The extracellular matrix (ECM) is essential for the proper organization of cells into tissues and coordinates their functions by modulating intracellular signals, controlling cell growth, proliferation, migration and viability. The correct turnover and remodelling of ECM is crucial for maintaining its mechanical and metabolic functions, especially in skeletal muscle, where ECM has a primary role in force transmission. Antxr2 (also called capillary morphogenesis protein 2 or CMG2) is a cell surface receptor involved in the recognition and entry of anthrax toxin from Bacillus anthracis. Interestingly, it was also identified as a key regulator of Collagen VI (COL6) internalization. Although COL6 has a major role in skeletal muscle homeostasis, the role of Antxr2 in this tissue has been never investigated. Mutations in the human ANTXR2 gene are associated with hyaline fibromatosis syndrome (HFS), a severe and debilitating disease, characterized by the formation of non-cellularized subcutaneous and visceral nodules of connective tissue, containing high levels of COL6. Here, the studies I conducted in skeletal muscles show that Antxr2-null (Antxr2¬–/–) mice display progressive COL6 accumulation in the endomysium of muscle fibers, accompanied by expansion of the perimysial ECM and fibrotic hallmarks. However, the transcription of collagen genes is not upregulated, as well as the transcription of genes involved in the fibrotic pathway, thus supporting a possible defect in ECM degradation. Of note, Antxr2¬–/– mice undergo age-dependent muscle hypertrophy, thus highlighting how this receptor plays also a role in muscle homeostasis. Indeed, Antxr2¬–/– male mice even display a myopathic phenotype characterized by tubular aggregates and muscle weakness. Further research will be essential in order to dissect the molecular mechanisms leading to muscle remodeling in Antxr2-null mice, as well as, to understand if Antxr2 is altered in COL6-related myopathies.

The extracellular matrix (ECM) is essential for the proper organization of cells into tissues and coordinates their functions by modulating intracellular signals, controlling cell growth, proliferation, migration and viability. The correct turnover and remodelling of ECM is crucial for maintaining its mechanical and metabolic functions, especially in skeletal muscle, where ECM has a primary role in force transmission. Antxr2 (also called capillary morphogenesis protein 2 or CMG2) is a cell surface receptor involved in the recognition and entry of anthrax toxin from Bacillus anthracis. Interestingly, it was also identified as a key regulator of Collagen VI (COL6) internalization. Although COL6 has a major role in skeletal muscle homeostasis, the role of Antxr2 in this tissue has been never investigated. Mutations in the human ANTXR2 gene are associated with hyaline fibromatosis syndrome (HFS), a severe and debilitating disease, characterized by the formation of non-cellularized subcutaneous and visceral nodules of connective tissue, containing high levels of COL6. Here, the studies I conducted in skeletal muscles show that Antxr2-null (Antxr2¬–/–) mice display progressive COL6 accumulation in the endomysium of muscle fibers, accompanied by expansion of the perimysial ECM and fibrotic hallmarks. However, the transcription of collagen genes is not upregulated, as well as the transcription of genes involved in the fibrotic pathway, thus supporting a possible defect in ECM degradation. Of note, Antxr2¬–/– mice undergo age-dependent muscle hypertrophy, thus highlighting how this receptor plays also a role in muscle homeostasis. Indeed, Antxr2¬–/– male mice even display a myopathic phenotype characterized by tubular aggregates and muscle weakness. Further research will be essential in order to dissect the molecular mechanisms leading to muscle remodeling in Antxr2-null mice, as well as, to understand if Antxr2 is altered in COL6-related myopathies.

Investigating the role of Antxr2 in skeletal muscle extracellular matrix remodeling

SIGNOR, MATTEO
2021/2022

Abstract

The extracellular matrix (ECM) is essential for the proper organization of cells into tissues and coordinates their functions by modulating intracellular signals, controlling cell growth, proliferation, migration and viability. The correct turnover and remodelling of ECM is crucial for maintaining its mechanical and metabolic functions, especially in skeletal muscle, where ECM has a primary role in force transmission. Antxr2 (also called capillary morphogenesis protein 2 or CMG2) is a cell surface receptor involved in the recognition and entry of anthrax toxin from Bacillus anthracis. Interestingly, it was also identified as a key regulator of Collagen VI (COL6) internalization. Although COL6 has a major role in skeletal muscle homeostasis, the role of Antxr2 in this tissue has been never investigated. Mutations in the human ANTXR2 gene are associated with hyaline fibromatosis syndrome (HFS), a severe and debilitating disease, characterized by the formation of non-cellularized subcutaneous and visceral nodules of connective tissue, containing high levels of COL6. Here, the studies I conducted in skeletal muscles show that Antxr2-null (Antxr2¬–/–) mice display progressive COL6 accumulation in the endomysium of muscle fibers, accompanied by expansion of the perimysial ECM and fibrotic hallmarks. However, the transcription of collagen genes is not upregulated, as well as the transcription of genes involved in the fibrotic pathway, thus supporting a possible defect in ECM degradation. Of note, Antxr2¬–/– mice undergo age-dependent muscle hypertrophy, thus highlighting how this receptor plays also a role in muscle homeostasis. Indeed, Antxr2¬–/– male mice even display a myopathic phenotype characterized by tubular aggregates and muscle weakness. Further research will be essential in order to dissect the molecular mechanisms leading to muscle remodeling in Antxr2-null mice, as well as, to understand if Antxr2 is altered in COL6-related myopathies.
2021
Investigating the role of Antxr2 in skeletal muscle extracellular matrix remodeling
The extracellular matrix (ECM) is essential for the proper organization of cells into tissues and coordinates their functions by modulating intracellular signals, controlling cell growth, proliferation, migration and viability. The correct turnover and remodelling of ECM is crucial for maintaining its mechanical and metabolic functions, especially in skeletal muscle, where ECM has a primary role in force transmission. Antxr2 (also called capillary morphogenesis protein 2 or CMG2) is a cell surface receptor involved in the recognition and entry of anthrax toxin from Bacillus anthracis. Interestingly, it was also identified as a key regulator of Collagen VI (COL6) internalization. Although COL6 has a major role in skeletal muscle homeostasis, the role of Antxr2 in this tissue has been never investigated. Mutations in the human ANTXR2 gene are associated with hyaline fibromatosis syndrome (HFS), a severe and debilitating disease, characterized by the formation of non-cellularized subcutaneous and visceral nodules of connective tissue, containing high levels of COL6. Here, the studies I conducted in skeletal muscles show that Antxr2-null (Antxr2¬–/–) mice display progressive COL6 accumulation in the endomysium of muscle fibers, accompanied by expansion of the perimysial ECM and fibrotic hallmarks. However, the transcription of collagen genes is not upregulated, as well as the transcription of genes involved in the fibrotic pathway, thus supporting a possible defect in ECM degradation. Of note, Antxr2¬–/– mice undergo age-dependent muscle hypertrophy, thus highlighting how this receptor plays also a role in muscle homeostasis. Indeed, Antxr2¬–/– male mice even display a myopathic phenotype characterized by tubular aggregates and muscle weakness. Further research will be essential in order to dissect the molecular mechanisms leading to muscle remodeling in Antxr2-null mice, as well as, to understand if Antxr2 is altered in COL6-related myopathies.
ANTXR2
Collagen VI
Extracellular matrix
Skeletal muscle
Muscle hypertrophy
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12608/41380