Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy

Abstract

The most common form of human congenital muscular dystrophy (CMD) is caused by mutations in the laminin-α2 gene. Loss of laminin-α2 function in this autosomal recessive type 1A form of CMD results in neuromuscular dysfunction and, often, early death. Laminin-α2-deficient skeletal muscles in both humans and mice show signs of muscle cell death by apoptosis. To examine the significance of apoptosis in CMD1A pathogenesis, we determined whether pathogenesis in laminin-α2-deficient (Lama2 -/-) mice could be ameliorated by inhibiting apoptosis through either (a) inactivation of the proapoptosis protein Bax or (b) overexpression of the antiapoptosis protein Bcl-2 from a muscle-specific transgene. We found that both of these genetic interventions produced a several-fold increase in the lifespan of Lama2 -/-mice. Bax inactivation also improved postnatal growth rate and myofiber histology and decreased fixed contractures of Lama2 -/-mice. Thus, Bcl-2 family-mediated apoptosis contributes significantly to pathogenesis in the mouse model of CMD1A, and antiapoptosis therapy may be a possible route to amelioration of neuromuscular dysfunction due to laminin-α2 deficiency in humans.

Deficiency of the Bax gene attenuates denervation-induced apoptosis

“…It is worth noting that by inactivating Bax, both the postnatal growth rate and muscle fibre morphology are improved while the amount of fixed muscular contractures is reduced in the skeletal muscle taken from the laminin-α2/Bax-deficient animals, and these findings denote that pro-apoptotic Bax plays an important role in the progression of muscular pathologies. 60 The data from our study are consistent with the idea that Bax-associated pro-apoptotic signalling is an important mediator in muscle wasting pathologies particularly induced by muscle denervation. Our results indicate that in response to the removal of nerve supply, the extent of muscle loss is attenuated and is accompanied by the suppression of pro-apoptotic signalling in skeletal muscle that is deficient of the Bax gene.…”

“…3,4,7,8,[51][52][53][54][55][56][57][58][59] A recent study clearly demonstrated that inhibition of apoptosis improves the outcome of skeletal muscle wasting pathology in the genetically knockout mice that were deficient of the laminin-α2 gene, an animal model of congenital muscular dystrophy. 60 By adopting genetic intervention by crossbreeding the laminin-α2-deficient mice with pro-apoptotic Bax-deficient mice or with mice carrying the muscle-specific anti-apoptotic Bcl-2 transgene, Girgenrath and colleagues 60 have shown that the extent of muscle pathology is ameliorated by either inactivation of the pro-apoptotic protein Bax or overexpression of the anti-apoptotic protein Bcl-2. It is worth noting that by inactivating Bax, both the postnatal growth rate and muscle fibre morphology are improved while the amount of fixed muscular contractures is reduced in the skeletal muscle taken from the laminin-α2/Bax-deficient animals, and these findings denote that pro-apoptotic Bax plays an important role in the progression of muscular pathologies.…”

Cystamine Suppresses Polyalanine Toxicity in a Mouse Model of Oculopharyngeal Muscular Dystrophy

“…The role of apoptosis in muscle fiber death and muscular dystrophy is unclear and is likely to vary among muscular dystrophies. There is activation of apoptosis in some muscular dystrophies, and antiapoptotic strategies, such as the genetic overexpression of Bcl2 or inactivation of BAX, are protective in some mouse models of muscular dystrophy (41,42).…”

Congenital Muscular Dystrophies: Toward Molecular Therapeutic Interventions

“…Suppression of apoptosis has been identified as a potential therapeutic strategy in laminin-α 2 deficiency, as there is evidence for ongoing apoptosis in the muscle of the animal model [31,32] as well as in patient muscle [33]. Overexpression of the antiapoptosis protein BCL2 in diseased muscles in Lama2dy-W mice has been achieved by crossing these animals with transgenic mice that overexpressed human BCL2 under control of muscle-specific MyoD or MRF4 promoter.…”