Myoscaffolds demonstrate differential matrix components across muscular dystrophies

Long, A. M.; Kwon, J.; Reiser, N. L.; Vaught, L. A.; O'Brien, J. G.; Page, P. G. T.; Lee, G.; Hadhazy, M.; Reynolds, J. C.; Crosbie, R. H.; McNally, E. M.; Demonbreun, A. R.

doi:10.1101/2022.10.31.514525

bioRxiv · 10.1101/2022.10.31.514525

Myoscaffolds demonstrate differential matrix components across muscular dystrophies

Long, A. M.·Kwon, J.·Reiser, N. L.·Vaught, L. A.·O'Brien, J. G.·Page, P. G. T.·Lee, G.·Hadhazy, M.·Reynolds, J. C.·Crosbie, R. H.·McNally, E. M.·Demonbreun, A. R.

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Abstract

Extracellular matrix (ECM) pathologic remodeling underlies many fibrotic disorders, including muscular dystrophy. Tissue decellularization removes cellular components while leaving behind ECM components. We generated "on-slide" decellularized tissue slices from genetically distinct dystrophic mouse models. The ECM of dystrophin-and sarcoglycan-deficient muscles had marked thrombospondin 4 deposition, while dysferlin-deficient muscle had excess decorin. Annexins A2 and A6 were present on all dystrophic decellularized ECMs, but annexin matrix deposition was excessive in dysferlin-deficient muscular dystrophy. Adeno-associated viral expression of annexin A6 specifically in muscle resulted in annexin A6 deposition throughout the ECM, indicating muscle as a source of this ECM protein. C2C12 myoblasts seeded onto decellularized matrices displayed differential myoblast mobility. Dystrophin-deficient decellularized matrices inhibited myoblast mobility while dysferlin-deficient decellularized matrices enhanced myoblast movement. Myoblasts treated with recombinant annexin A6 increased mobillity similar to that seen on dysferlin-deficient decellularized matrix. These findings demonstrate specific fibrotic signatures elicit effects on myoblast activity. TEASERFibrosis in muscular dystrophy has differential effects on myoblasts HIGHLIGHTSO_LISpatial architecture and composition of the ECM differ across genetically distinct forms of muscular dystrophy, especially with respect to Annexin A6 protein deposition C_LIO_LIMatrix from dystrophin-mediated muscular dystrophy inhibits myoblast movement C_LIO_LIMatrix from dysferlin-deficient muscular dystrophy promotes myoblast motility C_LIO_LIAnnexin A6 was sufficient to enhance myoblast motility C_LI

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Long, A. M., Kwon, J., Reiser, N. L., Vaught, L. A., O'Brien, J. G., Page, P. G. T., Lee, G., Hadhazy, M., Reynolds, J. C., Crosbie, R. H., McNally, E. M., Demonbreun, A. R.. 2022-10-31. Myoscaffolds demonstrate differential matrix components across muscular dystrophies. https://doi.org/10.1101/2022.10.31.514525

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