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Charles A. Thornton - One of the best experts on this subject based on the ideXlab platform.
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correction of clc 1 splicing eliminates chloride channelopathy and Myotonia in mouse models of myotonic dystrophy
Journal of Clinical Investigation, 2007Co-Authors: Thurman M Wheeler, John D Lueck, Maurice S. Swanson, Robert T Dirksen, Charles A. ThorntonAbstract:In myotonic dystrophy (dystrophia myotonica [DM]), an increase in the excitability of skeletal muscle leads to repetitive action potentials, stiffness, and delayed relaxation. This constellation of features, collectively known as Myotonia, is associated with abnormal alternative splicing of the muscle-specific chloride channel (ClC-1) and reduced conductance of chloride ions in the sarcolemma. However, the mechanistic basis of the chloride channelopathy and its relationship to the development of Myotonia are uncertain. Here we show that a morpholino antisense oligonucleotide (AON) targeting the 3′ splice site of ClC-1 exon 7a reversed the defect of ClC-1 alternative splicing in 2 mouse models of DM. By repressing the inclusion of this exon, the AON restored the full-length reading frame in ClC-1 mRNA, upregulated the level of ClC-1 mRNA, increased the expression of ClC-1 protein in the surface membrane, normalized muscle ClC-1 current density and deactivation kinetics, and eliminated myotonic discharges. These observations indicate that the Myotonia and chloride channelopathy observed in DM both result from abnormal alternative splicing of ClC-1 and that antisense-induced exon skipping offers a powerful method for correcting alternative splicing defects in DM.
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severity type and distribution of myotonic discharges are different in type 1 and type 2 myotonic dystrophy
Muscle & Nerve, 2007Co-Authors: Eric L Logigian, Richard T. Moxley, Nuran Dilek, Emma Ciafaloni, Christine L Quinn, Shree Pandya, Charles A. ThorntonAbstract:To characterize and compare electrical Myotonia in myotonic dystrophy type 1 (DM1) and type 2 (DM2), 16 patients with genetically confirmed DM1 and 17 patients with DM2 underwent standardized concentric needle electromyography of deltoid, biceps, extensor digitorum communis, first dorsal interosseous, tensor fascia lata (TFL), vastus lateralis (VL), tibialis anterior, and thoracic paraspinal muscles. Eight needle insertions per muscle were made by electromyographers blinded to DM type who recorded the presence and type of Myotonia (e.g., classic waxing-waning or less specific waning discharges). Manual muscle testing was performed by a physical therapist. Overall, Myotonia was more elicitable in DM1 than DM2; only in VL and TFL was Myotonia more elicitable in DM2 than DM1. The major type of Myotonia was waxing-waning in DM1, and waning in DM2. Four DM2 (24%), but no DM1 patients had only waning Myotonia. In the arms, Myotonia was distally predominant in both DM1 and DM2. In the legs, it was distally predominant in DM1, but both proximal and distal in DM2. The severity of Myotonia was positively correlated with muscle weakness and with the presence of waxing and waning discharges in DM1, but with neither in DM2. Thus, Myotonia is qualitatively and quantitatively different in DM1 than DM2. Except for proximal leg muscles, Myotonia is more evocable in DM1 than DM2. It tends to be waxing-waning in DM1 but waning in DM2, thus making electrodiagnosis of DM2 more challenging. Its severity correlates with muscle weakness and the presence of waxing-waning discharges in DM1 but not DM2.
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expanded cug repeats trigger aberrant splicing of clc 1 chloride channel pre mrna and hyperexcitability of skeletal muscle in myotonic dystrophy
Molecular Cell, 2002Co-Authors: Ami Mankodi, Masanori P. Takahashi, Stephen C. Cannon, Richard T. Moxley, Hong Jiang, Carol L Beck, William J Bowers, Charles A. ThorntonAbstract:In myotonic dystrophy (dystrophia myotonica, DM), expression of RNAs that contain expanded CUG or CCUG repeats is associated with degeneration and repetitive action potentials (Myotonia) in skeletal muscle. Using skeletal muscle from a transgenic mouse model of DM, we show that expression of expanded CUG repeats reduces the transmembrane chloride conductance to levels well below those expected to cause Myotonia. The expanded CUG repeats trigger aberrant splicing of pre-mRNA for ClC-1, the main chloride channel in muscle, resulting in loss of ClC-1 protein from the surface membrane. We also have identified a similar defect in ClC-1 splicing and expression in two types of human DM. We propose that a transdominant effect of mutant RNA on RNA processing leads to chloride channelopathy and membrane hyperexcitability in DM.
