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Review
. 2020 Aug 20;10(9):1206.
doi: 10.3390/biom10091206.

Caveolin-3: A Causative Process of Chicken Muscular Dystrophy

Tateki Kikuchi  1
Affiliations
Review

Caveolin-3: A Causative Process of Chicken Muscular Dystrophy

Tateki Kikuchi. Biomolecules. .

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.

Keywords: Caveolin-3; WWP1; chicken muscular dystrophy; stretching; β-dystroglycan.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chickens with muscular dystrophy (line 413) cannot right themselves from the spine position when they placed on their back while normal birds stand up instantly from this position (a). The pectoralis muscles from normal (b) and dystrophic (c) chickens at seven months are stained with Sirius Red. Normal pectoral muscle fibers (line 412) have polygonal contour and yellow cytoplasm outlined basal lamina by bright red line. They are wrapped by reddish connective tissue. Dystrophic pectoralis muscles are earliest and most severely affected, which are characterized by a marked variation in size with a proliferation of intracellular nuclei, necrotic phagocytosis (arrow), multivesicular fibers (arrow head) and fibrosis with lipid droplets. Note that dystrophic fibers lead to develop thicker endomysium layer compared to age matched wild-type ones. Bars in (b) and (c) indicate 80 and 100 μm, respectively.
Figure 2
Figure 2
Schematic model indicating the stereographic structure of the relationship among primary myotube (p-myotube), secondary myotube (s-myotube) and myoblasts proliferating within a primary muscle fascicle (a). The s-myotubes take gradually the 2D space on the surface of p-myotubes. They separate from p-myotubes and then occupy the 3D space within a primary muscle fascicle (a) (right). (b) A comparison of myotube formation between complexus and other muscles. Note that a remarkable growth of s-myotubes in complexus muscle loses both 2D and 3D spaces rapidly to develop around p-myotubes compared to other muscles [22,24].
Figure 3
Figure 3
Transverse sections stained for the acetylcholinesterase (AChE) activity with histochemical method at motor endplates (m) of: normal (a); heterozygous (b); and dystrophic (c) pectoralis muscles. The AChE activity in normal pectoralis muscle fibers is confined to the motor endplates, while it extends to the extrajunctional sarcoplasm diffusely in heterozygous and dystrophic fibers. The hypertrophied αR fibers are surrounded by atrophied αW fibers (white arrowheads in (b)), some of which have AChE positive endplates (arrowheads in (b)). The majority of dystrophic fibers (c) are hypertrophy and contain intense AChE activity in sarcoplasm and have motor endplates (m), which are stained weaker and thinner than those in other genotypes. Note a positively stained sarcoplasm, likely “Ring fiber”, at the right lower corner (c), Bars = 50 μm. [17].
Figure 4
Figure 4
Longitudinal section of succinic dehydrogenase (SDH) activity in: normal (a); dystrophic (b); and combined (normal + dystrophic) donor muscles (c), regenerating in normal host chicks at 56 days post-operation made at 10 days after hatching. The SDH activity in dystrophic fibers is higher than in normal fibers. Compared with homogeneous enzyme reaction in normal and dystrophic donor muscles, SDH activity in combined transplants is more variable along the length, higher (arrowhead) and lower in others (large arrow). Adopted from Kikuchi et al. 1980 [47]. (c) Bar = 100 μm.
Figure 5
Figure 5
(a) The schematic domain structure of chicken WWP1 and the site of missense mutation. Chicken WWP1 protein is composed of 922 amino acids indicating WWP1 functional domains: C2 domain, three WW domains and HECT domain. C in HECT domain indicates an active cysteine residue. The arrow indicates the site of missense mutation. WW domains bind proline-rich region. (b) Muscle-differentiation markers (Myog, MyoD, MyHC Ia and MyHC IIb) in WWP1-transfected (WT and R436Q) and empty vector-transfected (control) C2C12 cells. Note that the R436Q-transfected cells retained the high expression of both slow MyHC Ia and fast MyHC IIb isoforms compared to control cells. Y-axis indicates relative expression level of each gene to the GAPDH gene expression. Different letters indicate significantly differences (p < 0.05) among column graphs. Adopted from Matsumoto et al. 2008 and 2010 [63].
Figure 6
Figure 6
Expression of caveolin-3 (Cav-3) at protein and mRNA level. (a) Expression of Cav-3 in M. pectoralis superficialis (PS), M. anterior latissimus dorsi (ALD) and heart (H) was analyzed by Western blotting. Note that PS expressed higher amount of Cav-3 protein (7.12 ± 3.31-fold) in dystrophic chickens (D), while the expression in ALD and H was undetectable as in normal chickens (N). (b) The semi-quantitative RT-PCR analysis indicated that its mRNA expression was at the similar level between dystrophic (D) and normal (N) pectoralis muscle. Adopted from Matsumoto et al. 2010 [85].
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