Desmin myopathy involving cardiac, skeletal, and vascular smooth muscle: Report of a case with immunoelectron microscopy

Abraham, Susan C.; DeNofrio, David; Loh, Evan; Minda, Justina M.; Tomaszewski, John E.; Pietra, Giuseppe G.; Reynolds, Carol

doi:10.1016/s0046-8177(98)90460-9

Cited by 32 publications

(20 citation statements)

References 16 publications

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“…4), and this was consistent with reduced myofiber size. These changes are characteristic of desminopathies (Abraham et al 1998;Clemen et al 2013;Selcen et al 2004).…”

Section: Myofiber Morphology and Density Change In Association With Dmentioning

confidence: 93%

Abnormal Accumulation of Desmin in Gastrocnemius Myofibers of Patients with Peripheral Artery Disease

Koutakis¹,

Miserlis

Myers

et al. 2015

J Histochem Cytochem.

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SummaryPatients with peripheral artery disease (PAD) develop a myopathy in their ischemic lower extremities, which is characterized by myofiber degeneration, mitochondrial dysfunction and impaired limb function. Desmin, a protein of the cytoskeleton, is central to maintenance of the structure, shape and function of the myofiber and its organelles, especially the mitochondria, and to translation of sarcomere contraction into muscle contraction. In this study, we investigated the hypothesis that disruption of the desmin network occurs in gastrocnemius myofibers of PAD patients and correlates with altered myofiber morphology, mitochondrial dysfunction, and impaired limb function. Using fluorescence microscopy, we evaluated desmin organization and quantified myofiber content in the gastrocnemius of PAD and control patients. Desmin was highly disorganized in PAD but not control muscles and myofiber content was increased significantly in PAD compared to control muscles. By qPCR, we found that desmin gene transcripts were increased in the gastrocnemius of PAD patients as compared with control patients. Increased desmin and desmin gene transcripts in PAD muscles correlated with altered myofiber morphology, decreased mitochondrial respiration, reduced calf muscle strength and decreased walking performance. In conclusion, our studies identified disruption of the desmin system in gastrocnemius myofibers as an index of the myopathy and limitation of muscle function in patients with PAD. (J Histochem Cytochem 63:256-269, 2015)

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“…4), and this was consistent with reduced myofiber size. These changes are characteristic of desminopathies (Abraham et al 1998;Clemen et al 2013;Selcen et al 2004).…”

Section: Myofiber Morphology and Density Change In Association With Dmentioning

confidence: 93%

Abnormal Accumulation of Desmin in Gastrocnemius Myofibers of Patients with Peripheral Artery Disease

Koutakis¹,

Miserlis

Myers

et al. 2015

J Histochem Cytochem.

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“…These aggregates display a unique morphology at the ultrastructural level. 15 We recently created and characterized a TG mouse model of DRM, in which the disease is caused by TG overexpression of a desmin cDNA that carries a mutation that causes human disease. 17 Because CryAB associates with desmin, we wished to determine whether the R120G mutation resulted in a pathological outcome similar to DRM.…”

Section: R120g-cryab Causes Aberrant Desmin and Cryab Aggregationmentioning

confidence: 99%

“…14 Restrictive, hypertrophic, and dilated cardiomyopathies have all been observed in the desminopathies and often result in death. 12,15 Overexpression of R120G-CryAB in a muscle cell line caused formation of electron-dense aggregates containing CryAB in the center and desmin at the periphery. 14 However, there is no direct in vivo evidence, outside of linkage analysis, proving that the missense mutation of CryAB causes DRM.…”

mentioning

confidence: 99%

Expression of R120G–αB-Crystallin Causes Aberrant Desmin and αB-Crystallin Aggregation and Cardiomyopathy in Mice