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expanded cug repeats trigger aberrant splicing of clc 1 chloride channel pre mrna and hyperexcitability of skeletal muscle in myotonic dystrophy
Molecular Cell, 2002Co-Authors: Ami Mankodi, Masanori P. Takahashi, Stephen C. Cannon, Richard T. Moxley, Hong Jiang, Carol L Beck, William J Bowers, Charles A. ThorntonAbstract:Summary Jansen et al., 1996; Berul et al., 1999). It seems unlikely that loss of function for either DMPK or ZNF9 can pro- In myotonic dystrophy (dystrophia myotonica, DM), vide a unitary explanation for the pleomorphic manifes-expression of RNAs that contain expanded CUG or tations of DM. CCUG repeats is associated with degeneration and Unusual and similar features of the RNA produced repetitive action potentials(Myotonia) in skeletal mus- from mutant DM1 or DM2 alleles may explain the clinical cle. Using skeletal muscle from a transgenic mouse similarities in different types of DM. These transcripts model of DM, we show that expression of expanded are retained in the nucleus in one or more discrete foci CUG repeats reduces the transmembrane chloride (Tanejaetal.,1995;Liquorietal.,2001),raisingthepossi- conductance to levels well below those expected to bility that expanded CUG or CCUG repeats may ad- cause Myotonia. The expanded CUG repeats trigger versely affect nuclear function. Recent studies have
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Myotonic dystrophy with no trinucleotide repeat expansion.
Annals of neurology, 1994Co-Authors: Charles A. Thornton, Robert C. Griggs, Richard T. MoxleyAbstract:We report 3 patients from 2 families with myotonic dystrophy who do not show an abnormal expansion of CTG trinucleotide repeats within the myotonic dystrophy gene. Characteristic features of myotonic dystrophy in these patients were frontal balding, cataracts, cardiac conduction abnormalities, and testicular atrophy with Myotonia and muscle weakness. Results of muscle histopathology were consistent with myotonic dystrophy. Genetic analysis of leukocyte and muscle DNA showed a normal number of CTG repeats. The demonstration of normal CTG repeat number for the myotonic dystrophy gene does not exclude the diagnosis of myotonic dystrophy.
Richard T. Moxley - One of the best experts on this subject based on the ideXlab platform.
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The Nineteenth Annual Carrell-Krusen
2016Co-Authors: Richard T. MoxleyAbstract:The recent discoveries that mutations in the genes for the skeletal muscle sodium and chloride channels are responsible, respectively, for paraMyotonia/hyperkalemic periodic paralysis and for Myotonia congenita of Thomsen have made the classification, diagnosis, and treatment of these disorders much easier. The discovery that myotonic dystrophy results from an unstable [CTG]ntrinucleotide expansion has permitted the accurate diagnosis of both symptomatic and asymp-tomatic individuals, and has led to major advances in preventive treatment, including prenatal and genetic counseling. Diseases that resemble the inherited myotonic disorders are now easier to identify, and as a result of genetic testing a new clinical disorder that is similar to but distinct from myotonic dystrophy has emerged. This new disorder, proximal myotonic myopathy, does not appear to be linked to the genes for the sodium or chloride channels, and has cataracts, Myotonia, weakness, and no abnormal expansion of the [CTG]nrepeat in the gene for myotonic dystrophy. This review discusses the diagnosis and treatment of these myotonic disorders. (J Child Neurol 1997;12:116-129)
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Myotonic dystrophy type 2 and related myotonic disorders
