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Distinct effects of contraction-induced injury in vivo on four different murine models of dysferlinopathy.

Roche JA, Ru LW, Bloch RJ - J. Biomed. Biotechnol. (2012)

Bottom Line: B6.A/J showed ~30% torque loss post-LSI and more variable recovery.Torque loss and inflammation on D3 across all strains were linearly related to necrosis.Our results suggest that (1) dysferlin is not required for functional recovery 3 days after LSI; (2) B6.A/J mice recover from LSI erratically; (3) SJL/J and B10.SJL muscles recover rapidly, perhaps due to ongoing myopathy; (4) although they recover function to different levels, all 4 dysferlinopathic strains show increased inflammation and necrosis 3 days after LSI.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201, USA.

ABSTRACT
Mutations in the DYSF gene, encoding dysferlin, cause muscular dystrophies in man. We compared 4 dysferlinopathic mouse strains: SJL/J and B10.SJL-Dysf(im)/AwaJ (B10.SJL), and A/J and B6.A-Dysf(prmd)/GeneJ (B6.A/J). The former but not the latter two are overtly myopathic and weaker at 3 months of age. Following repetitive large-strain injury (LSI) caused by lengthening contractions, all except B6.A/J showed ~40% loss in contractile torque. Three days later, torque in SJL/J, B10.SJL and controls, but not A/J, recovered nearly completely. B6.A/J showed ~30% torque loss post-LSI and more variable recovery. Pre-injury, all dysferlinopathic strains had more centrally nucleated fibers (CNFs) and all but A/J showed more inflammation than controls. At D3, all dysferlinopathic strains showed increased necrosis and inflammation, but not more CNFs; controls were unchanged. Dystrophin- DMD(mdx) mice showed more necrosis and inflammation than all dysferlin-s. Torque loss and inflammation on D3 across all strains were linearly related to necrosis. Our results suggest that (1) dysferlin is not required for functional recovery 3 days after LSI; (2) B6.A/J mice recover from LSI erratically; (3) SJL/J and B10.SJL muscles recover rapidly, perhaps due to ongoing myopathy; (4) although they recover function to different levels, all 4 dysferlinopathic strains show increased inflammation and necrosis 3 days after LSI.

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Regression analyses of contractile torque versus macrophage counts and macrophage counts versus necrosis. A regression analysis of the number of macrophages on D3 as the independent variable and torque at D3 as the dependent variable showed a good linear fit (a). Similarly, analysis of the number of necrotic fibers as the independent variable and the number of macrophages as the dependent variable also showed a good linear fit (b). The analyses suggest that that macrophage counts are a reliable negative predictor of functional recovery at D3 and that the number of necrotic fibers predicts the extent of macrophage invasion.
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fig9: Regression analyses of contractile torque versus macrophage counts and macrophage counts versus necrosis. A regression analysis of the number of macrophages on D3 as the independent variable and torque at D3 as the dependent variable showed a good linear fit (a). Similarly, analysis of the number of necrotic fibers as the independent variable and the number of macrophages as the dependent variable also showed a good linear fit (b). The analyses suggest that that macrophage counts are a reliable negative predictor of functional recovery at D3 and that the number of necrotic fibers predicts the extent of macrophage invasion.

Mentions: We also quantitated the number of macrophages (CD68+ cells) in TA muscles of each strain, both before and after injury. Focal areas of necrosis in uninjured muscles were invaded by macrophages in all dysferlinopathic strains (Figure 4). However, macrophage counts were not significantly different from uninjured C57Bl/6J (Figure 8). All dysferlinopathic strains showed significant increases in macrophages at D3 post-LSI (Figure 8), with the highest counts detected in A/J. DMDmdx muscle at D3 had significantly greater macrophage infiltration than A/J. Regression analysis with D3 torque regressed on macrophage counts showed a linear relationship (Figure 9(a); adjusted r2 = 0.836, P = 0.007), with all strains falling within the 95% confidence interval. Similarly, a regression analysis with macrophage counts regressed on necrosis at D3 also showed a linear relationship (Figure 9(b); adjusted r2 = 0.896, P = 0.003), with all strains falling within the 95% confidence interval.


