Integrating Mechanical Loading, Mechanotransduction, and Biological Responses in Musculoskeletal Tissues Across the Lifespan: Regulation Influenced by Cells, Extracellular Matrix, and Sex.

Development of cellular mechanisms to facilitate mechanosensing and mechanotransduction occurred very early in evolution during adaptation to the boundary conditions of Earth, in particular, gravity. Subsequently, with the evolution of increasingly complex organisms leading to Homo sapiens, multiple levels of biological regulatory control of mechanical loading were introduced for connective tissues of the musculoskeletal system. Integration of mechanosensing mechanisms with biological regulatory variables exhibits tissue-specific, lifespan-specific, sex specific features. A key integration component is the regulation of response to ground reaction forces. This chapter will discuss various features of this integration and its dynamic nature across the lifespan, and the critical role of the cell-extracellular matrix relationship, and how sex-specific variables appear to influence the functioning of connective tissues, particularly in females, where lifespan transitions (i.e., puberty, pregnancy and lactation, and menopause) appear to contribute to tissue responses to loading.