Defining the Role of Collagen XII in Regulating Skeletal Muscle and Tendon during Aging

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Project Summary Collagen XII is known to bind to collagen I fibrils to create inter-fibrillar bridges that influence collagen fibril assembly and organization. Collagen XII also localizes at the cell surface in the pericellular matrix to form inter-cellular bridges that are critical for establishing cell organization in bone and tendon during development. Clinically, collagen XII deficiency presents with both features of connective tissue disorders and myopathy, and similar functional deficits have been recapitulated in a murine model for collagen XII deficiency. Recent work has established the role of collagen XII in development and injury regeneration in various tissues. However, despite myopathy appearing in middle-age collagen XII-deficient patients and worsening with age, no work has been done on aged (post-skeletal maturity) collagen XII-deficient animals to determine what is driving this clinical pattern. Thus, the mechanisms by which collagen XII regulates muscle-tendon structure and mechanical function during aging remain unknown. Therefore, our overall goal is to determine the differential role of collagen XII in the murine muscle-tendon unit in progressing age-associated changes to overall tissue function and regulating overall tissue function after skeletal maturity. Our global hypothesis is that collagen XII bridging is necessary for gap junction formation between cells throughout the muscle-tendon unit after development and that collagen XII mediates matrix interactions that maintain muscle-tendon unit composition, structure, and function during aging. Using powerful genetic mouse models that allow us to alter the expression of collagen XII, we will study the following aims: Aim 1: Define the role of collagen XII in cell-cell communication and ECM remodeling across the murine muscle-tendon unit during aging; Aim 2: Elucidate the differential roles of collagen XII in determining changes to structure, composition, and function across the murine muscle-tendon unit during aging. Rigorous, carefully chosen, and well-established structural, functional, compositional, and biological assays will allow us to define the differential role of collagen XII in musculoskeletal tissues in the contexts of aging and disease. The activities described by this proposal provide a strong foundation for scientific inquiry in the fields of musculoskeletal biology and biomechanics, preparing me to be valuable contributor to these fields as an independent investigator.