2011Co-Authors: Giovanni Meola, Rosanna Cardani, Richard T. MoxleyAbstract:The myotonic disorders result from dysfunction in either the chloride or sodium channel and these disorders fall in the category of nondystrophic Myotonias. The other group is represented by myotonic dystrophies. The myotonic dystrophies are multisystem, autosomal dominantly inherited, highly variable muscle disease more frequent in adults. So far two distinct entities have been described: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2/PROMM). The latter is similar but distinct from classic, myotonic dystrophy of Steinert. In this review, we will focus on clinical features, genetics, pathophysiology, clinical laboratory tests, and treatment of DM2. Related more frequent myotonic disorders (ie, autosomal-dominant and autosomal-recessive Myotonia congenita) will also be described. Sodium channel Myotonia and myotonic-like disorders (ie, Schwartz-Jampel syndrome) will not be covered in this review
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severity type and distribution of myotonic discharges are different in type 1 and type 2 myotonic dystrophy
Muscle & Nerve, 2007Co-Authors: Eric L Logigian, Richard T. Moxley, Nuran Dilek, Emma Ciafaloni, Christine L Quinn, Shree Pandya, Charles A. ThorntonAbstract:To characterize and compare electrical Myotonia in myotonic dystrophy type 1 (DM1) and type 2 (DM2), 16 patients with genetically confirmed DM1 and 17 patients with DM2 underwent standardized concentric needle electromyography of deltoid, biceps, extensor digitorum communis, first dorsal interosseous, tensor fascia lata (TFL), vastus lateralis (VL), tibialis anterior, and thoracic paraspinal muscles. Eight needle insertions per muscle were made by electromyographers blinded to DM type who recorded the presence and type of Myotonia (e.g., classic waxing-waning or less specific waning discharges). Manual muscle testing was performed by a physical therapist. Overall, Myotonia was more elicitable in DM1 than DM2; only in VL and TFL was Myotonia more elicitable in DM2 than DM1. The major type of Myotonia was waxing-waning in DM1, and waning in DM2. Four DM2 (24%), but no DM1 patients had only waning Myotonia. In the arms, Myotonia was distally predominant in both DM1 and DM2. In the legs, it was distally predominant in DM1, but both proximal and distal in DM2. The severity of Myotonia was positively correlated with muscle weakness and with the presence of waxing and waning discharges in DM1, but with neither in DM2. Thus, Myotonia is qualitatively and quantitatively different in DM1 than DM2. Except for proximal leg muscles, Myotonia is more evocable in DM1 than DM2. It tends to be waxing-waning in DM1 but waning in DM2, thus making electrodiagnosis of DM2 more challenging. Its severity correlates with muscle weakness and the presence of waxing-waning discharges in DM1 but not DM2.
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expanded cug repeats trigger aberrant splicing of clc 1 chloride channel pre mrna and hyperexcitability of skeletal muscle in myotonic dystrophy
Molecular Cell, 2002Co-Authors: Ami Mankodi, Masanori P. Takahashi, Stephen C. Cannon, Richard T. Moxley, Hong Jiang, Carol L Beck, William J Bowers, Charles A. ThorntonAbstract:In myotonic dystrophy (dystrophia myotonica, DM), expression of RNAs that contain expanded CUG or CCUG repeats is associated with degeneration and repetitive action potentials (Myotonia) in skeletal muscle. Using skeletal muscle from a transgenic mouse model of DM, we show that expression of expanded CUG repeats reduces the transmembrane chloride conductance to levels well below those expected to cause Myotonia. The expanded CUG repeats trigger aberrant splicing of pre-mRNA for ClC-1, the main chloride channel in muscle, resulting in loss of ClC-1 protein from the surface membrane. We also have identified a similar defect in ClC-1 splicing and expression in two types of human DM. We propose that a transdominant effect of mutant RNA on RNA processing leads to chloride channelopathy and membrane hyperexcitability in DM.
