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Cellular and Molecular Life Sciences :... Dec 2013A characteristic histological feature of striated muscle cells is the presence of deep invaginations of the plasma membrane (sarcolemma), most commonly referred to as... (Review)
Review
A characteristic histological feature of striated muscle cells is the presence of deep invaginations of the plasma membrane (sarcolemma), most commonly referred to as T-tubules or the transverse-axial tubular system (TATS). TATS mediates the rapid spread of the electrical signal (action potential) to the cell core triggering Ca(2+) release from the sarcoplasmic reticulum, ultimately inducing myofilament contraction (excitation-contraction coupling). T-tubules, first described in vertebrate skeletal muscle cells, have also been recognized for a long time in mammalian cardiac ventricular myocytes, with a structure and a function that in recent years have been shown to be far more complex and pivotal for cardiac function than initially thought. Renewed interest in T-tubule function stems from the loss and disorganization of T-tubules found in a number of pathological conditions including human heart failure (HF) and dilated and hypertrophic cardiomyopathies, as well as in animal models of HF, chronic ischemia and atrial fibrillation. Disease-related remodeling of the TATS leads to asynchronous and inhomogeneous Ca(2+)-release, due to the presence of orphan ryanodine receptors that have lost their coupling with the dihydropyridine receptors and are either not activated or activated with a delay. Here, we review the physiology of the TATS, focusing first on the relationship between function and structure, and then describing T-tubular remodeling and its reversal in disease settings and following effective therapeutic approaches.
Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium Signaling; Excitation Contraction Coupling; Heart Diseases; Humans; Models, Cardiovascular; Myocardial Contraction; Myocytes, Cardiac; Sarcolemma
PubMed: 23846763
DOI: 10.1007/s00018-013-1410-5 -
Journal of Muscle Research and Cell... Mar 2011We studied the biomechanical properties of the sarcolemma and its links through costameres to the contractile apparatus in single mammalian myofibers of Extensor...
We studied the biomechanical properties of the sarcolemma and its links through costameres to the contractile apparatus in single mammalian myofibers of Extensor digitorum longus muscles isolated from wild (WT) and dystrophin-null (mdx) mice. Suction pressures (P) applied through a pipette to the sarcolemma generated a bleb, the height of which increased with increasing P. Larger increases in P broke the connections between the sarcolemma and myofibrils and eventually caused the sarcolemma to burst. We used the values of P at which these changes occurred to estimate the tensions and stiffness of the system and its individual elements. Tensions of the whole system and the sarcolemma, as well as the maximal tension sustained by the costameres, were all significantly lower (1.8-3.3 fold) in muscles of mdx mice compared to WT. Values of P at which separation and bursting occurred, as well as the stiffness of the whole system and of the isolated sarcolemma, were ~2-fold lower in mdx than in WT. Our results indicate that the absence of dystrophin reduces muscle stiffness, increases sarcolemmal deformability, and compromises the mechanical stability of costameres and their connections to nearby myofibrils.
Topics: Animals; Costameres; Dystrophin; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Fibers, Skeletal; Sarcolemma
PubMed: 21312057
DOI: 10.1007/s10974-011-9238-9 -
Journal of Muscle Research and Cell... Dec 2019The cardiomyocyte plasma membrane, termed the sarcolemma, is fundamental for regulating a myriad of cellular processes. For example, the structural integrity of the...
The cardiomyocyte plasma membrane, termed the sarcolemma, is fundamental for regulating a myriad of cellular processes. For example, the structural integrity of the cardiomyocyte sarcolemma is essential for mediating cardiac contraction by forming microdomains such as the t-tubular network, caveolae and the intercalated disc. Significantly, remodelling of these sarcolemma microdomains is a key feature in the development and progression of heart failure (HF). However, despite extensive characterisation of the associated molecular and ultrastructural events there is a lack of clarity surrounding the mechanisms driving adverse morphological rearrangements. The sarcolemma also provides protection, and is the cell's first line of defence, against external stresses such as oxygen and nutrient deprivation, inflammation and oxidative stress with a loss of sarcolemma viability shown to be a key step in cell death via necrosis. Significantly, cumulative cell death is also a feature of HF, and is linked to disease progression and loss of cardiac function. Herein, we will review the link between structural and molecular remodelling of the sarcolemma associated with the progression of HF, specifically considering the evidence for: (i) Whether intrinsic, evolutionary conserved, plasma membrane injury-repair mechanisms are in operation in the heart, and (ii) if deficits in key 'wound-healing' proteins (annexins, dysferlin, EHD2 and MG53) may play a yet to be fully appreciated role in triggering sarcolemma microdomain remodelling and/or necrosis. Cardiomyocytes are terminally differentiated with very limited regenerative capability and therefore preserving cell viability and cardiac function is crucially important. This review presents a novel perspective on sarcolemma remodelling by considering whether targeting proteins that regulate sarcolemma injury-repair may hold promise for developing new strategies to attenuate HF progression.
