Disruption of Dag1 in Differentiated Skeletal Muscle Reveals a Role for Dystroglycan in Muscle Regeneration

Abstract

Striated muscle-specific disruption of the dystroglycan (DAG1) gene results in loss of the dystrophin-glycoprotein complex in differentiated muscle and a remarkably mild muscular dystrophy with hypertrophy and without tissue fibrosis. We find that satellite cells, expressing dystroglycan, support continued efficient regeneration of skeletal muscle along with transient expression of dystroglycan in regenerating muscle fibers. We demonstrate a similar phenomenon of reexpression of functional dystroglycan in regenerating muscle fibers in a mild form of human muscular dystrophy caused by disruption of posttranslational dystroglycan processing. Thus, maintenance of regenerative capacity by satellite cells expressing dystroglycan is likely responsible for mild disease progression in mice and possibly humans. Therefore, inadequate repair of skeletal muscle by satellite cells represents an important mechanism affecting the pathogenesis of muscular dystrophy.

B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I

“…50 Mice bearing a floxed allele of Dag1 (Dag1 lox/lox ) and the Pax3-Cre transgene (P3Pro-Cre) were kindly provided by Jeffery Miner (Washington University Medical School). Dag1 lox/lox mice were originally generated by Campbell and colleagues, 51 and P3Pro-Cre mice were originally generated by Epstein and colleagues. 52 For breeding, female Dag1 lox/lox mice were bred with male P3Pro-Cre transgenic mice to produce P3Pro-CreDag1 lox/þ mice.…”

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

“…[38][39][40] Admittedly, loss of the entire dystroglycan protein might have effects beyond those caused by defects in its glycosylation, but these data nevertheless support the possibility that all glycosylation defects in the dystroglycanopathies could be centered on dystroglycan. This characterization represents the current state of the literature.…”

Bex1 knock out mice show altered skeletal muscle regeneration

“…Regeneration is the result of many biological processes, such as inflammation, angiogenesis, arteriogenesis, and myogenic progenitor cell mediated myogenesis, all of which lead to the reconstitution of functional skeletal muscle tissue [2]. When this controlled repair system is impaired, continuous muscle degeneration and regeneration can occur [3]. Such is the case with Duchenne's muscular dystrophy (DMD), the most common form of inherited neuromuscular disorder [4].…”