TY - JOUR
T1 - The super-healing MRL strain promotes muscle growth in muscular dystrophy through a regenerative extracellular matrix
AU - O'Brien, Joseph G.
AU - Willis, Alexander B.
AU - Long, Ashlee M.
AU - Kwon, Jason
AU - Lee, Ga Hyun
AU - Li, Frank W.
AU - Page, Patrick G.T.
AU - Vo, Andy H.
AU - Hadhazy, Michele
AU - Spencer, Melissa J.
AU - Crosbie, Rachelle H.
AU - Demonbreun, Alexis R.
AU - McNally, Elizabeth M.
N1 - Publisher Copyright:
© 2024, O'Brien et al.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.173246
DO - 10.1172/jci.insight.173246
M3 - Article
C2 - 38175727
AN - SCOPUS:85184667453
SN - 2379-3708
VL - 9
JO - JCI Insight
JF - JCI Insight
IS - 3
M1 - e173246
ER -