scholarly journals Obscurin is required for ankyrinB-dependent dystrophin localization and sarcolemma integrity

2013 ◽  
Vol 200 (4) ◽  
pp. 523-536 ◽  
Author(s):  
Davide Randazzo ◽  
Emiliana Giacomello ◽  
Stefania Lorenzini ◽  
Daniela Rossi ◽  
Enrico Pierantozzi ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Exercise Tolerance ◽  
Myofibrillar Protein ◽  
Mutant Mice ◽  
Striated Muscles ◽  
Muscle Exercise ◽  
Microtubule Cytoskeleton ◽  
Sarcolemmal Integrity

Obscurin is a large myofibrillar protein that contains several interacting modules, one of which mediates binding to muscle-specific ankyrins. Interaction between obscurin and the muscle-specific ankyrin sAnk1.5 regulates the organization of the sarcoplasmic reticulum in striated muscles. Additional muscle-specific ankyrin isoforms, ankB and ankG, are localized at the subsarcolemma level, at which they contribute to the organization of dystrophin and β-dystroglycan at costameres. In this paper, we report that in mice deficient for obscurin, ankB was displaced from its localization at the M band, whereas localization of ankG at the Z disk was not affected. In obscurin KO mice, localization at costameres of dystrophin, but not of β-dystroglycan, was altered, and the subsarcolemma microtubule cytoskeleton was disrupted. In addition, these mutant mice displayed marked sarcolemmal fragility and reduced muscle exercise tolerance. Altogether, the results support a model in which obscurin, by targeting ankB at the M band, contributes to the organization of subsarcolemma microtubules, localization of dystrophin at costameres, and maintenance of sarcolemmal integrity.

Sarcoplasmic Reticulum Function in Smooth Muscle

2010 ◽  
Vol 90 (1) ◽  
pp. 113-178 ◽  
Author(s):  
Susan Wray ◽  
Theodor Burdyga
Keyword(s):  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Physiological Activity ◽  
Smooth Muscles ◽  
Outward Current ◽  
Integrated Approach ◽  
Transient Outward Current ◽  
Coupling Mechanism ◽  
Striated Muscles ◽  
Development And Aging

The sarcoplasmic reticulum (SR) of smooth muscles presents many intriguing facets and questions concerning its roles, especially as these change with development, disease, and modulation of physiological activity. The SR's function was originally perceived to be synthetic and then that of a Ca store for the contractile proteins, acting as a Ca amplification mechanism as it does in striated muscles. Gradually, as investigators have struggled to find a convincing role for Ca-induced Ca release in many smooth muscles, a role in controlling excitability has emerged. This is the Ca spark/spontaneous transient outward current coupling mechanism which reduces excitability and limits contraction. Release of SR Ca occurs in response to inositol 1,4,5-trisphosphate, Ca, and nicotinic acid adenine dinucleotide phosphate, and depletion of SR Ca can initiate Ca entry, the mechanism of which is being investigated but seems to involve Stim and Orai as found in nonexcitable cells. The contribution of the elemental Ca signals from the SR, sparks and puffs, to global Ca signals, i.e., Ca waves and oscillations, is becoming clearer but is far from established. The dynamics of SR Ca release and uptake mechanisms are reviewed along with the control of luminal Ca. We review the growing list of the SR's functions that still includes Ca storage, contraction, and relaxation but has been expanded to encompass Ca homeostasis, generating local and global Ca signals, and contributing to cellular microdomains and signaling in other organelles, including mitochondria, lysosomes, and the nucleus. For an integrated approach, a review of aspects of the SR in health and disease and during development and aging are also included. While the sheer versatility of smooth muscle makes it foolish to have a “one model fits all” approach to this subject, we have tried to synthesize conclusions wherever possible.

scholarly journals Phospholamban Knockout Breaks Arrhythmogenic Ca 2+ Waves and Suppresses Catecholaminergic Polymorphic Ventricular Tachycardia in Mice

2013 ◽  
Vol 113 (5) ◽  
pp. 517-526 ◽  
Author(s):  
Yunlong Bai ◽  
Peter P. Jones ◽  
Jiqing Guo ◽  
Xiaowei Zhong ◽  
Robert B. Clark ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Mouse Model ◽  
Ventricular Myocytes ◽  
Mutant Mice ◽  
Polymorphic Ventricular Tachycardia ◽  
Patch Clamp Recording ◽  
Plasmic Reticulum ◽  
Paradoxical Effects ◽  
Triggered Arrhythmias ◽  
The Impact

