A-kinase anchoring proteins: Molecular regulators of the cardiac stress response

Diviani, Dario; Maric, Darko; López, Irene Pérez; Cavin, Sabrina; Vescovo, Cosmo Damiano del

doi:10.1016/j.bbamcr.2012.07.014

Cited by 25 publications

(23 citation statements)

References 75 publications

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“…The anti-synemin antibody was made against GST fused to the COOH-terminal 108 amino acid residues of Mus musculus synemin (21 st Century Biochemicals, Marlborough, MA). The antibody was purified on Sepharose beads activated with CNBr (GE Healthcare, Laurel, MD) and coupled covalently to a fusion protein of MBP and the last 108 amino acids of synemin.…”

Section: Methodsmentioning

confidence: 99%

Myopathic changes in murine skeletal muscle lacking synemin

García‐Pelagio

Muriel

O’Neill

et al. 2015

American Journal of Physiology-Cell Physiology

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(IF) proteins are associated with defects in the organization of the contractile apparatus and its links to costameres, which connect the sarcomeres to the cell membrane. Here we study the role in skeletal muscle of synemin, a type IV IF protein, by examining mice null for synemin (synm-null). Synm-null mice have a mild skeletal muscle phenotype. Tibialis anterior (TA) muscles show a significant decrease in mean fiber diameter, a decrease in twitch and tetanic force, and an increase in susceptibility to injury caused by lengthening contractions. Organization of proteins associated with the contractile apparatus and costameres is not significantly altered in the synm-null. Elastimetry of the sarcolemma and associated contractile apparatus in extensor digitorum longus myofibers reveals a reduction in tension consistent with an increase in sarcolemmal deformability. Although fatigue after repeated isometric contractions is more marked in TA muscles of synm-null mice, the ability of the mice to run uphill on a treadmill is similar to controls. Our results suggest that synemin contributes to linkage between costameres and the contractile apparatus and that the absence of synemin results in decreased fiber size and increased sarcolemmal deformability and susceptibility to injury. Thus synemin plays a moderate but distinct role in fast twitch skeletal muscle. cytoskeleton; costameres; elastimetry; biomechanical properties; desmin A LARGE NUMBER OF HUMAN DISEASES, ranging from skin disorders (51), to premature aging (34, 64), to skeletal and cardiac myopathies (19,37), are linked to mutations in genes encoding intermediate filament (IF) proteins (25). Since the discovery of desmin, the major IF protein of striated muscle (49), its role and that of other IF proteins in muscle have been of keen interest to many laboratories (reviewed in 16). Our research on muscle IF proteins has addressed their role in force transmission and in organizing the sarcoplasm and stabilizing it against injury during force generation.Force generated in muscle can be transmitted radially, from the myofibrils, across the sarcolemma to the extracellular matrix and neighboring cells (11, 67). As a result, a significant amount of force is exerted on the sarcolemma and the structures that link it to the underlying contractile apparatus and the extracellular matrix. The ability of the sarcolemma with the underlying contractile apparatus to withstand the distortions caused during isotonic contractions (2, 11, 12) depends on specialized structures, termed "costameres" (66), that mediate the radial transmission of force across the sarcolemma (11). Costameres are structures at the sarcolemma of striated muscle fibers that align circumferentially around the Z disks and the M bands of the nearest myofibrils, and longitudinally, to form a rectilinear sarcolemmal network comprised of integral membrane proteins (such as dystroglycan, the sarcoglycans, and Na-K-ATPase), proteins of the extracellular matrix (such as laminin and collagen IV), and proteins of t...

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Section: Methodsmentioning

confidence: 99%

Myopathic changes in murine skeletal muscle lacking synemin

García‐Pelagio

Muriel

O’Neill

et al. 2015

American Journal of Physiology-Cell Physiology

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“…Cardiovascular diseases cAMP signaling also governs many aspects of cardiac function (Diviani et al, 2013;Perera and Nikolaev, 2013). Significantly, cAMP is the predominant second messenger downstream of sympathetic heart stimulation by catecholamines.…”

Section: Diabetesmentioning

confidence: 99%

Local cAMP signaling in disease at a glance

Gold

Gonen

Scott

2013

Journal of Cell Science

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Summary The second messenger cyclic AMP (cAMP) operates in discrete subcellular regions within which proteins that synthesize, break down or respond to the second messenger are precisely organized. A burgeoning knowledge of compartmentalized cAMP signaling is revealing how the local control of signaling enzyme activity impacts upon disease. The aim of this Cell Science at a Glance article and the accompanying poster is to highlight how misregulation of local cyclic AMP signaling can have pathophysiological consequences. We first introduce the core molecular machinery for cAMP signaling, which includes the cAMP-dependent protein kinase (PKA), and then consider the role of A-kinase anchoring proteins (AKAPs) in coordinating different cAMP-responsive proteins. The latter sections illustrate the emerging role of local cAMP signaling in four disease areas: cataracts, cancer, diabetes and cardiovascular diseases.

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“…Defects in cellular signaling mechanisms also lead to hypertrophic cardiomyopathy [49–53]. As synemin is a structural protein associated with both sarcomeres and sarcolemma, and an AKAP that can indirectly regulate the phosphorylation state of nearby proteins [21,23,54], it is not surprising that its absence can lead to a mixed phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…PKA can be activated by a number of hormones and growth factors and can lead to physiologically significant changes in cardiac function through its ability to phosphorylate phospholamban and several contractile proteins [50]. ERK1/2, which can phosphorylate over 100 possible substrates, has also been linked to cardiovascular disease [54,55] and is likely to contribute to hypertrophy in the myocardium ([56–59], but see [60]), consistent with our finding of a change in pERK1/2 levels in the myopathic synm −/− heart. Thus, our finding that PKARII and pERK1/2 are altered in synm-null hearts provides a possible molecular pathway underlying the cardiomyopathy we have characterized.…”

Section: Discussionmentioning

confidence: 99%

Absence of synemin in mice causes structural and functional abnormalities in heart

García‐Pelagio

Chen

Joca

et al. 2018

Journal of Molecular and Cellular Cardiology

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Cardiomyopathies have been linked to changes in structural proteins, including intermediate filament (IF) proteins located in the cytoskeleton. IFs associate with the contractile machinery and costameres of striated muscle and with intercalated disks in the heart. Synemin is a large IF protein that mediates the association of desmin with Z-disks and stabilizes intercalated disks. It also acts as an A-kinase anchoring protein (AKAP). In murine skeletal muscle, the absence of synemin causes a mild myopathy. Here, we report that the genetic silencing of synemin in mice (synm −/−) causes left ventricular systolic dysfunction at 3 months and 12–16 months of age, and left ventricular hypertrophy and dilatation at 12–16 months of age. Isolated cardiomyocytes showed alterations in calcium handling that indicate defects intrinsic to the heart. Although contractile and costameric proteins remained unchanged in the old synm −/− hearts, we identified alterations in several signaling proteins (PKA-RII, ERK and p70S6K) critical to cardiomyocyte function. Our data suggest that synemin plays an important regulatory role in the heart and that the consequences of its absence are profound.

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A-kinase anchoring proteins: Molecular regulators of the cardiac stress response

Cited by 25 publications

References 75 publications

Myopathic changes in murine skeletal muscle lacking synemin

Myopathic changes in murine skeletal muscle lacking synemin

Local cAMP signaling in disease at a glance

Absence of synemin in mice causes structural and functional abnormalities in heart

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