Myofibrillar myopathy

Engel, Andrew G.

doi:10.1002/1531-8249(199911)46:5<681::aid-ana1>3.0.co;2-b

Cited by 58 publications

(42 citation statements)

References 37 publications

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“…We found that denervated runx1 mutant myofibers have structural aberrations that are not evident in atrophic denervated control myofibers, but are reminiscent of structural abnormalities found in a variety of congenital myopathies (Fig. 4;Engel 1999;Nishino 2003;. First, in denervated runx1 mutant muscles, the Z-discs are misaligned, fragmented, and irregularly spaced.…”

Section: Runx1 Induction Is Required To Prevent Disused Myofibers Fromentioning

confidence: 49%

Runx1 prevents wasting, myofibrillar disorganization, and autophagy of skeletal muscle

Wang

Blagden²,

Fan³

et al. 2005

Genes Dev.

153

144

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Disruptions in the use of skeletal muscle lead to muscle atrophy. After short periods of disuse, muscle atrophy is reversible, and even after prolonged periods of inactivity, myofiber degeneration is uncommon. The pathways that regulate atrophy, initiated either by peripheral nerve damage, immobilization, aging, catabolic steroids, or cancer cachexia, however, are poorly understood. Previously, we found that Runx1 (AML1), a DNA-binding protein that is homologous to Drosophila Runt and has critical roles in hematopoiesis and leukemogenesis, is poorly expressed in innervated muscle, but strongly induced in muscle shortly after denervation. To determine the function of Runx1 in skeletal muscle, we generated mice in which Runx1 was selectively inactivated in muscle. Here, we show that Runx1 is required to sustain muscle by preventing denervated myofibers from undergoing myofibrillar disorganization and autophagy, structural defects found in a variety of congenital myopathies. We find that only 29 genes, encoding ion channels, signaling molecules, and muscle structural proteins, depend upon Runx1 expression, suggesting that their misregulation causes the dramatic muscle wasting. These findings demonstrate an unexpected role for electrical activity in regulating muscle wasting, and indicate that muscle disuse induces compensatory mechanisms that limit myofiber atrophy. Moreover, these results suggest that reduced muscle activity could cause or contribute to congenital myopathies if Runx1 or its target genes were compromised.

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Section: Runx1 Induction Is Required To Prevent Disused Myofibers Fromentioning

confidence: 49%

Runx1 prevents wasting, myofibrillar disorganization, and autophagy of skeletal muscle

Wang

Blagden²,

Fan³

et al. 2005

Genes Dev.

153

144

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“…2,11,15,78,110 History of slowly progressive muscle weakness, dyspnea, dysphonia, dysphagia and cardiac symptoms. Physical examination reveals distal and proximal weakness; trunk, neckflexor and facial muscles are involved in some patients.…”

Section: Diagnostic Criteriamentioning

confidence: 99%

“…78,110 The common pathological pattern is myofibrillar dissolution, accumulation of myofibrillar degradation products and ectopic expression of multiple proteins. Mutations in six genes have been identified as causing MFM: desmin, alphaB-crystallin, selenoprotein 1, myotilin, ZASP and gamma-filamin.…”

Section: Relationships Between Desminopathy and Other Myofibrillar Mymentioning

confidence: 99%

Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

107

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Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alphaB-crystallin. The inheritance pattern in familial desminopathy is characterized as autosomal dominant or autosomal recessive, but many cases have no family history. At least some and likely most sporadic desminopathy cases are associated with de novo DES mutations. The age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Typically, the illness presents with lower and later upper limb muscle weakness slowly spreading to involve truncal, neckflexor, facial and bulbar muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks, arrhythmias and chronic heart failure resulting in premature sudden death. Respiratory muscle weakness is a major complication in some patients. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing chimeric aggregates consisting of desmin and other cytoskeletal proteins. Various DES gene mutations: point mutations, an insertion, small in-frame deletions and a larger exon-skipping deletion, have been identified in desminopathy patients. The majority of these mutations are located in conserved alpha-helical segments, but additional mutations have recently been identified in the tail domain. Filament and network assembly studies indicate that most but not all disease-causing mutations make desmin assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. AlphaBcrystallin serves as a chaperone for desmin preventing its aggregation under various forms of stress; mutant CRYAB causes cardiac and skeletal myopathies identical to those resulting from DES mutations.

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“…[4] This latter term refers to the myofibrillar lesions occurring when desmin accumulates within muscle fibers and, thus, emphasizes the sequelae to protein aggregation and disruption of sarcomeres. Clinically, DRM are often of adult onset and, thereby, deviating from the experience in other CM, which usually commence in childhood.…”

Section: Pam Suggesting Faulty Protein Degradationmentioning

confidence: 99%

“…Another feature in the two types of myopathies, actinopathy and myosinopathy is the preservation of sarcomeres close to the accumulating actin filaments and hyaline bodies while in DRM the sarcomeric pattern is severely disturbed, giving rise to the term 'myofibrillar myopathy'. [4,26] Actinopathies Actin, the major component of thin myofilaments, appears to accumulate within muscle fibers in a two pathomorphological forms: first, as inclusion bodies, (nonspecific filamentous bodies) frequently seen in the subsarcolemmal region by electron microscopy and Hirano bodies, once described in muscle fibers in a nonspecific myopathy [27] similar to Hirano bodies seen in aged neurons of the hippocampus, as another nonspecific morphological phenomenon. The second morphological feature of filamentous actin aggregation appears as plaques, patches, or areas devoid of sarcomeres, particularly but not exclusively situated underneath the sarcolemma, in actin myopathies.…”

Section: Protein Aggregate Myopathies Due To Possible Developmental Dmentioning

confidence: 99%