Mechanosensing en signaaltransductie in skeletspieren onder veranderde mechanische belastingscondities.

Skeletal muscle (SkM) has an intrinsic capacity for sensing mechanical stimuli (mechanosensing) and converting these into biochemical events that regulate adaptive protein synthesis. Converting mechanical energy into biological events is termed mechanotransduction. However, the mechanisms underlying the link between mechanosensing, mechanotransduction and the subsequent regulation of protein synthesis and breakdown remain poorly understood. Within SkM fibers, the signal transduction machinery is physically fixed to the cytoskeleton and spatially integrated within the costameres. Costameres are sites where the extracellular matrix (ECM) is physically coupled to the cytoskeleton within skeletal tissue. These connections between the extracellular and intracellular space are important for transmitting mechanical forces and for maintaining SkM fiber quality. One of the major components of the costameres are integrins. Integrins bind ligands that are components of extracellular matrices (e.g., fibronectin, and collagen). These ligands cluster integrins, thereby forming an integrin receptor complex (IRC). The IRC transduces biochemical signals and plays a pivotal role in proliferation, differentiation, and survival in skeletal and cardiac myocytes. Moreover, the key regulators of integrin-mediated signaling form a heterotrimeric complex termed IPP (ILK-PINCH-parvin). Within this complex, ILK seems to serve as the central component since is important for muscle integrity and recruits actin binding and actin regulatory proteins such as PINCH and parvin. Therefore, my project will focus on IRC/IPP components since this central mechanosensor complex governs mechanical loading management in SkM. Nevertheless, these complexes remain understudied in SkM tissue. Especially in physiologically loaded and unloaded models, these IRC/IPP constituents are neglected yet. Therefore, my project will be (one of) the first project(s) to investigate fiber type-specific changes in biological events underlying mechanotransduction upon strength training and disuse. Hence, our results will provide a novel understanding of molecular mechanisms governing SkM loading management.