Wang

Osińska

Klevitsky

et al. 2001

Circulation Research

277

368

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Abstract-Upregulation of ␣B-crystallin (CryAB), a small heat shock protein, is associated with a variety of diseases, including the desmin-related myopathies. CryAB, which binds to both desmin and cytoplasmic actin, may participate as a chaperone in intermediate filament formation and maintenance, but the physiological consequences of CryAB upregulation are unknown. A mutation in CryAB, R120G, has been linked to a familial desminopathy. However, it is unclear whether the mutation is directly causative. We created multiple transgenic mouse lines that overexpressed either murine wild-type CryAB or the R120G mutation in cardiomyocytes. Overexpression of wild-type CryAB was relatively benign, with no increases in mortality and no induction of desmin-related cardiomyopathy even in a line in which CryAB mRNA expression was increased Ϸ104-fold and the protein level increased by 11-fold. In contrast, lines expressing the R120G mutation were compromised, with a high-expressing line exhibiting 100% mortality by early adulthood. Modest expression levels resulted in a phenotype that was strikingly similar to that observed for the desmin-related cardiomyopathies. The desmin filaments in the cardiomyocytes were overtly affected, myofibril alignment was significantly impaired, and a hypertrophic response occurred at both the molecular and cellular levels. The data show that the R120G mutation causes a desminopathy, is dominant negative, and results in cardiac hypertrophy. Key Words: transgenic Ⅲ heart disease Ⅲ mouse Ⅲ cardiac Ⅲ genetics T he small heat shock-related protein ␣B-crystallin (CryAB) was originally discovered and classified as a lens protein. 1 CryAB is also found in nonlenticular tissues and is abundant in cardiac and skeletal muscle. 2,3 CryAB binds both desmin and cytoplasmic actin and possesses molecular chaperone function in vitro. 4 -6 When a cell is subjected to stress, CryAB transits from the cytosol onto the cytoskeleton. 7 Phosphorylation by mitogen-activated protein kinase, p38, and other kinases may regulate this translocation and presumably its chaperone function. 8,9 The upregulation of the gene and subsequent accumulation of CryAB occurs in a number of cardiac disorders including familial hypertrophic cardiomyopathy and desminopathy, 10 -12 as well as degenerative neural pathologies such as Alexander and Alzheimer diseases. 2,13 However, the pathophysiological significance, if any, of CryAB protein upregulation in muscle remains obscure.A missense mutation (R120G) of CryAB has recently been linked to familial desmin-related myopathy (DRM), a disease that is characterized by intrasarcoplasmic accumulation of desmin. 14 Restrictive, hypertrophic, and dilated cardiomyopathies have all been observed in the desminopathies and often result in death. 12,15 Overexpression of R120G-CryAB in a muscle cell line caused formation of electron-dense aggregates containing CryAB in the center and desmin at the periphery. 14 However, there is no direct in vivo evidence, outside of linkage analysis, proving that th...

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“…Desmin myopathy is characterized by abnormal aggregates of desmin-type intermediate filaments in the skeletal, cardiac and rarely the intestinal smooth muscle [75, 77]. The desmin filament lattice surrounds the Z-discs, interconnects them to each other and links the contractile apparatus to the sarcolemma, cytoskeleton, cytoplasmic organelles and the nucleus [78].…”

Section: Myopathies With Cardiac Involvementmentioning

confidence: 99%

“…Desmin myopathies are genetically heterogeneous (table 1). CI in desmin myopathy comprises ECG abnormalities like atrial flutter, AV block and ventricular tachycardia [76, 77, 79]. Additionally, there may be myocardial thickening, dilatation and heart failure with systolic and restrictive diastolic dysfunction [76, 78, 80, 81, 82, 83].…”

Section: Myopathies With Cardiac Involvementmentioning

confidence: 99%

Cardiac Involvement in Primary Myopathies

Finsterer

Stöllberger

2000

Cardiology

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Simultaneous or temporarily staggered affection of both the skeletal as well as the cardiac muscle (cardiac involvement, CI) is a frequent finding in primary myopathies (MPs). CI leads to impulse generation defects, impulse conduction defects, thickened myocardium, left ventriculalr hypertrabeculation, dilatation of the cardiac cavities, secondary valve insufficiency, reduction of coronary vasodilative reserve, intracardial thrombus formation, and heart failure with systolic and diastolic dysfunction. CI has been found in Duchenne muscular dystrophy (MD), Becker MD, Emery-Dreifuss MD, facioscapulohumeral MD, sarcoglycanopathies, myotubular congenital MD, myotonic dystrophies type 1 and 2, proximal myotonic myopathy, myoadenylate deaminase deficiency, glycogenosis type II, III, IV, VII and IX, carnitine deficiency, mitochondriopathy, desmin MP, nemaline MP, central core disease, multicore MP, congenital fiber-type disproportion MP, Barth syndrome, McLeod syndrome and Bethlem MP. Patients with any of the above-mentioned myopathies should be cardiologically investigated as soon as their diagnosis is established, since sufficient cardiac therapy improves CI in MPs and since management of these patients is influenced by the degree of CI.

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Desmin myopathy involving cardiac, skeletal, and vascular smooth muscle: Report of a case with immunoelectron microscopy

Cited by 32 publications

References 16 publications

Abnormal Accumulation of Desmin in Gastrocnemius Myofibers of Patients with Peripheral Artery Disease

Abnormal Accumulation of Desmin in Gastrocnemius Myofibers of Patients with Peripheral Artery Disease

Expression of R120G–αB-Crystallin Causes Aberrant Desmin and αB-Crystallin Aggregation and Cardiomyopathy in Mice

Cardiac Involvement in Primary Myopathies

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