM Ca2+, a significant depression in Ca2+ activated ATPase activity occurred in the E, 5R, 15R, and 30R groups (1.61 ± 0.17, 1.87 ± 0.14, 1.43 ± 0.29, and 1.62 ± 0.1 μmol Pi∙mg−1∙10 min−1) compared with C values (2.41 ± 0.34 μmol Pi∙mg−1∙10 min−1) (p ≤ 0.05). At 5.0 μM, Ca2+ activated ATPase activity remained depressed in the E, 5R, and 15R groups compared with C and 30R groups (p ≤ 0.05). At 0.75 μM Ca2+, there was no significant difference between groups (p ≥ 0.05). The results suggest that Ca2+ activated SR ATPase activity of fatigued FT muscle may contribute to the decreased force production at exhaustion.

scholarly journals Ryanodine receptor fragmentation and sarcoplasmic reticulum Ca2+ leak after one session of high-intensity interval exercise

2015 ◽  
Vol 112 (50) ◽  
pp. 15492-15497 ◽  
Author(s):  
Nicolas Place ◽  
Niklas Ivarsson ◽  
Tomas Venckunas ◽  
Daria Neyroud ◽  
Marius Brazaitis ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
High Intensity ◽  
Human Subjects ◽  
Force Production ◽  
Interval Training ◽  
Endurance Athletes ◽  
Release Channel ◽  
Force Depression ◽  
High Intensity Interval

High-intensity interval training (HIIT) is a time-efficient way of improving physical performance in healthy subjects and in patients with common chronic diseases, but less so in elite endurance athletes. The mechanisms underlying the effectiveness of HIIT are uncertain. Here, recreationally active human subjects performed highly demanding HIIT consisting of 30-s bouts of all-out cycling with 4-min rest in between bouts (≤3 min total exercise time). Skeletal muscle biopsies taken 24 h after the HIIT exercise showed an extensive fragmentation of the sarcoplasmic reticulum (SR) Ca2+ release channel, the ryanodine receptor type 1 (RyR1). The HIIT exercise also caused a prolonged force depression and triggered major changes in the expression of genes related to endurance exercise. Subsequent experiments on elite endurance athletes performing the same HIIT exercise showed no RyR1 fragmentation or prolonged changes in the expression of endurance-related genes. Finally, mechanistic experiments performed on isolated mouse muscles exposed to HIIT-mimicking stimulation showed reactive oxygen/nitrogen species (ROS)-dependent RyR1 fragmentation, calpain activation, increased SR Ca2+ leak at rest, and depressed force production due to impaired SR Ca2+ release upon stimulation. In conclusion, HIIT exercise induces a ROS-dependent RyR1 fragmentation in muscles of recreationally active subjects, and the resulting changes in muscle fiber Ca2+-handling trigger muscular adaptations. However, the same HIIT exercise does not cause RyR1 fragmentation in muscles of elite endurance athletes, which may explain why HIIT is less effective in this group.

Skeletal muscle overload upregulates the sarcoplasmic reticulum slow calcium pump gene

1994 ◽  
Vol 266 (5) ◽  
pp. C1190-C1197 ◽  
Author(s):  
S. C. Kandarian ◽  
D. G. Peters ◽  
J. A. Taylor ◽  
J. H. Williams
Keyword(s):  
Skeletal Muscle ◽  
Monoclonal Antibody ◽  
Sarcoplasmic Reticulum ◽  
Cdna Probe ◽  
Force Production ◽  
Surgical Removal ◽  
Muscle Loading ◽  
Protein Isoform ◽  
Fast Twitch ◽  
Kinetics Of

