scholarly journals Interactions of Dichlorodiphenyltrichloroethane (DDT) and Dichlorodiphenyldichloroethylene (DDE) With Skeletal Muscle Ryanodine Receptor Type 1

2019 ◽  
Vol 170 (2) ◽  
pp. 509-524
Author(s):  
Kim M Truong ◽  
Gennady Cherednichenko ◽  
Isaac N Pessah
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Membrane Vesicles ◽  
Receptor Type ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Voltage Gated Sodium Channels ◽  
Muscle Health ◽  
Living Organisms

Abstract Dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) are ubiquitous in the environment and detected in tissues of living organisms. Although DDT owes its insecticidal activity to impeding closure of voltage-gated sodium channels, it mediates toxicity in mammals by acting as an endocrine disruptor (ED). Numerous studies demonstrate DDT/DDE to be EDs, but studies examining muscle-specific effects mediated by nonhormonal receptors in mammals are lacking. Therefore, we investigated whether o,p′-DDT, p,p′-DDT, o,p′-DDE, and p,p′-DDE (DDx, collectively) alter the function of ryanodine receptor type 1 (RyR1), a protein critical for skeletal muscle excitation-contraction coupling and muscle health. DDx (0.01–10 µM) elicited concentration-dependent increases in [3H]ryanodine ([3H]Ry) binding to RyR1 with o,p′-DDE showing highest potency and efficacy. DDx also showed sex differences in [3H]Ry-binding efficacy toward RyR1, where [3H]Ry-binding in female muscle preparations was greater than male counterparts. Measurements of Ca2+ transport across sarcoplasmic reticulum (SR) membrane vesicles further confirmed DDx can selectively engage with RyR1 to cause Ca2+ efflux from SR stores. DDx also disrupts RyR1-signaling in HEK293T cells stably expressing RyR1 (HEK-RyR1). Pretreatment with DDx (0.1–10 µM) for 100 s, 12 h, or 24 h significantly sensitized Ca2+-efflux triggered by RyR agonist caffeine in a concentration-dependent manner. o,p′-DDE (24 h; 1 µM) significantly increased Ca2+-transient amplitude from electrically stimulated mouse myotubes compared with control and displayed abnormal fatigability. In conclusion, our study demonstrates DDx can directly interact and modulate RyR1 conformation, thereby altering SR Ca2+-dynamics and sensitize RyR1-expressing cells to RyR1 activators, which may ultimately contribute to long-term impairments in muscle health.

Treatment of Normal Skeletal Muscle with FK506 or Rapamycin Results in Halothane-induced Muscle Contracture

1998 ◽  
Vol 89 (3) ◽  
pp. 693-698. ◽  
Author(s):  
Richard L. Brooksbank ◽  
Margaret E. Badenhorts ◽  
Hyam Isaacs ◽  
Nerina Savage
Keyword(s):  
Carbon Dioxide ◽  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Human Skeletal Muscle ◽  
Receptor Type ◽  
Muscle Strip ◽  
Healthy Human ◽  
Healthy Persons

Background FKBP12 is a protein that is closely associated with the ryanodine receptor type 1 of skeletal muscle and modulates Ca2+ release by the channel. The immunosuppressants FK506 and rapamycin both bind to FKBP12 and in turn dissociate the protein from the ryanodine receptor. By treating healthy human skeletal muscle strips with FK506 or rapamycin and then subjecting the strips to the caffeine-halothane contracture test, this study determined that FK506 and rapamycin alter the sensitivity of the muscle strip to halothane, caffeine, or both. Methods Skeletal muscle strips from 10 healthy persons were incubated in Krebs medium equilibrated with a 95% oxygen and 5% carbon dioxide mixture, which contained either 12 microM FK506 (n = 8) or 12 microM rapamycin (n = 6), for 15 min at 37 degrees C. The strips were subjected to the caffeine-halothane contracture test for malignant hyperthermia according to the European Malignant Hyperthermia Group protocol. Results Treatment of normal skeletal muscle strips with FK506 and rapamycin resulted in halothane-induced contractures of 0.44+/-0.16 g and 0.6+/-0.49 g, respectively, at 2% halothane. Conclusions The results obtained show that pre-exposure of healthy skeletal muscle strips to either FK506 or rapamycin is sufficient to give rise to halothane-induced contractures. This is most likely caused by destabilization of Ca2+ release by the ryanodine receptor as a result of the dissociation of FKBP12. This finding suggests that a mutation in FKBP12 or changes in its capacity to bind to the ryanodine receptor could alter the halothane sensitivity of the skeletal muscle ryanodine receptor and thereby predispose the person to malignant hyperthermia.

scholarly journals Discovery of Galangin as a Potential DPP-4 Inhibitor That Improves Insulin-Stimulated Skeletal Muscle Glucose Uptake: A Combinational Therapy for Diabetes

