Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse

• Published in: Human molecular genetics 2016-04, Vol.25 (7), p.1357-1369
• Main Authors: de Greef, Jessica C, Hamlyn, Rebecca, Jensen, Braden S, O'Campo Landa, Raul, Levy, Jennifer R, Kobuke, Kazuhiro, Campbell, Kevin P
• Format: Article
• Language: English
• Subjects: Animals; Collagen Type VI - metabolism; Down-Regulation; Mice; Mice, Knockout; Muscle, Skeletal - metabolism; Muscular Dystrophy, Animal - metabolism; Muscular Dystrophy, Animal - pathology; Muscular Dystrophy, Animal - physiopathology; Sarcoglycanopathies - metabolism; Sarcoglycanopathies - pathology; Sarcoglycanopathies - physiopathology
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddw018

Muscular dystrophy is characterized by progressive skeletal muscle weakness and dystrophic muscle exhibits degeneration and regeneration of muscle cells, inflammation and fibrosis. Skeletal muscle fibrosis is an excessive deposition of components of the extracellular matrix including an accumulation of Collagen VI. We hypothesized that a reduction of Collagen VI in a muscular dystrophy model that presents with fibrosis would result in reduced muscle pathology and improved muscle function. To test this hypothesis, we crossed γ-sarcoglycan-null mice, a model of limb-girdle muscular dystrophy type 2C, with a Col6a2-deficient mouse model. We found that the resulting γ-sarcoglycan-null/Col6a2Δex5 mice indeed exhibit reduced muscle pathology compared with γ-sarcoglycan-null mice. Specifically, fewer muscle fibers are degenerating, fiber size varies less, Evans blue dye uptake is reduced and serum creatine kinase levels are lower. Surprisingly, in spite of this reduction in muscle pathology, muscle function is not significantly improved. In fact, grip strength and maximum isometric tetanic force are even lower in γ-sarcoglycan-null/Col6a2Δex5 mice than in γ-sarcoglycan-null mice. In conclusion, our results reveal that Collagen VI-mediated fibrosis contributes to skeletal muscle pathology in γ-sarcoglycan-null mice. Importantly, however, our data also demonstrate that a reduction in skeletal muscle pathology does not necessarily lead to an improvement of skeletal muscle function, and this should be considered in future translational studies.