The Sgcb-null mouse, with knocked-down β-
sarcoglycan, develops severe
muscular dystrophy as in type 2E human
limb girdle muscular dystrophy. The mdx mouse, lacking
dystrophin, is the most used model for
Duchenne muscular dystrophy (DMD). Unlike DMD, the mdx mouse has mild clinical features and shows little
fibrosis in limb muscles. To characterize ECM
protein deposition and the progression of muscle
fibrosis, we evaluated
protein and transcript levels of
collagens I, III and VI,
decorin, and TGF-β1, in quadriceps and diaphragm, at 2, 4, 8, 12, 26, and 52 weeks in Sgcb-null mice, and
protein levels at 12, 26, and 52 weeks in mdx mice. In Sgcb-null mice, severe morphological disruption was present from 4 weeks in both quadriceps and diaphragm, and included conspicuous deposition of extracellular matrix components. Histopathological features of Sgcb-null mouse muscles were similar to those of age-matched mdx muscles at all ages examined, but, in the Sgcb-null mouse, the extent of connective tissue deposition was generally greater than mdx. Furthermore, in the Sgcb-null mouse, the amount of all three
collagen isoforms increased steadily, while, in the mdx, they remained stable. We also found that, at 12 weeks, macrophages were significantly more numerous in mildly inflamed areas of Sgcb-null quadriceps compared to mdx quadriceps (but not in highly inflamed regions), while, in the diaphragm, macrophages did not differ significantly between the two models, in either region.
Osteopontin mRNA was also significantly greater at 12 weeks in
laser-dissected highly inflamed areas of the Sgcb-null quadriceps compared to the mdx quadriceps. TGF-β1 was present in areas of degeneration-regeneration, but levels were highly variable and in general did not differ significantly between the two models and controls. The roles of the various subtypes of macrophages in muscle repair and
fibrosis in the two models require further study. The Sgcb-null mouse, which develops early
fibrosis in limb muscles, appears more promising than the mdx mouse for probing pathogenetic mechanisms of muscle
fibrosis and for developing anti-fibrotic treatments. Highlights • The Sgcb-null mouse develops severe
muscular dystrophy, the mdx mouse does not. •
Fibrosis developed earlier in Sgcb-null quadriceps and diaphragm than mdx. • Macrophages were commoner in mildly inflamed parts of Sgcb-null quadriceps than mdx. • The Sgcb-null model appears more useful than mdx for studying fibrotic mechanisms. • The Sgcb-null model also appears more useful for developing anti-fibrotic treatments.