Caveolin-3: A Causative Process of Chicken Muscular Dystrophy.

Tateki Kikuchi

doi:10.3390/biom10091206

Abstract

The etiology of chicken muscular dystrophy is the synthesis of aberrant WW domain containing E3 ubiquitin-protein ligase 1 (WWP1) protein made by a missense mutation of WWP1 gene. The β-dystroglycan that confers stability to sarcolemma was identified as a substrate of WWP protein, which induces the next molecular collapse. The aberrant WWP1 increases the ubiquitin ligase-mediated ubiquitination following severe degradation of sarcolemmal and cytoplasmic β-dystroglycan, and an erased β-dystroglycan in dystrophic αW fibers will lead to molecular imperfection of the dystrophin-glycoprotein complex (DGC). The DGC is a core protein of costamere that is an essential part of force transduction and protects the muscle fibers from contraction-induced damage. Caveolin-3 (Cav-3) and dystrophin bind competitively to the same site of β-dystroglycan, and excessive Cav-3 on sarcolemma will block the interaction of dystrophin with β-dystroglycan, which is another reason for the disruption of the DGC. It is known that fast-twitch glycolytic fibers are more sensitive and vulnerable to contraction-induced small tears than slow-twitch oxidative fibers under a variety of diseased conditions. Accordingly, the fast glycolytic αW fibers must be easy with rapid damage of sarcolemma corruption seen in chicken muscular dystrophy, but the slow oxidative fibers are able to escape from these damages.

Highlights

In 1954, an animal model with inherited muscular dystrophy was found in a commercial flock of New Hampshire chickens
These results indicate that chicken muscular dystrophy inhibits the myofibrillar protein genes switching that normally occur during muscle maturation
The WWP1 mutated in the coding region of the protein provides the most likely candidate responsible for causing chicken muscular dystrophy

Summary

Introduction

In 1954, an animal model with inherited muscular dystrophy was found in a commercial flock of New Hampshire chickens. Among fast-twitch muscles, pectoralis muscle was the earliest and most severely affected soon after 2–3 weeks ex ovo Chickens flap their wings using these muscles for flying up and right themselves instantly from the spine position when placed on their back [4]. MBioumsoclelceusl.esT2h02Bi0sio,m9m,oxloecvuelems 2e0n20t, p9,exrformance is designated as flip test or ex2haofus19tion test to evalua muscles. The genetic analysis and positional cloning revealed a dystrophin gene mutation responsible for the Duchenne muscular dystrophy in 1987 [20]. The positional cloning for the genetic screenings opened new avenues to identify the gene mutation responsible for the chicken muscular dystrophy. Matsumoto et al (2008) identified a WWP1 gene mutation that led to an arg441-to-glu (R441Q) substitution in chickens with inherited muscular dystrophy [21]. This review discusses how mutated WWP1 protein functions in muscle fibers and leads to the above abnormal phenotypes

Muscle Fiber Formation

Are Dystrophic αR Fibers Akin to Embryonic or Denervated?

WWP1: E3 Ubiquitin Ligases

Findings

Caveolin-3