Rationale : Phospholamban (PLN) is an inhibitor of cardiac sarco(endo)plasmic reticulum Ca 2+ ATPase. PLN knockout (PLN-KO) enhances sarcoplasmic reticulum Ca 2+ load and Ca 2+ leak. Conversely, PLN-KO accelerates Ca 2+ sequestration and aborts arrhythmogenic spontaneous Ca 2+ waves (SCWs). An important question is whether these seemingly paradoxical effects of PLN-KO exacerbate or protect against Ca 2+ -triggered arrhythmias. Objective : We investigate the impact of PLN-KO on SCWs, triggered activities, and stress-induced ventricular tachyarrhythmias (VTs) in a mouse model of cardiac ryanodine-receptor (RyR2)-linked catecholaminergic polymorphic VT. Methods and Results : We generated a PLN-deficient, RyR2-mutant mouse model (PLN −/− /RyR2-R4496C +/− ) by crossbreeding PLN-KO mice with catecholaminergic polymorphic VT–associated RyR2-R4496C mutant mice. Ca 2+ imaging and patch-clamp recording revealed cell-wide propagating SCWs and triggered activities in RyR2-R4496C +/− ventricular myocytes during sarcoplasmic reticulum Ca 2+ overload. PLN-KO fragmented these cell-wide SCWs into mini-waves and Ca 2+ sparks and suppressed the triggered activities evoked by sarcoplasmic reticulum Ca 2+ overload. Importantly, these effects of PLN-KO were reverted by partially inhibiting sarco(endo)plasmic reticulum Ca 2+ ATPase with 2,5-di-tert-butylhydroquinone. However, Bay K, caffeine, or Li + failed to convert mini-waves to cell-wide SCWs in PLN −/− /RyR2-R4496C +/− ventricular myocytes. Furthermore, ECG analysis showed that PLN-KO mice are not susceptible to stress-induced VTs. On the contrary, PLN-KO protected RyR2-R4496C mutant mice from stress-induced VTs. Conclusions : Our results demonstrate that despite severe sarcoplasmic reticulum Ca 2+ leak, PLN-KO suppresses triggered activities and stress-induced VTs in a mouse model of catecholaminergic polymorphic VT. These data suggest that breaking up cell-wide propagating SCWs by enhancing Ca 2+ sequestration represents an effective approach for suppressing Ca 2+ -triggered arrhythmias.

scholarly journals Binding of an ankyrin-1 isoform to obscurin suggests a molecular link between the sarcoplasmic reticulum and myofibrils in striated muscles

2003 ◽  
Vol 160 (2) ◽  
pp. 245-253 ◽  
Author(s):  
Paola Bagnato ◽  
Virigina Barone ◽  
Emiliana Giacomello ◽  
Daniela Rossi ◽  
Vincenzo Sorrentino
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Binding Site ◽  
Physiological Activity ◽  
Ryanodine Receptors ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Structural Function ◽  
Striated Muscles

Assembly of specialized membrane domains, both of the plasma membrane and of the ER, is necessary for the physiological activity of striated muscle cells. The mechanisms that mediate the structural organization of the sarcoplasmic reticulum with respect to the myofibrils are, however, not known. We report here that ank1.5, a small splice variant of the ank1 gene localized on the sarcoplasmic reticulum membrane, is capable of interacting with a sequence of 25 aa located at the COOH terminus of obscurin. Obscurin is a giant sarcomeric protein of ∼800 kD that binds to titin and has been proposed to mediate interactions between myofibrils and other cellular structures. The binding sites and the critical aa required in the interaction between ank1.5 and obscurin were characterized using the yeast two-hybrid system, in in vitro pull-down assays and in experiments in heterologous cells. In differentiated skeletal muscle cells, a transfected myc-tagged ank1.5 was found to be selectively restricted near the M line region where it colocalized with endogenous obscurin. The M line localization of ank1.5 required a functional obscurin-binding site, because mutations of this domain resulted in a diffused distribution of the mutant ank1.5 protein in skeletal muscle cells. The interaction between ank1.5 and obscurin represents the first direct evidence of two proteins that may provide a direct link between the sarcoplasmic reticulum and myofibrils. In keeping with the proposed role of obscurin in mediating an interaction with ankyrins and sarcoplasmic reticulum, we have also found that a sequence with homology to the obscurin-binding site of ank1.5 is present in the ank2.2 isoform, which in striated muscles has been also shown to associate with the sarcoplasmic reticulum. Accordingly, a peptide containing the COOH terminus of ank2.2 fused with GST was found to bind to obscurin. Based on reported evidence showing that the COOH terminus of ank2.2 is necessary for the localization of ryanodine receptors and InsP3 receptors in the sarcoplasmic reticulum, we propose that obscurin, through multiple interactions with ank1.5 and ank2.2 isoforms, may assemble a large protein complex that, in addition to a structural function, may play a role in the organization of specific subdomains in the sarcoplasmic reticulum.

