The extracellular matrix differentially directs myoblast motility and differentiation in distinct forms of muscular dystrophy

• Published in: Matrix biology 2024-05, Vol.129, p.44-58
• Main Authors: Long, Ashlee M., Kwon, Jason M., Lee, GaHyun, Reiser, Nina L., Vaught, Lauren A., O'Brien, Joseph G., Page, Patrick G.T., Hadhazy, Michele, Reynolds, Joseph C., Crosbie, Rachelle H., Demonbreun, Alexis R., McNally, Elizabeth M.
• Format: Article
• Language: English
• Subjects: Annexin; Duchenne muscular dystrophy; Dysferlin; Extracellular matrix; Limb girdle muscular dystrophy; Muscle; Myoblast
• ISSN: 0945-053X; 1569-1802
• DOI: 10.1016/j.matbio.2024.04.001

•Spatial architecture and composition of the ECM differ across genetically distinct forms of muscular dystrophy, especially with respect to Annexin A6 protein deposition.•Matrix from dystrophin-mediated muscular dystrophy inhibits myoblast movement.•Matrix from dysferlin-deficient muscular dystrophy promotes myoblast motility and fusion potential.•Annexin A6 was sufficient to enhance myoblast motility.•Recombinant annexin A6 promotes myoblast differentiation. Extracellular matrix (ECM) pathologic remodeling underlies many 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. Muscle-directed viral expression of annexin A6 resulted in annexin A6 in the ECM. C2C12 myoblasts seeded onto decellularized matrices displayed differential myoblast mobility and fusion. Dystrophin-deficient decellularized matrices inhibited myoblast mobility, while dysferlin-deficient decellularized matrices enhanced myoblast movement and differentiation. Myoblasts treated with recombinant annexin A6 increased mobility and fusion like that seen on dysferlin-deficient decellularized matrix and demonstrated upregulation of ECM and muscle cell differentiation genes. These findings demonstrate specific fibrotic signatures elicit effects on myoblast activity. [Display omitted]