2019 ◽  
Vol 20 (5) ◽  
pp. 1228 ◽  
Author(s):  
Poonam Kalhotra ◽  
Veera Chittepu ◽  
Guillermo Osorio-Revilla ◽  
Tzayhri Gallardo-Velázquez
Keyword(s):  
Diabetes Mellitus ◽  
Skeletal Muscle ◽  
Side Effects ◽  
Therapeutic Drug ◽  
Diabetic Patients ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Glucose Levels ◽  
Muscle Health

Dipeptidyl peptidase-4 (DPP-4) is a well-known therapeutic drug target proven to reduce blood glucose levels in diabetes mellitus, and clinically, DPP-4 inhibitors are used in combination with other anti-diabetic agents. However, side effects and skeletal muscle health are not considered in the treatment for diabetic patients. Recently, natural compounds have been proven to inhibit DPP-4 with fewer side effects. In this work, initially, molecular docking simulations revealed that a natural compound, Galangin, possess a binding energy of −24 KJ/mol and interaction residues SER 630 and TYR 547, that are responsible for potent DPP-4 inhibition. In vitro studies showed that galangin not only inhibits DPP-4 in a concentration-dependent manner but also regulates glucose levels, enabling the proliferation of rat L6 skeletal muscle cells. The combination of galangin with insulin benefits regulation of glucose levels significantly in comparison to galangin alone (p < 0.05). These findings suggest the beneficial effect of the use of galangin, both alone or in combination with insulin, to reduce glucose levels and improve skeletal muscle health in diabetes mellitus.

scholarly journals Modifications of skeletal muscle ryanodine receptor type 1 and exercise intolerance in heart failure

2013 ◽  
Vol 32 (9) ◽  
pp. 925-929 ◽  
Author(s):  
Eric Rullman ◽  
Daniel C. Andersson ◽  
Michael Melin ◽  
Steven Reiken ◽  
Donna M. Mancini ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Receptor Type ◽  
Exercise Intolerance

Abstract 237: Antioxidant and Ryanodine Receptor Stabilizing Therapy Prevent Statin-Induced Contractile Dysfunction in a Tissue-Engineered Skeletal Muscle Model

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Malte Tiburcy ◽  
Guenther Engel ◽  
Sonka J Sanders ◽  
Wolfram H Zimmermann
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Muscle Model ◽  
Contractile Dysfunction ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Force Reduction ◽  
Muscle Toxicity

Rationale: Skeletal muscle toxicity of HMG-CoA-reductase inhibitors (statins) ranges from reversible myalgia to irreversible rhabdomyolysis. The underlying molecular mechanisms are not well defined. Tissue engineering models may help to gain insight into these clinically limiting pathologies. Objective: Here we aimed to model a phenotype of reversible myalgia in vitro to decipher mechanisms that contribute to the early stage of statin toxicity. Methods and Results: Engineered skeletal muscle (ESM) was generated from rat myoblasts, matrigel, and collagen. Isometrically suspended ESM developed 1.2±0.1 mN force under tetanic field stimulation (80 Hz; 200 mA; n=25). Exposure of ESM to statins for 5 days resulted in a loss of force and increased fatiguability in a concentration dependent manner. Cerivastatin was identified as the most potent statin with respect to muscle toxicity with a TC50 (=50% force reduction) of 0.02 µmol/L (n=25/group). Interestingly, at low cerivastatin concentration (0.01 µmol/L) contractile force of ESM was impaired without obvious signs for structural muscle damage (sarcomeric actin content, CK activity unchanged, n=4). Importantly, ESM dysfunction was fully reversible if challenged with TC50 statin concentrations (n=12-14/group). We reasoned that contractile dysfunction with increased fatiguability resulted from calcium leak via the ryanodine receptor. To test this hypothesis we co-administered S107 and observed a concentration-dependent inhibition of statin-induced force reduction (n=12) and calpain activitiy (a calcium-dependent protease, n=4-6). We further argued that RYR destabilization may have been caused by reactive nitrogen (RNS) and/or reactive oxygen species (ROS). Interestingly, the antioxidant N-acetyl cysteine (1 mmol/L, n=3/group), but not L-NAME (10 mmol/L; NO-synthase inhibition, n=6-12/group) prevented contractile dysfunction. Conclusion: We utilized a novel tissue engineered skeletal muscle model to decipher mechanisms of statin-induced muscle toxicity and provide evidence for a central role of ryanodine receptor leak, possibly caused by oxidative damage. Our data suggest that antioxidant and RYR-stabilizing approaches may be useful in counteracting statin myopathy.

scholarly journals Inositol 1,4,5 Trisphosphate Receptor Type 1 (IP3R1) Activate Ryanodine Receptor (RyR1) to Mediate Ca2+ Spark Signaling in Adult Mammalian Skeletal Muscle

