title: Loss of dystrophin and β-sarcoglycan significantly exacerbates the phenotype of laminin α2 chain-deficient animals.
abstract: The adhesion molecule laminin α2 chain interacts with the dystrophin-glycoprotein complex, contributes to normal muscle function, and protects skeletal muscles from damage. Complete loss of the laminin α2 chain in mice results in a severe muscular dystrophy phenotype and death at approximately 3 weeks of age. However, it is not clear if the remaining members of the dystrophin-glycoprotein complex further protect laminin α2 chain-deficient skeletal muscle fibers from degeneration. Hence, we generated mice deficient in laminin α2 chain and dystrophin (dy(3K)/mdx) and mice devoid of laminin α2 chain and β-sarcoglycan (dy(3K)/Sgcb). Severe muscular dystrophy and a lack of nourishment inevitably led to massive muscle wasting and death in double-knockout animals. The dy(3K)/Sgcb mice were generally more severely affected than dy(3K)/mdx mice. However, both double-knockout strains displayed exacerbated muscle degeneration, inflammation, fibrosis, and reduced life span (5 to 13 days) compared with single-knockout animals. However, neither extraocular nor cardiac muscle was affected in double-knockout animals. Our results suggest that, although laminin α2 chain, dystrophin, and β-sarcoglycan are all part of the same adhesion complex, they have complementary, but nonredundant, roles in maintaining sarcolemmal integrity and protecting skeletal muscle fibers from damage. Moreover, the double-knockout mice could potentially serve as models in which to study extremely aggressive muscle-wasting conditions.
authors.affiliation: Muscle Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Kinga I
authors.initials: KI
authors.lastname: Gawlik
authors.affiliation: Muscle Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Holmberg
authors.affiliation: Muscle Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden. Electronic address: madeleine.durbeej-hjalt@med.lu.se.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Durbeej
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007797:Laminin / Q000172:deficiency / Q000235:genetics*; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000473:pathology*; D010641:Phenotype; D012038:Regeneration; D049031:Sarcoglycans / Q000235:genetics / Q000378:metabolism*
chemical_list: D016189:Dystrophin; D007797:Laminin; D049031:Sarcoglycans; C102645:laminin alpha 2