Functional data suggest that the kinetics of force production and relaxation are slowed in hypertrophied skeletal muscle because of chronic overload. The purpose of this study was to determine whether gene expression of the slow/cardiac isoform of the sarcoplasmic reticulum (SR) Ca(2+)-adenosinetriphosphatase (ATPase) pump is upregulated in overloaded fast-twitch plantaris muscles. Increased active muscle loading was induced in rat plantaris muscles bilaterally by surgical removal of gastrocnemius and soleus muscles. Mass of the plantaris muscle was 80% greater 5 wk after surgery than in age-matched unoperated control rats (P < 0.05). Expression of the slow pump mRNA was 135% greater in hypertrophied muscles, as determined from autoradiograms of Northern blots with use of a cDNA probe specific for the slow/cardiac isoform. A monoclonal antibody (7E6) was used to quantify slow Ca2+ pump in SR vesicles with use of Western blot analysis. Densitometry of blots showed that the relative expression of the slow pump protein was 130% greater in hypertrophied plantaris muscles. Expression of the fast SR Ca2+ pump protein isoform, assessed using monoclonal antibody A52, was 25% less in hypertrophied than in control muscles. The Ca2+ uptake rate and ATPase activity of SR vesicles was approximately 15% lower in hypertrophied plantaris muscles (P < 0.05). Differential phospholamban expression could not account for changes in SR Ca2+ handling, because it could not be detected in rat slow- or fast-twitch skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Regulation of dihydropyridine receptor gene expression in mouse skeletal muscles by stretch and disuse

2004 ◽  
Vol 287 (5) ◽  
pp. C1445-C1452 ◽  
Author(s):  
Tatiana L. Radzyukevich ◽  
Judith A. Heiny
Keyword(s):  
Gene Expression ◽  
Skeletal Muscles ◽  
Receptor Gene ◽  
Dihydropyridine Receptor ◽  
Passive Tension ◽  
Nerve Section ◽  
In Vivo Models ◽  
Fast Twitch

This study examined dihydropyridine receptor (DHPR) gene expression in mouse skeletal muscles during physiological adaptations to disuse. Disuse was produced by three in vivo models—denervation, tenotomy, and immobilization—and DHPR α1s mRNA was measured by quantitative Northern blot. After 14-day simultaneous denervation of the soleus (Sol), tibialis anterior (TA), extensor digitorum longus (EDL), and gastrocnemius (Gastr) muscles by sciatic nerve section, DHPR mRNA increased preferentially in the Sol and TA (+1.6-fold), whereas it increased in the EDL (+1.6-fold) and TA (+1.8-fold) after selective denervation of these muscles by peroneal nerve section. It declined in all muscles (−1.3- to −2.6-fold) after 14-day tenotomy, which preserves nerve input but removes mechanical tension. Atrophy was comparable in denervated and tenotomized muscles. These results suggest that factor(s) in addition to inactivity per se, muscle phenotype, or associated atrophy can regulate DHPR gene expression. To test the contribution of passive tension to this regulation, we subjected the same muscles to disuse by limb immobilization in a maximally dorsiflexed position. DHPR α1s mRNA increased in the stretched muscles (Sol, +2.3-fold; Gastr, +1.5-fold) and decreased in the shortened muscles (TA, −1.4-fold; EDL, −1.3-fold). The effect of stretch was confirmed in vitro. DHPR protein did not change significantly after 4-day immobilization, suggesting that additional levels of regulation may exist. These results demonstrate that DHPR α1s gene expression is regulated as an integral part of the adaptive response of skeletal muscles to disuse in both slow- and fast-twitch muscles and identify passive tension as an important signal for its regulation in vivo.

Muscle function and protein metabolism after initiation of eccentric contraction-induced injury

1995 ◽  
Vol 79 (4) ◽  
pp. 1260-1270 ◽  
Author(s):  
D. A. Lowe ◽  
G. L. Warren ◽  
C. P. Ingalls ◽  
D. B. Boorstein ◽  
R. B. Armstrong
Keyword(s):  
Protein Degradation ◽  
Protein Metabolism ◽  
Muscle Function ◽  
Muscle Protein ◽  
Force Production ◽  
Eccentric Contraction ◽  
Skeletal Muscle Function ◽  
Elevated Protein ◽  
Degradation Rates