Myoneural Junctions in Toadfish Swimbladder Muscle

1972 ◽  
Vol 30 ◽  
pp. 30-31
Author(s):  
James M. Sidle
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Neuromuscular Junctions ◽  
Contraction Time ◽  
Striated Muscles ◽  
Opsanus Tau

Among vertebrate striated muscles studied to date, the toadfish swimbladder muscle is fastest with an average contraction time of 5 msec. The ultrastructure of this muscle has been examined, particularly with regard to the elaborate sarcoplasmic reticulum present, and a light-microscoplc study of the neuromuscular junctions has been performed. Motorneurons which innervate the swimbladder muscle were found to be electronically coupled by way of axo-somatic and dendro-somatic junctions.The ultrastructure of the myoneural junctions in the Atlantic toadfish (Opsanus tau) was examined and the findings conform to those obtained from several other teleost twitch fibers.

scholarly journals Murine obscurin and Obsl1 have functionally redundant roles in sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Jordan Blondelle ◽  
Valeria Marrocco ◽  
Madison Clark ◽  
Patrick Desmond ◽  
Stephanie Myers ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Muscle Metabolism ◽  
Sarcolemmal Integrity

scholarly journals Minor sarcoplasmic reticulum membrane components that modulate excitation-contraction coupling in striated muscles

2009 ◽  
Vol 587 (13) ◽  
pp. 3071-3079 ◽  
Author(s):  
Susan Treves ◽  
Mirko Vukcevic ◽  
Marcin Maj ◽  
Raphael Thurnheer ◽  
Barbara Mosca ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Striated Muscles ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Sarcoplasmic Reticulum Membrane ◽  
Membrane Components

scholarly journals Modulation of sarcoplasmic reticulum Ca2+ release in skeletal muscle expressing ryanodine receptor impaired in regulation by calmodulin and S100A1

2011 ◽  
Vol 300 (5) ◽  
pp. C998-C1012 ◽  
Author(s):  
Naohiro Yamaguchi ◽  
Benjamin L. Prosser ◽  
Farshid Ghassemi ◽  
Le Xu ◽  
Daniel A. Pasek ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Action Potential ◽  
Ryanodine Receptor ◽  
Repetitive Stimulation ◽  
Mutant Mice ◽  
High Frequency Stimulation ◽  
Single Action ◽  
Single Action Potential ◽  
Release Flux

In vitro, calmodulin (CaM) and S100A1 activate the skeletal muscle ryanodine receptor ion channel (RyR1) at submicromolar Ca2+ concentrations, whereas at micromolar Ca2+ concentrations, CaM inhibits RyR1. One amino acid substitution (RyR1-L3625D) has previously been demonstrated to impair CaM binding and regulation of RyR1. Here we show that the RyR1-L3625D substitution also abolishes S100A1 binding. To determine the physiological relevance of these findings, mutant mice were generated with the RyR1-L3625D substitution in exon 74, which encodes the CaM and S100A1 binding domain of RyR1. Homozygous mutant mice ( Ryr1 D/D) were viable and appeared normal. However, single RyR1 channel recordings from Ryr1 D/D mice exhibited impaired activation by CaM and S100A1 and impaired CaCaM inhibition. Isolated flexor digitorum brevis muscle fibers from Ryr1 D/D mice had depressed Ca2+ transients when stimulated by a single action potential. However, during repetitive stimulation, the mutant fibers demonstrated greater relative summation of the Ca2+ transients. Consistently, in vivo stimulation of tibialis anterior muscles in Ryr1 D/D mice demonstrated reduced twitch force in response to a single action potential, but greater summation of force during high-frequency stimulation. During repetitive stimulation, Ryr1 D/D fibers exhibited slowed inactivation of sarcoplasmic reticulum Ca2+ release flux, consistent with increased summation of the Ca2+ transient and contractile force. Peak Ca2+ release flux was suppressed at all voltages in voltage-clamped Ryr1 D/D fibers. The results suggest that the RyR1-L3625D mutation removes both an early activating effect of S100A1 and CaM and delayed suppressing effect of CaCaM on RyR1 Ca2+ release, providing new insights into CaM and S100A1 regulation of skeletal muscle excitation-contraction coupling.

