Exercise affects many vital processes and biological functions in the human body, acting as a multistressor for most of the organ systems and inducing their adaptive responses to exercise stress. Skeletal muscle is a paradigm of an organ on which exercise exerts multiple stress, e.g., metabolic and mechanical, and which exhibits a remarkable plasticity, possessing the ability to adapt to mechanical stimuli by changing its mass and overall contractile phenotype. The magnitude to which mechanical loading applied on the muscle can lead to its specific adaptations depends on the complex relationships between muscle shape, loading state, structural interactions, and metabolic status. When muscle tissue is subjected to mechanical deformation, mmechanosensitive complexes (mechanosensors) situated in the muscle cell membrane sense mechanical alterations and activate intracellular signaling pathways (mechanotransduction), resulting in a plethora of acute molecular and cellular responses, as well as chronic adaptations. This chapter focuses mainly on the cellular and molecular mechanisms that mediate the transformation of mechanical loading-induced muscle deformation into biochemical responses.