The super-healing MRL strain promotes muscle growth in muscular dystrophy through a regenerative extracellular matrix
Joseph G. O’Brien, Alexander B. Willis, Ashlee M. Long, Jason Kwon, GaHyun Lee, Frank W. Li, Patrick G.T. Page, Andy H. Vo, Michele Hadhazy, Melissa J. Spencer, Rachelle H. Crosbie, Alexis R. Demonbreun, Elizabeth M. McNally
Joseph G. O’Brien, Alexander B. Willis, Ashlee M. Long, Jason Kwon, GaHyun Lee, Frank W. Li, Patrick G.T. Page, Andy H. Vo, Michele Hadhazy, Melissa J. Spencer, Rachelle H. Crosbie, Alexis R. Demonbreun, Elizabeth M. McNally
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Research Article Muscle biology Stem cells

The super-healing MRL strain promotes muscle growth in muscular dystrophy through a regenerative extracellular matrix

Abstract

The Murphy Roths Large (MRL) mouse strain has “super-healing” properties that enhance recovery from injury. In mice, the DBA/2J strain intensifies many aspects of muscular dystrophy, so we evaluated the ability of the MRL strain to suppress muscular dystrophy in the Sgcg-null mouse model of limb girdle muscular dystrophy. A comparative analysis of Sgcg-null mice in the DBA/2J versus MRL strains showed greater myofiber regeneration, with reduced structural degradation of muscle in the MRL strain. Transcriptomic profiling of dystrophic muscle indicated strain-dependent expression of extracellular matrix (ECM) and TGF-β signaling genes. To investigate the MRL ECM, cellular components were removed from dystrophic muscle sections to generate decellularized myoscaffolds. Decellularized myoscaffolds from dystrophic mice in the protective MRL strain had significantly less deposition of collagen and matrix-bound TGF-β1 and TGF-β3 throughout the matrix. Dystrophic myoscaffolds from the MRL background, but not the DBA/2J background, were enriched in myokines like IGF-1 and IL-6. C2C12 myoblasts seeded onto decellularized matrices from Sgcg–/– MRL and Sgcg–/– DBA/2J muscles showed the MRL background induced greater myoblast differentiation compared with dystrophic DBA/2J myoscaffolds. Thus, the MRL background imparts its effect through a highly regenerative ECM, which is active even in muscular dystrophy.

Authors

Joseph G. O’Brien, Alexander B. Willis, Ashlee M. Long, Jason Kwon, GaHyun Lee, Frank W. Li, Patrick G.T. Page, Andy H. Vo, Michele Hadhazy, Melissa J. Spencer, Rachelle H. Crosbie, Alexis R. Demonbreun, Elizabeth M. McNally

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Figure 1

The MRL background reduced fibrosis in the muscles of Sgcg–/– mice.

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The MRL background reduced fibrosis in the muscles of Sgcg–/– mice. Comp...
Comparative phenotypic assessment of skeletal muscle in the Sgcg-MRL, Sgcg-D2, WT-MRL, and WT-D2 strains was conducted over 20 weeks, including 5 males and 5 females. (A) Representative Masson’s trichrome staining of the diaphragm muscles (20 weeks) showed the MRL background significantly improved fibrosis in Sgcg–/– mice. (B) Reduction of mean fibrosis (blue staining) relative to total muscle area in the MRL background (WT-MRL 0.03, Sgcg-MRL 0.15, WT-D2 0.04, and Sgcg-D2 0.41 AU). (C) Average Penh, a measure of impaired respiratory function, was corrected by the MRL background (WT-MRL 0.05, Sgcg-MRL 0.06, WT-D2 0.05, and Sgcg-D2 0.09 AU). (D) Representative images of the quadriceps muscles with reduced fibrosis in Sgcg-MRL mice. (E) Reduction of mean fibrosis in the quadriceps muscles relative to total muscle area in the MRL strain (WT-MRL 0.07, Sgcg-MRL 0.26, WT-D2 0.08, and Sgcg-D2 0.62 AU). (F) Mean percentage of fibers containing centralized nuclei was increased in the Sgcg-MRL mice (WT-MRL 2%, Sgcg-MRL 70%, WT-D2 2%, Sgcg-D2 27%). (G) Body mass was increased in the MRL background. (H) Mean fat mass was highest in the WT-MRL cohort (WT-MRL 12.5, Sgcg-MRL 7, WT-D2 5.7, and Sgcg-D2 3.2 g). (I) Mean lean mass was significantly higher in both MRL models compared with the D2 models (WT-MRL 31.8, Sgcg-MRL 18.5, WT-D2 33.1, and Sgcg-D2 17.1 g). (J) Representative image depicting the size variation between the Sgcg-MRL and Sgcg-D2 mice. Scale bars (B and D): 100 μm. Data are presented as mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 2-way ANOVA with Tukey’s multiple-comparison test.