Absence of keratin 19 in mice causes skeletal myopathy with mitochondrial and sarcolemmal reorganization

Stone, Michele R.; O’Neill, Andrea; Lovering, Richard M.; Strong, John; Resneck, Wendy G.; Reed, Patrick W.; Toivola, Diana M.; Ursitti, Jeanine A.; Omary, M. Bishr; Bloch, Robert J.

doi:10.1242/jcs.009241

Cited by 86 publications

(88 citation statements)

References 65 publications

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“…We measured maximal isometric torque and its loss upon injury, using a previously described model in which injury results from 15 forced lengthening contractions (54,88). Maximal isometric torque of the ankle dorsiflexors, of which the TA is the dominant muscle (57), was significantly lower in the synm-null mouse, consistent with our measurements of absolute isometric force.…”

Section: C454 Characterization Of Skeletal Muscle Lacking Syneminsupporting

confidence: 77%

“…The major IF protein is desmin, which surrounds the contractile apparatus at Z disks and serves as an important linkage to costameres at the sarcolemma (16). Synemin, which copolymerizes with desmin (59,91), is also present in striated muscle, although at lower levels (40,88). Keratin 19 is present in striated muscle (54,88) as well.…”

Section: Discussionmentioning

confidence: 99%

“…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 the membraneassociated cytoskeleton (such as dystrophin, syntrophins, spectrin, ankyrin, and vinculin) (12,23,26,41,48,66,71,76,82,87,93,95). Many muscular dystrophies are attributable to mutations in costameric proteins, especially to mutations of proteins of the dystrophin-glycoprotein complex (2,6,10,12,15,27,42,63,74,95).Costameres are linked to the superficial myofibrils of the contractile apparatus by microfilaments, comprised at least in part of ␥-actin (26,43,82), and by IFs, including desmin and several forms of keratin (4,5,7,10,49,54,68,73,88,92). Elimination of these proteins by homologous recombination leads to myopathies.…”

mentioning

confidence: 99%

“…Costameres are linked to the superficial myofibrils of the contractile apparatus by microfilaments, comprised at least in part of ␥-actin (26,43,82), and by IFs, including desmin and several forms of keratin (4,5,7,10,49,54,68,73,88,92). Elimination of these proteins by homologous recombination leads to myopathies.…”

mentioning

confidence: 99%

“…Nestin (type VI) plays a role in the accumulation of acetylcholine receptors at the neuromuscular junction and in the development of myogenic cells (86,94). Muscles lacking keratin 19 (type I) or desmin (type III) are mildly myopathic and are weaker and more easily injured than wild-type (WT) (1,54,88). The role in muscle of synemin, a type IV IF protein that can associate with IFs formed by desmin or keratins (4,56,59,91), has not yet been fully explored.…”

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confidence: 99%

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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: C454 Characterization Of Skeletal Muscle Lacking Syneminsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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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The Dystrophin Complex: Structure, Function, and Implications for Therapy

Gao

McNally

2015

Comprehensive Physiology

358

309

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The dystrophin complex stabilizes the plasma membrane of striated muscle cells. Loss of function mutations in the genes encoding dystrophin, or the associated proteins, triggers instability of the plasma membrane and myofiber loss. Mutations in dystrophin have been extensively cataloged providing remarkable structure-function correlation between predicted protein structure and clinical outcomes. These data have highlighted dystrophin regions necessary for in vivo function and fueled the design of viral vectors and now, exon skipping approaches for use in dystrophin restoration therapies. However, dystrophin restoration is likely more complex, owing to the role of the dystrophin complex as a broad cytoskeletal integrator. This review will focus on dystrophin restoration, with emphasis on the regions of dystrophin essential for interacting with its associated proteins and discuss the structural implications of these approaches.

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Overview of the Muscle Cytoskeleton

Henderson

Gomez

Novak

et al. 2017

Comprehensive Physiology

234

193

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Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease.

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Absence of keratin 19 in mice causes skeletal myopathy with mitochondrial and sarcolemmal reorganization

Cited by 86 publications

References 65 publications

Myopathic changes in murine skeletal muscle lacking synemin

Myopathic changes in murine skeletal muscle lacking synemin

The Dystrophin Complex: Structure, Function, and Implications for Therapy

Overview of the Muscle Cytoskeleton

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