Distinct effects of contraction-induced injury in vivo on four different murine models of dysferlinopathy.

Roche JA, Ru LW, Bloch RJ - J. Biomed. Biotechnol. (2012)

Regression analyses of contractile torque versus macrophage counts and macrophage counts versus necrosis. A regression analysis of the number of macrophages on D3 as the independent variable and torque at D3 as the dependent variable showed a good linear fit (a). Similarly, analysis of the number of necrotic fibers as the independent variable and the number of macrophages as the dependent variable also showed a good linear fit (b). The analyses suggest that that macrophage counts are a reliable negative predictor of functional recovery at D3 and that the number of necrotic fibers predicts the extent of macrophage invasion.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3303924&req=5

fig9: Regression analyses of contractile torque versus macrophage counts and macrophage counts versus necrosis. A regression analysis of the number of macrophages on D3 as the independent variable and torque at D3 as the dependent variable showed a good linear fit (a). Similarly, analysis of the number of necrotic fibers as the independent variable and the number of macrophages as the dependent variable also showed a good linear fit (b). The analyses suggest that that macrophage counts are a reliable negative predictor of functional recovery at D3 and that the number of necrotic fibers predicts the extent of macrophage invasion.
Mentions: We also quantitated the number of macrophages (CD68+ cells) in TA muscles of each strain, both before and after injury. Focal areas of necrosis in uninjured muscles were invaded by macrophages in all dysferlinopathic strains (Figure 4). However, macrophage counts were not significantly different from uninjured C57Bl/6J (Figure 8). All dysferlinopathic strains showed significant increases in macrophages at D3 post-LSI (Figure 8), with the highest counts detected in A/J. DMDmdx muscle at D3 had significantly greater macrophage infiltration than A/J. Regression analysis with D3 torque regressed on macrophage counts showed a linear relationship (Figure 9(a); adjusted r2 = 0.836, P = 0.007), with all strains falling within the 95% confidence interval. Similarly, a regression analysis with macrophage counts regressed on necrosis at D3 also showed a linear relationship (Figure 9(b); adjusted r2 = 0.896, P = 0.003), with all strains falling within the 95% confidence interval.

Bottom Line: B6.A/J showed ~30% torque loss post-LSI and more variable recovery.Torque loss and inflammation on D3 across all strains were linearly related to necrosis.Our results suggest that (1) dysferlin is not required for functional recovery 3 days after LSI; (2) B6.A/J mice recover from LSI erratically; (3) SJL/J and B10.SJL muscles recover rapidly, perhaps due to ongoing myopathy; (4) although they recover function to different levels, all 4 dysferlinopathic strains show increased inflammation and necrosis 3 days after LSI.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201, USA.

ABSTRACT
Mutations in the DYSF gene, encoding dysferlin, cause muscular dystrophies in man. We compared 4 dysferlinopathic mouse strains: SJL/J and B10.SJL-Dysf(im)/AwaJ (B10.SJL), and A/J and B6.A-Dysf(prmd)/GeneJ (B6.A/J). The former but not the latter two are overtly myopathic and weaker at 3 months of age. Following repetitive large-strain injury (LSI) caused by lengthening contractions, all except B6.A/J showed ~40% loss in contractile torque. Three days later, torque in SJL/J, B10.SJL and controls, but not A/J, recovered nearly completely. B6.A/J showed ~30% torque loss post-LSI and more variable recovery. Pre-injury, all dysferlinopathic strains had more centrally nucleated fibers (CNFs) and all but A/J showed more inflammation than controls. At D3, all dysferlinopathic strains showed increased necrosis and inflammation, but not more CNFs; controls were unchanged. Dystrophin- DMD(mdx) mice showed more necrosis and inflammation than all dysferlin-s. Torque loss and inflammation on D3 across all strains were linearly related to necrosis. Our results suggest that (1) dysferlin is not required for functional recovery 3 days after LSI; (2) B6.A/J mice recover from LSI erratically; (3) SJL/J and B10.SJL muscles recover rapidly, perhaps due to ongoing myopathy; (4) although they recover function to different levels, all 4 dysferlinopathic strains show increased inflammation and necrosis 3 days after LSI.

Show MeSH
Related in: MedlinePlus