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

O'Brien, J. G.; Willis, A. B.; Long, A. M.; Kwon, J.; Lee, G.; Li, F.; Page, P. G.; Vo, A. H.; Hadhazy, M.; Crosbie, R. H.; Demonbreun, A. R.; McNally, E. M.

doi:10.1101/2023.06.29.547098

bioRxiv · 10.1101/2023.06.29.547098

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

O'Brien, J. G.·Willis, A. B.·Long, A. M.·Kwon, J.·Lee, G.·Li, F.·Page, P. G.·Vo, A. H.·Hadhazy, M.·Crosbie, R. H.·Demonbreun, A. R.·McNally, E. M.

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Abstract

Genetic background shifts the severity of muscular dystrophy. In mice, the DBA/2J strain confers a more severe muscular dystrophy phenotype, whereas the Murphys Roth Large (MRL) strain has "super-healing" properties that reduce fibrosis. A comparative analysis of the Sgcg null model of Limb Girdle Muscular Dystrophy in the DBA/2J versus MRL strain showed the MRL background was associated with greater myofiber regeneration and reduced structural degradation of muscle. Transcriptomic profiling of dystrophic muscle in the DBA/2J and MRL strains indicated strain-dependent expression of the extracellular matrix (ECM) and TGF-{beta} 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-{beta}1 and TGF-{beta}3 throughout the matrix, and dystrophic myoscaffolds from the MRL background were enriched in myokines. C2C12 myoblasts were seeded onto decellularized matrices from Sgcg-/- MRL and Sgcg-/- DBA/2J matrices. Acellular myoscaffolds from the dystrophic MRL background induced myoblast differentiation and growth compared to dystrophic myoscaffolds from the DBA/2J matrices. These studies establish that the MRL background also generates its effect through a highly regenerative ECM, which is active even in muscular dystrophy. Brief SummaryThe extracellular matrix of the super-healing MRL mouse strain harbors regenerative myokines that improve skeletal muscle growth and function in muscular dystrophy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/547098v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@18543eborg.highwire.dtl.DTLVardef@2e3386org.highwire.dtl.DTLVardef@138d5ccorg.highwire.dtl.DTLVardef@5c4ef6_HPS_FORMAT_FIGEXP M_FIG C_FIG

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O'Brien, J. G., Willis, A. B., Long, A. M., Kwon, J., Lee, G., Li, F., Page, P. G., Vo, A. H., Hadhazy, M., Crosbie, R. H., Demonbreun, A. R., McNally, E. M.. 2023-06-30. The super-healing MRL strain promotes muscle growth in muscular dystrophy through a regenerative extracellular matrix. https://doi.org/10.1101/2023.06.29.547098

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