Topics: Heart Failure; Humans; Myocytes, Cardiac; Sarcolemma
PubMed: 31520263
DOI: 10.1007/s10974-019-09539-5 -
Pharmacology & Therapeutics May 2019α2-adrenoceptor (α2-AR) isoforms, abundant in sympathetic synapses and noradrenergic neurons of the central nervous system, are integral in the presynaptic feed-back... (Review)
Review
α2-adrenoceptor (α2-AR) isoforms, abundant in sympathetic synapses and noradrenergic neurons of the central nervous system, are integral in the presynaptic feed-back loop mechanism that moderates norepinephrine surges. We recently identified that postsynaptic α2-ARs, found in the myocellular sarcolemma, also contribute to a muscle-delimited feedback control capable of attenuating mobilization of intracellular Ca and myocardial contractility. This previously unrecognized α2-AR-dependent rheostat is able to counteract competing adrenergic receptor actions in cardiac muscle. Specifically, in ventricular myocytes, nitric oxide (NO) and cGMP are the intracellular messengers of α2-AR signal transduction pathways that gauge the kinase-phosphatase balance and manage cellular Ca handling preventing catecholamine-induced Ca overload. Moreover, α2-AR signaling counterbalances phospholipase C - PKC-dependent mechanisms underscoring a broader cardioprotective potential under sympathoadrenergic and angiotensinergic challenge. Recruitment of such tissue-specific features of α2-AR under sustained sympathoadrenergic drive may, in principle, be harnessed to mitigate or prevent cardiac malfunction. However, cardiovascular disease may compromise peripheral α2-AR signaling limiting pharmacological targeting of these receptors. Prospective cardiac-specific gene or cell-based therapeutic approaches aimed at repairing or improving stress-protective α2-AR signaling may offer an alternative towards enhanced preservation of cardiac muscle structure and function.
Topics: Animals; Feedback, Physiological; Heart; Heart Diseases; Humans; Receptors, Adrenergic, alpha-2; Sarcolemma
PubMed: 30703415
DOI: 10.1016/j.pharmthera.2019.01.007 -
NMR in Biomedicine Mar 2022Phosphorus magnetic resonance spectroscopy ( P-MRS) has been shown to detect altered energetic status (e.g. the ratio of inorganic phosphate to phosphocreatine:...
Phosphorus magnetic resonance spectroscopy ( P-MRS) has been shown to detect altered energetic status (e.g. the ratio of inorganic phosphate to phosphocreatine: Pi/PCr), intracellular acid-base status, and free intracellular magnesium ([Mg ]) in dystrophic muscle compared with unaffected muscle; however, the causes of these differences are not well understood. The purposes of this study were to examine P-MRS indices of energetic status and sarcolemma integrity in young mdx mice compared with wild-type and to evaluate the effects of downhill running to induce muscle damage on P-MRS indices in dystrophic muscle. In vivo P-MRS spectra were acquired from the posterior hindlimb muscles in young (4-10 weeks of age) mdx (C57BL/10ScSn-DMDmdx) and wild-type (C57BL/10ScSnJ) mice using an 11.1-T MR system. The flux of phosphate from PCr to ATP was estimated by P-MRS saturation transfer experiments. Relative concentrations of high-energy phosphates were measured, and intracellular pH and [Mg ] were calculated. H O-T was measured using single-voxel H-MRS from the gastrocnemius and soleus using a 4.7-T MR system. Downhill treadmill running was performed in a subset of mice. Young mdx mice were characterized by elevated H O-T (p < 0.01) Pi/PCr (p = 0.02), PCr to ATP flux (p = 0.04) and histological inflammatory markers (p < 0.05) and reduced (p < 0.01) [Mg ] compared with wild-type. Furthermore, 24 h after downhill running, an increase (p = 0.02) in Pi/PCr was observed in mdx and wild-type mice compared with baseline, and a decrease (p < 0.001) in [Mg ] and a lower (p = 0.048) intracellular [H ] in damaged muscle regions of mdx mice were observed, consistent with impaired sarcolemma integrity. Overall, our findings demonstrate that P-MRS markers of energetic status and sarcolemma integrity are altered in young mdx compared with wild-type mice, and these indices are exacerbated following downhill running.
