Extracellular Matrix–Driven Dysregulation of Skeletal Muscle Homeostasis in Collagen VI Deficiency Across Ageing

Collagen VI (COL6) is a key extracellular matrix component of skeletal muscle that integrates mechanical stability with cellular homeostatic signaling. Mutations in COL6 genes cause a spectrum of inherited neuromuscular disorders collectively termed COL6–related myopathies, characterized by progressive muscle weakness, impaired regeneration, and premature functional decline. Although mitochondrial dysfunction, defective autophagy, and stem cell niche alterations have been implicated in disease pathogenesis, how COL6 deficiency affects muscle homeostasis across aging and through intercellular communication remains incompletely understood. In this thesis, I investigated the consequences of COL6 deficiency using complementary in vivo and in vitro models, with particular emphasis on aging, extracellular signaling, and cell–matrix interactions. First, I performed a comprehensive phenotypic and transcriptomic analysis of COL6 null (Col6a1⁻/⁻) mice at different ages, revealing progressive loss of muscle mass and function, chronic myofiber remodeling, accelerated depletion of the satellite cell pool, and age-dependent transcriptional reprogramming of myogenic populations. Single-nucleus RNA sequencing identified dysregulated differentiation programs in COL6–deficient myoblasts and highlighted Secreted Modular Calcium-binding Protein 2 (SMOC2) as a uniquely altered extracellular matrix–associated factor linking aging, myogenic dysfunction, and niche remodeling. Second, using immortalized human myoblasts derived from patients with Ullrich congenital muscular dystrophy (UCMD), I characterized extracellular vesicles released under COL6–deficient conditions and assessed their functional effects on inflammation, fibrosis, and wound healing. UCMD-derived vesicles exhibited pro-inflammatory properties and context-dependent effects on tissue repair, suggesting a role for altered vesicle-mediated communication in disease pathophysiology. Third, I investigated primary cilium dynamics in human COL6–deficient myoblasts and demonstrated delayed ciliogenesis and abnormal ciliary morphology, which could be improved by pharmacological modulation of cAMP signaling. These findings identify defective ciliary signaling as an additional layer of cellular dysfunction downstream of extracellular matrix abnormalities. Together, this work demonstrates that COL6 deficiency disrupts skeletal muscle homeostasis through coordinated effects on extracellular matrix integrity, stem cell regulation, intercellular communication, and aging-associated adaptation. By integrating in vivo aging models with human cell-based systems, the results obtained with this thesis provide new insights into the cellular and molecular mechanisms underlying COL6–related myopathies and identify new pathways and candidate targets relevant for therapeutic intervention.