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
View: Text | PDF
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

×

Figure 2

The MRL strain increased myofiber size and maximum tetanic force in Sgcg–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
The MRL strain increased myofiber size and maximum tetanic force in Sgcg...
TA muscle was analyzed at 20 weeks. (A) Representative immunofluorescence microscopy (IFM) images showed larger myofibers in the TA of the Sgcg-MRL stained for laminin-α2 (LAMA2). Scale bars: 50 μm. (B) Cross-sectional area (CSA) of myofibers was shifted rightward in Sgcg-MRL muscle. (C) CSA was increased in the MRL background (WT-MRL 2544, Sgcg-MRL 2619, WT-D2 2560, and Sgcg-D2 2154 μm2). (D) MRL background increased the minimum Feret diameter in the Sgcg–/– muscle (WT-MRL 49.1, Sgcg-MRL 49.6, WT-D2 49.6, and Sgcg-D2 45.1 μm). (E) Force measurements from male TA muscles showing maximum tetanic force was significantly reduced in the Sgcg-D2 strains compared with all other strains (WT-MRL 1085, Sgcg-MRL 828.5, WT-D2 836.3, and Sgcg-D2 458.7 mN). (F) Physiological CSA (PCSA) was smaller in D2 compared with MRL muscle for both Sgcg–/– and WT (WT-MRL 7.44, Sgcg-MRL 8.14, WT-D2 5.1, and Sgcg-D2 4.85 mm2). (G) Specific force was reduced for Sgcg–/– compared with WT in the D2 strain but not the MRL strain (WT-MRL 145, Sgcg-MRL 102.3, WT-D2 163.5, and Sgcg-D2 96.0 mN/mm2). 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.