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expanded cug repeats trigger aberrant splicing of clc 1 chloride channel pre mrna and hyperexcitability of skeletal muscle in myotonic dystrophy
Molecular Cell, 2002Co-Authors: Ami Mankodi, Masanori P. Takahashi, Stephen C. Cannon, Richard T. Moxley, Hong Jiang, Carol L Beck, William J Bowers, Charles A. ThorntonAbstract:Summary Jansen et al., 1996; Berul et al., 1999). It seems unlikely that loss of function for either DMPK or ZNF9 can pro- In myotonic dystrophy (dystrophia myotonica, DM), vide a unitary explanation for the pleomorphic manifes-expression of RNAs that contain expanded CUG or tations of DM. CCUG repeats is associated with degeneration and Unusual and similar features of the RNA produced repetitive action potentials(Myotonia) in skeletal mus- from mutant DM1 or DM2 alleles may explain the clinical cle. Using skeletal muscle from a transgenic mouse similarities in different types of DM. These transcripts model of DM, we show that expression of expanded are retained in the nucleus in one or more discrete foci CUG repeats reduces the transmembrane chloride (Tanejaetal.,1995;Liquorietal.,2001),raisingthepossi- conductance to levels well below those expected to bility that expanded CUG or CCUG repeats may ad- cause Myotonia. The expanded CUG repeats trigger versely affect nuclear function. Recent studies have
Stephen C. Cannon - One of the best experts on this subject based on the ideXlab platform.
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expanded cug repeats trigger aberrant splicing of clc 1 chloride channel pre mrna and hyperexcitability of skeletal muscle in myotonic dystrophy
Molecular Cell, 2002Co-Authors: Ami Mankodi, Masanori P. Takahashi, Stephen C. Cannon, Richard T. Moxley, Hong Jiang, Carol L Beck, William J Bowers, Charles A. ThorntonAbstract:Summary Jansen et al., 1996; Berul et al., 1999). It seems unlikely that loss of function for either DMPK or ZNF9 can pro- In myotonic dystrophy (dystrophia myotonica, DM), vide a unitary explanation for the pleomorphic manifes-expression of RNAs that contain expanded CUG or tations of DM. CCUG repeats is associated with degeneration and Unusual and similar features of the RNA produced repetitive action potentials(Myotonia) in skeletal mus- from mutant DM1 or DM2 alleles may explain the clinical cle. Using skeletal muscle from a transgenic mouse similarities in different types of DM. These transcripts model of DM, we show that expression of expanded are retained in the nucleus in one or more discrete foci CUG repeats reduces the transmembrane chloride (Tanejaetal.,1995;Liquorietal.,2001),raisingthepossi- conductance to levels well below those expected to bility that expanded CUG or CCUG repeats may ad- cause Myotonia. The expanded CUG repeats trigger versely affect nuclear function. Recent studies have
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expanded cug repeats trigger aberrant splicing of clc 1 chloride channel pre mrna and hyperexcitability of skeletal muscle in myotonic dystrophy
Molecular Cell, 2002Co-Authors: Ami Mankodi, Masanori P. Takahashi, Stephen C. Cannon, Richard T. Moxley, Hong Jiang, Carol L Beck, William J Bowers, Charles A. ThorntonAbstract:In myotonic dystrophy (dystrophia myotonica, DM), expression of RNAs that contain expanded CUG or CCUG repeats is associated with degeneration and repetitive action potentials (Myotonia) in skeletal muscle. Using skeletal muscle from a transgenic mouse model of DM, we show that expression of expanded CUG repeats reduces the transmembrane chloride conductance to levels well below those expected to cause Myotonia. The expanded CUG repeats trigger aberrant splicing of pre-mRNA for ClC-1, the main chloride channel in muscle, resulting in loss of ClC-1 protein from the surface membrane. We also have identified a similar defect in ClC-1 splicing and expression in two types of human DM. We propose that a transdominant effect of mutant RNA on RNA processing leads to chloride channelopathy and membrane hyperexcitability in DM.
