Dystrophin and utrophin: Genetic analyses of their role in skeletal muscle

Abstract

Since the identification of dystrophin as the causitive factor in Duchenne muscular dystrophy, there has been substantial progress in understanding the functions and interactions of this protein. Dystrophin has been shown to interact with a group of peripheral‐ and trans‐membrane proteins known as the dystrophin‐associated protein complex (DAPC) and mutations in some of the members of this complex have been shown to account for other forms of muscular dystrophy. This review summarizes the experiments using transgenic and knockout mouse models that have defined the roles of dystrophin, and the dystrophin‐related protein utrophin at the skeletal muscle membrane and at the neuromuscular junction. These studies are presented in the context of other known interactions at the muscle membrane. Studies of the dystrophin‐deficient mdx mouse have lead to a greater understanding of the human disease. Knockouts and transgenics of utrophin have shown this protein to be sufficient to functionally compensate for dystrophin. Dystrophin transgenic mice combined with the mdx mouse have been used to study the function of specific domains of the dystrophin protein. Together these animal models have led to a delineation of protein functions and localization patterns that will be useful for the generation of potential therapies for DMD. Microsc. Res. Tech. 48:155–166, 2000. © 2000 Wiley‐Liss, Inc.

CAPON expression in skeletal muscle is regulated by position, repair, NOS activity, and dystrophy

“…The highest gene expression was in diaphragm, in myotubes, satellite cells, and probable myoblasts. CAPON expression may be modified with fiber type and size, or differences in maturation and use, as reported for utrophin [65,66]. The hypertrophy of activated satellite cells that is prominent in the diaphragm [29,67] may partly account for variations among muscles.…”

Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue

“…Similarly to dystroglycan, Dp140 is only expressed during kidney development [226]. Low levels of Dp71 are detectable in adult kidney [32,82,224,[226][227][228][229][230], although a specific splice variant has been reported to be abundant, in particular in the cortex [29]. In contrast, utrophin is prominent in all segments of the nephron except proximal tubules (Fig.…”

Haploinsufficiency of utrophin gene worsens skeletal muscle inflammation and fibrosis in mdx mice

“…Overexpression of utrophin in skeletal muscle restored dystrophin protein complex (DPC) and rescued the muscular dystrophy phenotype in a dose-dependent manner in mdx mice [15,16]. These findings suggest that dystrophin and utrophin can exert similar functions once distributed to the sarcolemma, and the mild muscular dystrophy phenotype in mdx mice is probably due to the compensation by endogenous utrophin.…”