Muscle diseases in ageing
The loss of skeletal muscle mass, known as sarcopenia, significantly affects the quality of life during ageing even in the absence of any other recognised disease, with a dramatic impact of worsening the clinical outcomes of a broad range of diseases and pathologies. Vascular mural cell (smooth muscle cells, pericytes) defects play a key part in cerebral small vessel disease, which underlies 45% of vascular dementia cases, and brain bleeding, while ageing effects on smooth muscle cell and vascular tissue function significantly impact many body tissues.
In WP3 the DCs will investigate animal (mouse and zebrafish) and cell models of skeletal muscle and vascular diseases to provide critical novel mechanistic insights into causal mechanisms and their earlier progression towards ageing (DC3, DC7, DC12).
Mutations in collagen VI genes (COL6A1-A6) cause a distinct class of congenital muscular diseases that include both milder forms (Bethlem myopathy) and severe rapidly progressing forms (Ullrich congenital muscular dystrophy). Patients and animal models for collagen VI-related myopathies primarily exhibit myopathic features linked with deregulated autophagy and increased apoptosis. On the other hand, collagen VI is found in almost every tissue of the body and its depletion mice affects adipose tissue, articular cartilage, and trabecular bone, causing accelerated osteoarthritic joint degeneration and delayed secondary ossification process with reduced bone mineral density. Mutations in collagen type IV coding genes (COL4A1 & COL4A2) cause a multi-systemic disorder - COL4A1 syndrome - encompassing early onset severe vascular disease including haemorrhagic stroke and small vessel disease, vascular cognitive impairment and aneurysms, progressive renal failure, and eye defects. Common variants in these genes are a risk factor for haemorrhagic stroke and small vessel disease in the general population, but importantly, the mechanistic cross talk between altered collagen IV gene expression and ageing, and any convergent/divergent molecular pathways with early onset stroke due to COL4A1/2 missense mutations remains unexplored. Moreover, as these mutations are rare, and collagen IV is expressed in every tissue including articular cartilage, it is conceivable these mutations affect other tissues e.g. cartilage and bone that are unexplored to date. Thus, WP3 DCs will interact via secondments with WP1 and WP2, and secondments with the expertise of the team involved in WP4 will also propel their training and research projects. Furthermore, the combined expertise of the WP3 partners provides a platform for muscular and vascular analyses of the models studied in WP1 and WP2.
WP Lead: University of Padova