Topics: Adenosine Triphosphate; Animals; Energy Metabolism; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Muscular Dystrophy, Animal; Phosphocreatine; Phosphorus; Physical Conditioning, Animal; Sarcolemma
PubMed: 34841594
DOI: 10.1002/nbm.4659 -
Proceedings. Biological Sciences Sep 2011The transverse tubules (t-tubules) are invaginations of the cell membrane rich in several ion channels and other proteins devoted to the critical task of... (Review)
Review
The transverse tubules (t-tubules) are invaginations of the cell membrane rich in several ion channels and other proteins devoted to the critical task of excitation-contraction coupling in cardiac muscle cells (cardiomyocytes). They are thought to promote the synchronous activation of the whole depth of the cell despite the fact that the signal to contract is relayed across the external membrane. However, recent work has shown that t-tubule structure and function are complex and tightly regulated in healthy cardiomyocytes. In this review, we outline the rapidly accumulating knowledge of its novel roles and discuss the emerging evidence of t-tubule dysfunction in cardiac disease, especially heart failure. Controversy surrounds the t-tubules' regulatory elements, and we draw attention to work that is defining these elements from the genetic and the physiological levels. More generally, this field illustrates the challenges in the dissection of the complex relationship between cellular structure and function.
Topics: Animals; Cell Membrane Structures; Disease Models, Animal; Heart; Heart Diseases; Humans; Myocytes, Cardiac; Rats; Sarcolemma
PubMed: 21697171
DOI: 10.1098/rspb.2011.0624 -
Clinical and Translational Science Aug 2010Phospholemman (PLM), a member of the FXYD family of regulators of ion transport, is a major sarcolemmal substrate for protein kinases A and C in cardiac and skeletal... (Review)
Review
Phospholemman (PLM), a member of the FXYD family of regulators of ion transport, is a major sarcolemmal substrate for protein kinases A and C in cardiac and skeletal muscle. In the heart, PLM co-localizes and co-immunoprecipitates with Na(+)-K(+)-ATPase, Na(+)/Ca(2+) exchanger, and L-type Ca(2+) channel. Functionally, when phosphorylated at serine(68), PLM stimulates Na(+)-K(+)-ATPase but inhibits Na(+)/Ca(2+) exchanger in cardiac myocytes. In heterologous expression systems, PLM modulates the gating of cardiac L-type Ca(2+) channel. Therefore, PLM occupies a key modulatory role in intracellular Na(+) and Ca(2+) homeostasis and is intimately involved in regulation of excitation-contraction (EC) coupling. Genetic ablation of PLM results in a slight increase in baseline cardiac contractility and prolongation of action potential duration. When hearts are subjected to catecholamine stress, PLM minimizes the risks of arrhythmogenesis by reducing Na(+) overload and simultaneously preserves inotropy by inhibiting Na(+)/Ca(2+) exchanger. In heart failure, both expression and phosphorylation state of PLM are altered and may partly account for abnormalities in EC coupling. The unique role of PLM in regulation of Na(+)-K(+)-ATPase, Na(+)/Ca(2+) exchanger, and potentially L-type Ca(2+) channel in the heart, together with the changes in its expression and phosphorylation in heart failure, make PLM a rational and novel target for development of drugs in our armamentarium against heart failure. Clin Trans Sci 2010; Volume 3: 189-196.
Topics: Animals; Heart; Heart Failure; Humans; Membrane Proteins; Phosphoproteins; Sarcolemma; Stress, Physiological
PubMed: 20718822
DOI: 10.1111/j.1752-8062.2010.00213.x -
Pharmacology & Therapeutics Nov 2013Diazoxide has been identified over the past 50years to have a number of physiological effects, including lowering the blood pressure and rectifying hypoglycemia. Today... (Review)
Review
Diazoxide has been identified over the past 50years to have a number of physiological effects, including lowering the blood pressure and rectifying hypoglycemia. Today it is used clinically to treat these conditions. More recently, another important mode of action emerged: diazoxide has powerful protective properties against cardiac ischemia. The heart has intrinsic protective mechanisms against ischemia injury; one of which is ischemic preconditioning. Diazoxide mimics ischemic preconditioning. The purpose of this treatise is to review the literature in an attempt to identify the many effectors of diazoxide and discuss how they may contribute to diazoxide's cardioprotective properties. Particular emphasis is placed on the concentration ranges in which diazoxide affects its different targets and how this compares with the concentrations commonly used to study cardioprotection. It is concluded that diazoxide may have several potential effectors that may potentially contribute to cardioprotection, including KATP channels in the pancreas, smooth muscle, endothelium, neurons and the mitochondrial inner membrane. Diazoxide may also affect other ion channels and ATPases and may directly regulate mitochondrial energetics. It is possible that the success of diazoxide lies in this promiscuity and that the compound acts to rebalance multiple physiological processes during cardiac ischemia.