Endurance training ameliorates the metabolic and performance characteristics of circadian Clock mutant mice

2013 ◽  
Vol 114 (8) ◽  
pp. 1076-1084 ◽  
Author(s):  
Stephen Pastore ◽  
David A. Hood
Keyword(s):  
Transcription Factor ◽  
Endurance Training ◽  
Exercise Tolerance ◽  
Mutant Mice ◽  
Peroxisome Proliferator ◽  
Activity Levels ◽  
Mitochondrial Content ◽  
Clock Mutant ◽  
Training Protocol ◽  
Clock Protein

Circadian locomotor output cycles kaput (CLOCK) is a nuclear transcription factor that is a component of the central autoregulatory feedback loop that governs the generation of biological rhythms. Homozygous Clock mutant mice contain a truncated CLOCKΔ19 protein within somatic cells, subsequently causing an impaired ability to rhythmically transactivate circadian genes. The present study sought to investigate whether the Clock mutation affects mitochondrial physiology within skeletal muscle, as well as the responsiveness of these mutant animals to adapt to a chronic voluntary endurance training protocol. Within muscle, Clock mutant mice displayed 44% and 45% reductions in peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) and mitochondrial transcription factor-A protein content, respectively, and an accompanying 16% decrease in mitochondrial content, as determined by cytochrome c oxidase enzyme activity. These decrements contributed to a 50% decrease in exercise tolerance in Clock mutant mice. Interestingly, the Clock mutation did not appear to alter subsarcolemmal or intermyofibrillar mitochondrial respiration within muscle or systemic glucose tolerance. Daily locomotor activity levels were similar between wild-type and Clock mutant mice throughout the training protocol. Endurance training ameliorated the decrease in PGC-1α protein expression and mitochondrial content in the Clock mutant mice, eliciting a 2.9-fold improvement in exercise tolerance. Thus our data suggest that a functional CLOCK protein is essential to ensure the maintenance of mitochondrial content within muscle although the absence of a functional CLOCK protein does not impair the ability of animals to adapt to chronic exercise.

The arrangement and ultrastructure of the musculature, nerves and epidermis, in the tail of the cercaria of Cryptocotyle lingua (Creplin) from Littorina littorea (L.)

1975 ◽  
Vol 190 (1099) ◽  
pp. 165-186 ◽  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Synaptic Vesicles ◽  
Transverse Section ◽  
Tail Length ◽  
Muscle Cells ◽  
Striated Muscles ◽  
Neuromuscular Synapses ◽  
Straight Line ◽  
T Tubules ◽  
Fibrillar Region

The ultrastructure of the caudal muscles of the cercaria of Cryptocotyle lingua is related to the rapid swimming movements. Dorsal and ventral striated longitudinal muscle cells extend in a straight line along the tail length each containing a single myofibril, U-shaped in transverse section and divided into sarcomeres. A-, I- and H-bands are recognizable and the fragmented Z-band consists of a row of dense bars to which the thin myofilaments are attached. A pair of proximal ventro-lateral striated muscles may be responsible for the figure of eight pattern of movement. Large mitochondria are abundant in the non-fibrillar region of the muscle cells. Tubular sarcoplasmic reticulum envelops the myofibril giving off branches at the Z-bands which extend into and across the myofibril alternating with the dense bars. T-tubules are absent but cisternae of the sarcoplasmic reticulum form numerous dyadic junctions with the sarcolemma. Dorsal and ventral motor caudal nerves arise from a nerve plexus behind the tail root; axo-axonal and neuromuscular synapses are frequent. Clear and dense synaptic vesicles occur in the presynaptic terminals.

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