Alternative splicing of RyR1 alters the efficacy of skeletal EC coupling

Kimura, Takashi; Lueck, John D.; Harvey, Peta J.; Pace, Suzy M.; Ikemoto, Noriaki; Casarotto, Marco G.; Dirksen, Robert T.; Dulhunty, Angela F.

doi:10.1016/j.ceca.2008.11.005

Cited by 51 publications

(47 citation statements)

References 39 publications

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“…Notably, we cannot rule out that amelioration of muscle relaxation also relies on splicing-independent mechanisms. In particular, changes in sodium-and calcium-activated potassium channels or in Ca 2+ homeostasis, which have also been suggested to contribute to myotonia in DM1 (55)(56)(57)(58)(59)(60), may mediate some of the observed effect. Consistently, AMPK has been shown to modulate chloride and potassium channels in several cell types, including cardiomyocytes (61,62).…”

Section: Discussionmentioning

confidence: 99%

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

Brockhoff¹,

Rion²,

Chojnowska³

et al. 2017

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

Brockhoff¹,

Rion²,

Chojnowska³

et al. 2017

Journal of Clinical Investigation

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“…One possible explanation for the divergence in EC-coupling deficit seen in myotubes and adult FDB fibers from heterozygous R163C mice is that adult fibers have more developed Ca 2ϩ release units than myotubes (Flucher and Franzini-Armstrong, 1996). Moreover, myotubes express RyR1 splice variants not found in adult fibers that magnify depolarization-dependent Ca 2ϩ release (Kimura et al, 2009). Alternatively, myotubes express a high-conductance ␣1 Cav 1.1 isoform not found in adult fibers (Tuluc et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Functional and Biochemical Properties of Ryanodine Receptor Type 1 Channels from Heterozygous R163C Malignant Hyperthermia-Susceptible Mice

et al. 2010

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ABSTRACT3 H]Ry receptor occupancy; 3) comparatively higher channel activity, even in reducing glutathione buffer; 4) enhanced RyR1 activity both at 25 and 37°C; and 5) elevated cytoplasmic [Ca 2ϩ ] rest . R163C channels are inherently more active than WT channels, a functional impairment that cannot be reversed by dephosphorylation with protein phosphatase. Dysregulated R163C channels produce a more overt phenotype in myotubes than in adult fibers in the absence of triggering agents, suggesting tighter negative regulation of R163C-RyR1 within the Ca 2ϩ release unit of adult fibers.

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“…The longer t EMG-MMG in DM1 may be explained by the alteration in the splicing of several proteins, such as SERCA1 and CACNA1S, involved in Ca 2+ homeostasis and in excitation-contraction coupling mechanism [6][7][8][9][10] thus possibly leading to a lengthened duration of the dihydropyridine and ryanodine receptors interaction, Ca 2+ release by sarcoplasmic reticulum, and troponin activation [9,10,35].…”

Section: Delays During Muscle Contractionmentioning

confidence: 99%

“…Experimental evidence demonstrates that an alteration in the splicing of several proteins involved in Ca 2+ homeostasis and in excitation-contraction coupling mechanisms may play a pivotal role [6][7][8][9][10]. Myotonia is characterised by a state of pathologically enhanced muscle excitability, in which involuntary trains of action potentials cause a delay in muscle relaxation after contraction [11].…”

Section: Introductionmentioning

confidence: 99%

Electromechanical delay components during skeletal muscle contraction and relaxation in patients with myotonic dystrophy type 1

Esposito

Cè

Rampichini

et al. 2016

Neuromuscular Disorders

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Highlights Patients with myotonic dystrophy type 1 (DM1) were investigated isometrically  We calculated the electromechanical delays during muscle contraction and relaxation  Delays were partitioned into electrochemical and mechanical components  Measurements reliability was very high in both patients and controls  Delays were longer in DM1, especially during muscle relaxation AbstractThe electromechanical delay during muscle contraction and relaxation can be partitioned into mainly electrochemical and mainly mechanical components by an EMG, mechanomyographic, and force combined approach. Components duration and measurements reliability were investigated during contraction and relaxation in a group of patients with myotonic dystrophy type 1 (DM1, n=13) and in healthy controls (n=13). EMG, mechanomyogram, and force were recorded in DM1 and in age-and body-matched controls from tibialis anterior (distal muscle) and vastus lateralis (proximal muscle) muscles during maximum voluntary and electrically-evoked isometric contractions. The electrochemical and mechanical components of the electromechanical delay during muscle contraction and relaxation were calculated off-line. Maximum strength was significantly lower in DM1 than in controls under both experimental conditions. All electrochemical and mechanical components were significantly longer in DM1 in both muscles.Measurements reliability was very high in both DM1 and controls. The high reliability of the measurements and the differences between DM1 patients and controls suggest that the EMG, mechanomyographic, and force combined approach could be utilized as a valid tool to assess the level of neuromuscular dysfunction in this pathology, and to follow the efficacy of pharmacological or non-pharmacological interventions.

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Alternative splicing of RyR1 alters the efficacy of skeletal EC coupling

Cited by 51 publications

References 39 publications

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

Functional and Biochemical Properties of Ryanodine Receptor Type 1 Channels from Heterozygous R163C Malignant Hyperthermia-Susceptible Mice

Electromechanical delay components during skeletal muscle contraction and relaxation in patients with myotonic dystrophy type 1

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