This study was designed to determine the relationship between skeletal muscle function and protein metabolism after initiation of eccentric contraction-induced injury. Mouse anterior crural muscles were injured in vivo, and then either immediately or 3, 6, 24, 48, 72, 120, or 336 h after injury muscles were isolated and studied for indexes of muscle function, injury, phagocyte infiltration, and protein metabolism. A group of mice were administered anti-polymorphonuclear cell and anti-macrophage antisera in an attempt to reduce phagocytic infiltration into injured muscle. Force production in extensor digitorum longus muscles was reduced 55% immediately after injury induction and did not recover significantly until 120 h postinjury (28% below baseline). However, rates of protein degradation were not elevated until 48 h postinjury (60% above normal) and were not correlated with the changes in force production (r = -0.37; P = 0.24). Phagocytic infiltration was evident 24–120 h postinjury and was correlated with the elevated protein degradation rates (r = 0.75; P < 0.01). Protein synthesis rates began to increase approximately 48 h after injury was induced and were elevated by 83% 5 days postinjury. Fourteen days after injury, muscle protein degradation and synthesis rates had returned to normal, as well as specific force production, and phagocytic infiltration was not detected. However, muscle mass, protein content, and absolute force production were lower than normal. Antisera-treated mice were rendered neutropenic, but there was no difference in any variable measured between muscles from these mice and muscles from normal mice.

Fast-twitch muscle unit properties in different rat medial gastrocnemius muscle compartments

1996 ◽  
Vol 75 (6) ◽  
pp. 2243-2254 ◽  
Author(s):  
C. J. DeRuiter ◽  
A. De Haan ◽  
A. J. Sargeant
Keyword(s):  
Force Production ◽  
Medial Gastrocnemius ◽  
Type I ◽  
Nerve Branch ◽  
Cross Sectional ◽  
Entire Area ◽  
Distal Muscle ◽  
Muscle Compartment ◽  
Fast Twitch

1. The effect of muscle unit (MU) localization on physiological properties was investigated within the fast-twitch fatigue-resistant (FR) and fast-fatigable (FF) MU populations of rat medial gastrocnemius (MG) muscle. Single MG MUs were functionally isolated by microdissection of the ventral roots. FR and FF MU properties of the most proximal and distal muscle compartments were compared. The most proximal and distal compartment are subvolumes of the MG innervated by the most proximal and distal primary nerve branch, respectively. A subsample of the isolated units was glycogen depleted and muscle cross sections were stained for glycogen and myosin-adenosinetriphosphatase. 2. It was shown that proximal FF and FR units reached optimum length for force production at shorter muscle lengths compared with the distal FR and FF units. 3. The fast MUs of the proximal compartment had small territories that were located close to and/or within the mixed region (containing type I, IIA, IIX, and IIB fibers) of the muscle. The fast MUs of the distal compartment had greater territories that were located in the more superficial muscle part (containing only type IIX and IIB fibers) and in some cases spanned the entire area of the distal muscle compartment. 4. FR and FF MUs consisted of muscle fibers identified histochemically as type IIX and IIB, respectively. 5. Within each of the FR and FF MU populations, MUs that were located in the most proximal muscle compartment were more resistant to fatigue compared with the units located in the most distal compartment. 6. Cross-sectional fiber areas were smaller for the proximal FR and FF fibers, but specific force did not differ among units. Consequently, when account was taken of the innervation ratio, the proximal FR and FF units produced less force than distal units of the same type. Tetanic forces were 87 +/- 27 (SD) mN (proximal FR), 154 +/- 53 (SD) mN (distal FR), 142 +/- 25 (SD) mN (proximal FF), and 229 +/- 86 (SD) mN (distal FF). 7. The present findings suggest that with increasing demand placed on rat MG during in vivo locomotion, recruitment is likely to proceed from proximal to distal muscle parts within the FR and FF MU populations.

scholarly journals Increased sensitivity of the ryanodine receptor to halothane-induced oligomerization in malignant hyperthermia-susceptible human skeletal muscle