2012 ◽  
Vol 102 (3) ◽  
pp. 226a
Author(s):  
Andoria Tjondrokoesoemo ◽  
Na Li ◽  
Zui Pan ◽  
Christopher J. Ferrante ◽  
Noah Weisleder ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Receptor Type ◽  
Mammalian Skeletal Muscle ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

scholarly journals Ryanodine Receptor Type 2: A Molecular Target for Dichlorodiphenyltrichloroethane (DDT)- and Dichlorodiphenyldichloroethylene (DDE)-Mediated Cardiotoxicity

2020 ◽  
Author(s):  
Kim M Truong ◽  
Wei Feng ◽  
Isaac N Pessah
Keyword(s):  
Ryanodine Receptor ◽  
Cardiac Tissue ◽  
Induced Pluripotent Stem Cell ◽  
Receptor Type ◽  
Wildtype Mouse ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Human Cardiomyocytes ◽  
Pre Treatment

Abstract Dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyl-dichloroethylene (DDE) are ubiquitously found in the environment and linked to cardiovascular diseases (CVDs) – with a majority of the work focused on hypertension. Studies investigating whether DDx can interact with molecular targets on cardiac tissue to directly affect cardiac function are lacking. Therefore, we investigated whether o,p’-DDT, p,p’-DDT, o,p’-DDE, or p,p’-DDE (DDx, collectively) can directly alter the function of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) by assessing their effect(s) on hiPSC-CMs Ca2+ dynamics. DDx (0.1-10 µM) affected hiPSC-CMs synchronous Ca2+ oscillation (SCO) frequency in a concentration-dependent manner, with p,p’-DDT and p,p’-DDE also decreasing Ca2+ stores. HEK-RyR2 cells cultured under antibiotic selection to induce expression of wildtype mouse ryanodine receptor type 2 are used to further investigate whether DDx alters hiPSC-CMs Ca2+ dynamics through engagement with ryanodine receptor type 2 (RyR2), a protein critical for cardiac muscle excitation-contraction coupling (ECC). Acute treatment with 10 µM DDx failed to induce Ca2+ release in HEK293-RyR2, whereas pre-treatment with DDx (0.1-10 µM) for 12- or 24-h significantly decreased SR Ca2+ stores in HEK-RyR2 cells challenged with caffeine (1 mM), an RyR agonist. [3H]ryanodine binding analysis using murine cardiac RyR2 homogenates further confirmed that all DDx isomers (10 µM) can directly engage with RyR2 to favor an open (leaky) confirmation, whereas only the DDT isomers (10 µM) modestly (≤10%) inhibited SERCA2a activity. The data demonstrate that DDx increases heart rate and depletes Ca2+ stores in human cardiomyocytes through a mechanism that impairs RyR2 function and Ca2+ dynamics.

Two novel types of calcium release from skeletal sarcoplasmic reticulum by phosphatidylinositol 4,5-bisphosphate

1999 ◽  
Vol 77 (4) ◽  
pp. 276-285 ◽  
Author(s):  
Yasushi Ohizumi ◽  
Yutaka Hirata ◽  
Atsuko Suzuki ◽  
Masaki Kobayashi
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Ruthenium Red ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Steady Level ◽  
Ryanodine Receptor 1 ◽  
Sarcoplasmic Reticulum Calcium

In both the heavy and light fractions of fragmented sarcoplasmic reticulum (SR) vesicles from the fast skeletal muscle, about 27 min after beginning the active Ca2+ uptake, the extravesicular Ca2+ concentration suddenly increased to reach a steady level (delayed Ca2+ release). Phosphatidylinositol 4,5-bisphosphate (PIP2) not only shortened the time to delayed Ca2+ release but also induced prompt Ca2+ release from the heavy fraction of SR. Delayed Ca2+ release and prompt Ca2+ release stimulated by 100 µM PIP2 were not modified by ruthenium red. PIP2 (>0.1 µM) markedly accelerated the rate of 45Ca2+ efflux from SR vesicles in a concentration-dependent manner. The PIP2-induced 45Ca2+ efflux was potentiated by ruthenium red but profoundly inhibited by La3+. The concentration-response curve for Ca2+ or Mg2+ in PIP2-induced 45Ca2+ release was clearly different from that in the Ca2+-induced Ca2+ release. PIP2 caused a concentration-dependent increase in Ca2+ release from SR of chemically skinned fibers from skeletal muscle. Furthermore, [3H]ryanodine or [3H]methyl-7-bromoeudistomin D (MBED) binding to SR was increased by PIP2 in a concentration-dependent manner. These observations present the first evidence that PIP2 most likely activates two types of SR Ca2+ release channels whose properties are entirely different from those of Ca2+-induced Ca2+ release channels (the ryanodine receptor 1).Key words: phosphatidylinositol 4,5-bisphosphate, sarcoplasmic reticulum, calcium release, ryanodine receptor, ryanodine.

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