M line–deficient titin causes cardiac lethality through impaired maturation of the sarcomere

Titin, the largest protein known to date, has been linked to sarcomereassembly and function through its elastic adaptor and signaling domains. Titin's M-line region contains a unique kinase domain that has been proposed to regulate sarcomereassembly via its substrate titincap (T-cap). In this study, we use a titinM line-deficient mouse to show that the initial assembly of the sarcomeredoes not depend on titin's M-line region or the phosphorylation of T-cap by the titinkinase. Rather, titin's M-line region is required to form a continuous titinfilament and to provide mechanical stability of the embryonic sarcomere. Even without titinintegrating into the M band, sarcomeresshow proper spacing and alignment of Z discs and M bands but fail to grow laterally and ultimately disassemble. The comparison of disassemblyin the developing and mature knockout sarcomeresuggests diverse functions for titin's M line in embryonic development and the adult heart that not only involve the differential expression of titinisoforms but also of titin-binding proteins.