2004 ◽  
Vol 96 (1) ◽  
pp. 11-18 ◽  
Author(s):  
Louise Glover ◽  
James J. A. Heffron ◽  
Kay Ohlendieck
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Human Skeletal Muscle ◽  
Dihydropyridine Receptor ◽  
Threshold Concentration ◽  
Release Channel ◽  
Functional Dynamics ◽  
Increased Sensitivity

Mutations in the skeletal muscle RyR1 isoform of the ryanodine receptor (RyR) Ca2+-release channel confer susceptibility to malignant hyperthermia, which may be triggered by inhalational anesthetics such as halothane. Using immunoblotting, we show here that the ryanodine receptor, calmodulin, junctin, calsequestrin, sarcalumenin, calreticulin, annexin-VI, sarco(endo)plasmic reticulum Ca2+-ATPase, and the dihydropyridine receptor exhibit no major changes in their expression level between normal human skeletal muscle and biopsies from individuals susceptible to malignant hyperthermia. In contrast, protein gel-shift studies with halothane-treated sarcoplasmic reticulum vesicles from normal and susceptible specimens showed a clear difference. Although the α2-dihydropyridine receptor and calsequestrin were not affected, clustering of the Ca2+-ATPase was induced at comparable halothane concentrations. In the concentration range of 0.014–0.35 mM halothane, anesthetic-induced oligomerization of the RyR1 complex was observed at a lower threshold concentration in the sarcoplasmic reticulum from patients with malignant hyperthermia. Thus the previously described decreased Ca2+-loading ability of the sarcoplasmic reticulum from susceptible muscle fibers is probably not due to a modified expression of Ca2+-handling elements, but more likely a feature of altered quaternary receptor structure or modified functional dynamics within the Ca2+-regulatory apparatus. Possibly increased RyR1 complex formation, in conjunction with decreased Ca2+ uptake, is of central importance to the development of a metabolic crisis in malignant hyperthermia.

scholarly journals Peptide fragments of the dihydropyridine receptor can modulate cardiac ryanodine receptor channel activity and sarcoplasmic reticulum Ca2+ release

2004 ◽  
Vol 379 (1) ◽  
pp. 161-172 ◽  
Author(s):  
Angela F. DULHUNTY ◽  
Suzanne M. CURTIS ◽  
Louise CENGIA ◽  
Magdalena SAKOWSKA ◽  
Marco G. CASAROTTO
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Lipid Bilayers ◽  
Ryanodine Receptor ◽  
Helical Structure ◽  
Dihydropyridine Receptor ◽  
Dependent Manner ◽  
Channel Activity ◽  
Peptide Fragments ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Receptor Channel

We show that peptide fragments of the dihydropyridine receptor II–III loop alter cardiac RyR (ryanodine receptor) channel activity in a cytoplasmic Ca2+-dependent manner. The peptides were AC (Thr-793–Ala-812 of the cardiac dihydropyridine receptor), AS (Thr-671–Leu-690 of the skeletal dihydropyridine receptor), and a modified AS peptide [AS(D-R18)], with an extended helical structure. The peptides added to the cytoplasmic side of channels in lipid bilayers at ≥10 nM activated channels when the cytoplasmic [Ca2+] was 100 nM, but either inhibited or did not affect channel activity when the cytoplasmic [Ca2+] was 10 or 100 µM. Both activation and inhibition were independent of bilayer potential. Activation by AS, but not by AC or AS(D-R18), was reduced at peptide concentrations >1 µM in a voltage-dependent manner (at +40 mV). In control experiments, channels were not activated by the scrambled AS sequence (ASS) or skeletal II–III loop peptide (NB). Resting Ca2+ release from cardiac sarcoplasmic reticulum was not altered by peptide AC, but Ca2+-induced Ca2+ release was depressed. Resting and Ca2+-induced Ca2+ release were enhanced by both the native and modified AS peptides. NMR revealed (i) that the structure of peptide AS(D-R18) is not influenced by [Ca2+] and (ii) that peptide AC adopts a helical structure, particularly in the region containing positively charged residues. This is the first report of specific functional interactions between dihydropyridine receptor A region peptides and cardiac RyR ion channels in lipid bilayers.

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