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Defective slow inactivation of sodium channels contributes to familial periodic paralysis
Neurology, 1999Co-Authors: Lawrence J. Hayward, Gisela M. Sandoval, Stephen C. CannonAbstract:Objective: To evaluate the effects of missense mutations within the skeletal muscle sodium (Na) channel on slow inactivation (SI) in periodic paralysis and related myotonic disorders. Background: Na channel mutations in hyperkalemic periodic paralysis and the nondystrophic Myotonias interfere with the normally rapid inactivation of muscle Na currents following an action potential. This defect causes persistent inward Na currents that produce muscle depolarization, Myotonia, or onset of weakness. Distinct from fast inactivation is the process called SI, which limits availability of Na channels on a time scale of seconds to minutes, thereby influencing muscle excitability. Methods: Human Na channel cDNAs containing mutations associated with paralytic and nonparalytic phenotypes were transiently expressed in human embryonic kidney cells for whole-cell Na current recording. Extent of SI over a range of conditioning voltages (−120 to +20 mV) was defined as the fraction of Na current that failed to recover within 20 ms at −100 mV. The time course of entry to SI at −30 mV was measured using a conditioning pulse duration of 20 ms to 60 seconds. Recovery from SI at −100 mV was assessed over 20 ms to 10 seconds. Results: The two most common hyperkalemic periodic paralysis (HyperPP) mutations responsible for episodic attacks of weakness or paralysis, T704M and M1592V, showed clearly impaired SI, as we and others have observed previously for the rat homologs of these mutations. In addition, a new paralysis-associated mutant, I693T, with cold-induced weakness, exhibited a comparable defect in SI. However, SI remained intact for both the HyperPP/paraMyotonia congenita (PMC) mutant, A1156T, and the nonparalytic potassium-aggravated Myotonia (PAM) mutant, V1589M. Conclusions: SI is defective in a subset of mutant Na channels associated with episodic weakness (HyperPP or PMC) but remains intact for mutants studied so far that cause Myotonia without weakness (PAM).
Ami Mankodi - One of the best experts on this subject based on the ideXlab platform.
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expanded cug repeats trigger aberrant splicing of clc 1 chloride channel pre mrna and hyperexcitability of skeletal muscle in myotonic dystrophy
Molecular Cell, 2002Co-Authors: Ami Mankodi, Masanori P. Takahashi, Stephen C. Cannon, Richard T. Moxley, Hong Jiang, Carol L Beck, William J Bowers, Charles A. ThorntonAbstract:In myotonic dystrophy (dystrophia myotonica, DM), expression of RNAs that contain expanded CUG or CCUG repeats is associated with degeneration and repetitive action potentials (Myotonia) in skeletal muscle. Using skeletal muscle from a transgenic mouse model of DM, we show that expression of expanded CUG repeats reduces the transmembrane chloride conductance to levels well below those expected to cause Myotonia. The expanded CUG repeats trigger aberrant splicing of pre-mRNA for ClC-1, the main chloride channel in muscle, resulting in loss of ClC-1 protein from the surface membrane. We also have identified a similar defect in ClC-1 splicing and expression in two types of human DM. We propose that a transdominant effect of mutant RNA on RNA processing leads to chloride channelopathy and membrane hyperexcitability in DM.
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expanded cug repeats trigger aberrant splicing of clc 1 chloride channel pre mrna and hyperexcitability of skeletal muscle in myotonic dystrophy
Molecular Cell, 2002Co-Authors: Ami Mankodi, Masanori P. Takahashi, Stephen C. Cannon, Richard T. Moxley, Hong Jiang, Carol L Beck, William J Bowers, Charles A. ThorntonAbstract:Summary Jansen et al., 1996; Berul et al., 1999). It seems unlikely that loss of function for either DMPK or ZNF9 can pro- In myotonic dystrophy (dystrophia myotonica, DM), vide a unitary explanation for the pleomorphic manifes-expression of RNAs that contain expanded CUG or tations of DM. CCUG repeats is associated with degeneration and Unusual and similar features of the RNA produced repetitive action potentials(Myotonia) in skeletal mus- from mutant DM1 or DM2 alleles may explain the clinical cle. Using skeletal muscle from a transgenic mouse similarities in different types of DM. These transcripts model of DM, we show that expression of expanded are retained in the nucleus in one or more discrete foci CUG repeats reduces the transmembrane chloride (Tanejaetal.,1995;Liquorietal.,2001),raisingthepossi- conductance to levels well below those expected to bility that expanded CUG or CCUG repeats may ad- cause Myotonia. The expanded CUG repeats trigger versely affect nuclear function. Recent studies have
Masanori P. Takahashi - One of the best experts on this subject based on the ideXlab platform.
