Muscle-specific BCL2 expression ameliorates muscle disease in laminin α2-deficient, but not in dystrophin-deficient, mice

Dominov, Janice A.; Kravetz, Amanda J.; Ardelt, Magdalena; Kostek, Christine A.; Beermann, Mary Lou; Miller, Jeffrey B.

doi:10.1093/hmg/ddi095

Cited by 71 publications

(79 citation statements)

References 57 publications

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“…Of note is that the MyoD-hBcl-2 transgene does not affect muscle morphology (Dominov et al 2005) or expression of the markers shown (Dominov, manuscript in preparation). All mice were genotyped as previously described (Dominov et al 2005). Muscle samples were collected at various ages and immediately snap frozen on dry ice for RNA analysis.…”

Section: Dy-wmentioning

confidence: 99%

Proinflammatory Signals and the Loss of Lymphatic Vessel Hyaluronan Receptor-1 (LYVE-1) in the Early Pathogenesis of Laminin Alpha2-deficient Skeletal Muscle

Wardrop

Dominov

2011

J Histochem Cytochem.

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Congenital muscular dystrophy type 1A, a severe neuromuscular disease characterized by early-onset muscle weakness and degeneration, is caused by insufficient levels of laminin α2 (LAMA2) in the basal lamina surrounding muscle fibers and other cells. A better understanding of the molecular mechanisms leading to muscle loss is needed to develop therapeutic interventions for this disease. Here, the authors show that inflammation is an early feature of pathogenesis in Lama2-deficient mouse muscle, indicated by elevated expression of tenascin C in the endomysium around muscle fibers, infiltration of macrophages, and induction of the inflammatory cytokines tumor necrosis factor α (TNFα) and IL-1β. In addition, the expression of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), a specific marker for lymphatic vessel endothelial cells, is dramatically reduced early in Lama2-deficient muscle pathogenesis. LYVE-1 expression, which is inhibited by TNFα, is also decreased in muscles undergoing degeneration due to dystrophin deficiency and cardiotoxin damage. LYVE-1 expression thus provides a useful biomarker to monitor the onset of muscle pathogenesis, likely serving as an indicator of inflammatory signals present in muscles. Together, the data show that inflammatory pathways are activated in the earliest stages of Lama2-deficient disease progression and could play a role in early muscle degeneration.

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Section: Dy-wmentioning

confidence: 99%

Proinflammatory Signals and the Loss of Lymphatic Vessel Hyaluronan Receptor-1 (LYVE-1) in the Early Pathogenesis of Laminin Alpha2-deficient Skeletal Muscle

Wardrop

Dominov

2011

J Histochem Cytochem.

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“…30 Muscle-specific Bcl-2 transgenic or Bax knockout mice reverse this phenotype, suggesting the importance of laminin/integrin or laminin/sarcoglycan signaling pathways for suppressing apoptosis in muscle. 31,32 Overall, however, the mechanisms regulating caspase-activation and apoptosis in muscle are largely unknown. BAG3 was reported to bind and functionally collaborate with Bcl-2 in suppressing apoptosis in vitro, 33 but BAG3 does not colocalize with Bcl-2 on mitochondria in muscle (data not shown), making it an unlikely regulator of Bcl-2 in muscle.…”

Section: Homma Et Almentioning

confidence: 99%

BAG3 Deficiency Results in Fulminant Myopathy and Early Lethality

Homma

Iwasaki

Shelton

et al. 2006

The American Journal of Pathology

222

252

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Bcl-2-associated athanogene 3 (BAG3) is a member of a conserved family of cyto-protective proteins that bind to and regulate Hsp70 family molecular chaperones. Here, we show that BAG3 is prominently expressed in striated muscle and colocalizes with Zdisks. Mice with homozygous disruption of the bag3 gene developed normally but deteriorated postnatally with stunted growth evident by 1 to 2 weeks of age and death by 4 weeks. BAG3-deficient animals developed a fulminant myopathy characterized by noninflammatory myofibrillar degeneration with apoptotic features. Knockdown of bag3 expression in cultured C2C12 myoblasts increased apoptosis on induction of differentiation, suggesting a need for bag3 for maintenance of myotube survival and confirming a cell autonomous role for bag3 in muscle. We conclude that although BAG3 is not required for muscle development, this co-chaperone appears to be critically important for maintenance of mature skeletal muscle.

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“…Laminin-receptor interaction is also thought to be involved in the apoptotic pathway that may underlie the pathogenesis of muscular dystrophy because of the increased signs of apoptosis that were reported in laminin-2-deficient mice and human patients (Miyagoe et al 1997;Hayashi et al 2001). Genetic interventions designed to inhibit the mitochondrial apoptotic pathway demonstrate an improvement of the disease pathology and lifespan of laminin-2-deficient mice (Girgenrath et al 2004;Dominov et al 2005), which suggests the possibility of using anti-apoptosis therapy for muscular dystrophies.…”

Section: Extracellular Matrix Proteins and Receptorsmentioning

confidence: 99%

The genetic and molecular basis of muscular dystrophy: roles of cell–matrix linkage in the pathogenesis

2006

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Muscular dystrophies are a heterogeneous group of genetic disorders. In addition to genetic information, a combination of various approaches such as the use of genetic animal models, muscle cell biology, and biochemistry has contributed to improving the understanding of the molecular basis of muscular dystrophy's etiology. Several lines of evidence confirm that the structural linkage between the muscle extracellular matrix and the cytoskeleton is crucial to prevent the progression of muscular dystrophy. The dystrophin-glycoprotein complex links the extracellular matrix to the cytoskeleton, and mutations in the component of this complex cause Duchenne-type or limb-girdle-type muscular dystrophy. Mutations in laminin or collagen VI, muscle matrix proteins, are known to cause a congenital type of muscular dystrophy. Moreover, it is not only the primary genetic defects in the structural or matrix proteins, but also the primary mutations of enzymes involved in the protein glycosylation pathway that are now recognized to disrupt the matrix-cell interaction in a certain group of muscular dystrophies. This group of diseases is caused by the secondary functional defects of dystroglycan, a transmembrane matrix receptor. This review considers recent advances in understanding the molecular pathogenesis of muscular dystrophies that can be caused by the disruption of the cell-matrix linkage.

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Muscle-specific BCL2 expression ameliorates muscle disease in laminin α2-deficient, but not in dystrophin-deficient, mice

Cited by 71 publications

References 57 publications

Proinflammatory Signals and the Loss of Lymphatic Vessel Hyaluronan Receptor-1 (LYVE-1) in the Early Pathogenesis of Laminin Alpha2-deficient Skeletal Muscle

Proinflammatory Signals and the Loss of Lymphatic Vessel Hyaluronan Receptor-1 (LYVE-1) in the Early Pathogenesis of Laminin Alpha2-deficient Skeletal Muscle

BAG3 Deficiency Results in Fulminant Myopathy and Early Lethality

The genetic and molecular basis of muscular dystrophy: roles of cell–matrix linkage in the pathogenesis

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