Mending the Achilles heels of titin in cardiac and musculoskeletal disease

Abstract Titin, the largest known human protein, spans the sarcomere from Z-disk to M-line and is central to muscle elasticity, force transmission, and structural integrity. Maybe not surprisingly, accumulated evidence over the last years shows that titin, despite its titanic size, is not devoid of molecular Achilles heels that can lead to dysfunction and disease. In this review, we summarize the fundamental roles of titin in muscle mechanics, mechanosignaling, and physiology as well as in genetic and acquired disorders of cardiac and skeletal muscle. We discuss the current understanding of how mutations and posttranslational processing (dys)regulate titin, while highlighting gaps of knowledge regarding underlying molecular mechanisms. Finally, we analyze emerging experimental titin-cleavage models that are uncovering novel pathways of titin-based pathogenesis, positioning the protein not only as a central player in myocyte biomechanics but also as a determinant of pathological tissue remodeling. A main driving force in the field is to exploit the accumulated knowledge on titin to find new avenues for therapeutic intervention in cardiac and musculoskeletal disease.