Collagen VI assembly and function in musculoskeletal disorders

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Collagen VI is a microfibrillar protein of the extracellular matrix with ubiquitous tissue distribution. Mutations in the genes encoding the three major collagen VI chains (COL6A1, COL6A2 and COL6A3) cause a group of myopathies of varying severity, including Bethlem myopathy and Ullrich congenital muscular dystrophy. Studies in patients and mouse models have unveiled pathognomonic features of collagen VI deficient muscles such as increased spontaneous apoptosis of myofibres, mitochondrial dysfunction, deficient autophagy and reduced regenerative potential. However, the exact mechanisms linking collagen VI deficiency to these specific cellular defects are still elusive. In this project, using a combination of high-throughput and high-resolution analysis, we aim to characterize the biochemical signals conveyed by collagen VI and to identify the cell populations that respond to these signals in vivo within skeletal muscles. Finally, we will describe at the single-cell level how mutations in this extracellular matrix protein are translated in specific cellular defects, and ultimately, in the loss of musculoskeletal tissue homeostasis. Our goal is to push forward our understanding of these human muscular disorders providing new information that can help the development of novel therapeutic approaches.