Gigantic variety: expression patterns of titin isoforms in striated muscles and consequences for myofibrillar passive stiffness

摘要

The giant muscle protein titin has become a focus of research interests in the field of muscle mechanics due to its importance for passive muscle stiffness. Here we summarize research activities leading to current understanding of titin's mechanical role in the sarcomere. We then show how low-porosity polyacrylamide-gel electrophoresis, optimised for resolving megadalton proteins, can identify differences in titin-isoform expression in the hearts of 10 different vertebrate species and in several skeletal muscles of the rabbit. A large variety of titin-expression patterns is apparent, which is analysed in terms of its effect on the passive tension of isolated myofibrils obtained from selected muscle types. We show and discuss evidence indicating that vertebrate striated muscle cells are capable of adjusting their passive stiffness in the following ways: (1) Cardiomyocytes co-express long (N2BA) and short (N2B) titin isoform in the same half-sarcomeres and vary the N2BA:N2B ratio to adjust stiffness. Hearts from different mammalian species vary widely in their N2BA:N2B ratio; right ventricles show higher ratios than left ventricles. There is also a significant gradient of N2BA:N2B ratio in a given heart, from basal to apical; transmural ratio differences are less distinct. (2) Skeletal muscles can express longer or shorter I-band-titin (N2A-isoform) to achieve lower or higher titin-derived stiffness, respectively. (3) Some skeletal muscles co-express longer (N2AL) and shorter (N2AS) titin isoforms, also at the single-fibre level (e.g., rabbit psoas); variations in overall N2AL:N2AS ratio may add to the fine-tuning of titin-based stiffness in the whole muscle. Whereas it is established that titin, together with extracellular collagen, determines the passive tension at physiological sarcomere lengths in cardiac muscle, it remains to be seen to which degree titin and/or extracellular structures are important for the physiological passive-tension generation of whole skeletal muscle.