Mechanosensatie: impact op het bewegingsapparaat en het hart

Mechanical forces intervene at every organizational level on every organism. Understanding how mechanical forces influence the organism for the correct development of physiological processes is fundamental for grasping how they can affect disease progress. Mechanical forces are interpreted through mechanosensing and the cells respond through mechanotransduction, a process in which cells convert mechanical stimuli into molecular responses. This mechanism is orchestrated with mechanosensors, proteins that carry out their function upon the presence of mechanical forces. The cardiovascular system is very sensitive to changes in mechanical load as an increase of pressure (hypertension) is one of the biggest promoters of illness in the heart. Changes in load due to physical activity levels or disease (like spinal injury) are cause of cardiac remodelling. Skeletal muscle, like the cardiovascular system, is very susceptible to changes in mechanical loads and due to its importance in whole body metabolism understanding the mechanisms involved in skeletal muscle wasting is crucial for its treatment. Joints and specifically articular cartilage, are weight bearing structures that are highly dependent on mechanical load for their homeostasis. In recent years, Kindlin-2, a mechanosensor, has been found to play a fundamental role in cartilage health as its deletion in mice leads to spontaneous development of osteoarthritis, a complex disease characterized by cartilage damage among other symptoms. In this thesis we explore the molecular profile of the heart of mice subjected to physical inactivity induced by tail suspension for 14 days and we find that while there are no histological evidence of damage, the molecular profile is significantly changed as autophagy and protein synthesis markers are dysregulated as well as ion channels gene markers. Two weeks of tail suspension generate skeletal muscle wasting conditions in the hindlimbs of mice where muscle metabolism is significantly affected as well as the molecular clock and mechanosensors belonging to costameres. Genetically induced downregulations of mechanosensors Ilk1 and FERMT2 caused a downregulated mechanosensor, molecular clock and metabolism-related gene expression in C2C12 cells. These data point to mechanosensors, ILK and Kindlin-2 as control hubs of skeletal muscle metabolism and its molecular clock. Finding therapeutic targets for osteoarthritis is paramount to find curative treatments for the disease. Kindlin-2 was noted by its importance in articular cartilage and the development of osteoarthritis, however its upstream modulation was as of yet, unexplored. We determined that through in silico analysis and further in vitro validation, FERMT2 expression is modulated by response to hypoxia in human cartilage and in osteoarthritis context. Finally, with the aim of providing new targets for the treatment of osteoarthritis we examined a possible role of SHIP2 involved in opsismodysplasia, a cartilage affecting disease. We found that in mice, SHIP2 does not affect the osteoarthritis phenotype in cartilage, synovial tissue or subchondral bone, making it possible to discard it as a possible therapeutic target.