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expanded cug repeats trigger aberrant splicing of clc 1 chloride channel pre mrna and hyperexcitability of skeletal muscle in myotonic dystrophy
Molecular Cell, 2002Co-Authors: Ami Mankodi, Masanori P. Takahashi, Stephen C. Cannon, Richard T. Moxley, Hong Jiang, Carol L Beck, William J Bowers, Charles A. ThorntonAbstract:Summary Jansen et al., 1996; Berul et al., 1999). It seems unlikely that loss of function for either DMPK or ZNF9 can pro- In myotonic dystrophy (dystrophia myotonica, DM), vide a unitary explanation for the pleomorphic manifes-expression of RNAs that contain expanded CUG or tations of DM. CCUG repeats is associated with degeneration and Unusual and similar features of the RNA produced repetitive action potentials(Myotonia) in skeletal mus- from mutant DM1 or DM2 alleles may explain the clinical cle. Using skeletal muscle from a transgenic mouse similarities in different types of DM. These transcripts model of DM, we show that expression of expanded are retained in the nucleus in one or more discrete foci CUG repeats reduces the transmembrane chloride (Tanejaetal.,1995;Liquorietal.,2001),raisingthepossi- conductance to levels well below those expected to bility that expanded CUG or CCUG repeats may ad- cause Myotonia. The expanded CUG repeats trigger versely affect nuclear function. Recent studies have
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expanded cug repeats trigger aberrant splicing of clc 1 chloride channel pre mrna and hyperexcitability of skeletal muscle in myotonic dystrophy
Molecular Cell, 2002Co-Authors: Ami Mankodi, Masanori P. Takahashi, Stephen C. Cannon, Richard T. Moxley, Hong Jiang, Carol L Beck, William J Bowers, Charles A. ThorntonAbstract:In myotonic dystrophy (dystrophia myotonica, DM), expression of RNAs that contain expanded CUG or CCUG repeats is associated with degeneration and repetitive action potentials (Myotonia) in skeletal muscle. Using skeletal muscle from a transgenic mouse model of DM, we show that expression of expanded CUG repeats reduces the transmembrane chloride conductance to levels well below those expected to cause Myotonia. The expanded CUG repeats trigger aberrant splicing of pre-mRNA for ClC-1, the main chloride channel in muscle, resulting in loss of ClC-1 protein from the surface membrane. We also have identified a similar defect in ClC-1 splicing and expression in two types of human DM. We propose that a transdominant effect of mutant RNA on RNA processing leads to chloride channelopathy and membrane hyperexcitability in DM.
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calcium increase in mouse skeletal muscles by triparanol a drug to induce myotonic dystrophy like clinical manifestations
Neuroscience Letters, 1999Co-Authors: Masanori P. Takahashi, Takehiko Yanagihara, Takashi Kimura, Saburo SakodaAbstract:Triparanol (Trp) is known to cause clinical features similar to those seen in myotonic dystrophy, including Myotonia, cataract and baldness. To explore the pathophysiological mechanism of myotonic dystrophy, we examined the effect of Trp on intracellular calcium in cultured skeletal myoblasts and myotubes as well as cardiac myocytes by using a fluorescent indicator. Trp preferentially induced increase of intracellular calcium in myotubes of skeletal muscles. Since the increase of calcium was inhibited by thapsigargin pretreatment but not by extracellular calcium elimination, it appears that triparanol might act mostly on intracellular calcium stores. Trp also inhibited the increase of calcium in myotubes induced by acetylcholine. Trp might cause Myotonia possibly through the increase of intracellular calcium from intracellular stores.