Topics: Animals; Cardiotonic Agents; Diazoxide; Humans; Insulin-Secreting Cells; KATP Channels; Mitochondria; Myocardial Ischemia; Myocytes, Smooth Muscle; Sarcolemma
PubMed: 23792087
DOI: 10.1016/j.pharmthera.2013.06.007 -
Traffic (Copenhagen, Denmark) Mar 2004Skeletal muscle tissue is made up of highly organized multinuclear cells. The internal organization of the muscle cell is dictated by the necessary regular arrangement... (Review)
Review
Skeletal muscle tissue is made up of highly organized multinuclear cells. The internal organization of the muscle cell is dictated by the necessary regular arrangement of repeated units within the protein myofibrils that mediate muscle contraction. Skeletal muscle cells have the usual membrane traffic pathways for partitioning newly synthesized proteins, internalizing cell surface receptors for hormones and nutrients, and mediating membrane repair. However, in muscle, these pathways must be further specialized to deal with targeting to and organizing muscle-specific membrane structures, satisfying the unique metabolic requirements of muscle and meeting the high demand for membrane repair in a tissue that is constantly under mechanical stress. Specialized membrane traffic pathways in muscle also play a role in the formation of muscle through fusion of myoblast membranes and the development of internal muscle-specific membrane structures during myogenesis and regeneration. It has recently become apparent that muscle-specific isoforms of proteins that are known to mediate ubiquitous membrane traffic pathways, as well as novel muscle-specific proteins, are involved in tissue-specific aspects of muscle membrane traffic. Here we describe the specialized membrane structures of skeletal muscle, how these are developed, maintained and repaired by specialized and generic membrane traffic pathways, and how defects in these pathways result in muscle disease.
Topics: Animals; Biological Transport; Cell Membrane; Humans; Membrane Fusion; Membrane Proteins; Muscle, Skeletal; Sarcolemma
PubMed: 15086789
DOI: 10.1111/j.1600-0854.2003.00164.x -
The Biochemical Journal Apr 19951. Several cell-surface domains of sarcolemma and T-tubule from skeletal-muscle fibre were isolated and characterized. 2. A protocol of subcellular fractionation was set...
1. Several cell-surface domains of sarcolemma and T-tubule from skeletal-muscle fibre were isolated and characterized. 2. A protocol of subcellular fractionation was set up that involved the sequential low- and high-speed homogenization of rat skeletal muscle followed by KCl washing, Ca2+ loading and sucrose-density-gradient centrifugation. This protocol led to the separation of cell-surface membranes from membranes enriched in sarcoplasmic reticulum and intracellular GLUT4-containing vesicles. 3. Agglutination of cell-surface membranes using wheat-germ agglutinin allowed the isolation of three distinct cell-surface membrane domains: sarcolemmal fraction 1 (SM1), sarcolemmal fraction 2 (SM2) and a T-tubule fraction enriched in protein tt28 and the alpha 2-component of dihydropyridine receptor. 4. Fractions SM1 and SM2 represented distinct sarcolemmal subcompartments based on different compositions of biochemical markers: SM2 was characterized by high levels of beta 1-integrin and dystrophin, and SM1 was enriched in beta 1-integrin but lacked dystrophin. 5. The caveolae-associated molecule caveolin was very abundant in SM1, SM2 and T-tubules, suggesting the presence of caveolae or caveolin-rich domains in these cell-surface membrane domains. In contrast, clathrin heavy chain was abundant in SM1 and T-tubules, but only trace levels were detected in SM2. 6. Immunoadsorption of T-tubule vesicles with antibodies against protein tt28 and against GLUT4 revealed the presence of GLUT4 in T-tubules under basal conditions and it also allowed the identification of two distinct pools of T-tubules showing different contents of tt28 and dihydropyridine receptors. 7. Our data on distribution of clathrin and dystrophin reveal the existence of subcompartments in sarcolemma from muscle fibre, featuring selective mutually exclusive components. T-tubules contain caveolin and clathrin suggesting that they contain caveolin- and clathrin-rich domains. Furthermore, evidence for the heterogeneous distribution of membrane proteins in T-tubules is also presented.
Topics: Animals; Calcium-Transporting ATPases; Caveolin 1; Caveolins; Cell Compartmentation; Cell Fractionation; Centrifugation, Density Gradient; Clathrin; Dystrophin; Glucose Transporter Type 4; Integrin beta1; Integrins; Intracellular Membranes; Male; Membrane Proteins; Monosaccharide Transport Proteins; Muscle Fibers, Skeletal; Muscle Proteins; Rats; Rats, Wistar; Sarcolemma; Subcellular Fractions
PubMed: 7536412
DOI: 10.1042/bj3070273