Titin Gene ( TTN )

Abstract

The titin locus located on chromosome 2q24 in the human genome expresses about 100 kb full‐length mRNAs, that are translated into giant up to 34.350‐residue large polypeptides. Therefore, titin is by far the largest known protein. The titin protein is abundant in vertebrate muscles, where it spans half of the sarcomere. In situ , 1–2 μm long titin polypeptides establish a sarcomeric filament system that is critical for myofibrillar integrity and elasticity. Biomechanically, titin's intrinsic elasticity is fine‐tuned in the different muscle tissues through alternative splicing, post‐translational modifications and protein–protein interactions. Moreover, a plethora of molecular interactions with stress‐regulated ligands positions titin centrally in stretch‐dependent signalling in muscle. Therefore, mutations in this filament system are important causes of hereditary cardiomyopathies and muscular dystrophies. Key Concepts: Sarcomeres consist of precisely assembled proteins that together form the basic functional units of striated muscle and give rise to efficient and finely tuned contraction. In muscle tissues, 1–2 μm single titin polypeptide chains span half of the sarcomere. The intrasarcomeric filamentous titin protein provides sarcomeres with intrinsic elasticity and couples stretch‐dependent signalling together with muscle remodelling. Titin molecule is tailored to physiological requirements of different muscles through alternative splicing, post‐translational modifications and protein–protein interactions. Mutations in the titin gene are associated with different heart and skeletal muscle diseases.

Muscle and Tendon Tissues: Constitutive Modeling and Computational Issues

“…The level of activation also affects the passive behavior of a muscle, i.e., when a stretch is imposed on a contracting muscle. Experiments with muscle fibers showed that calcium addition resulted in titin-based tension increase and thus passive force enhancement [20,21].…”

“…In Eq. (20), the nominal fiber strain e"¡ is defined relative to the optimal fiberlength i"¿ at full activation (/'a=l), i.e..…”

“…The functions/^,/r,/p, and/^^ in Eqs. (20) and (21) are defined based on the mechanical characteristics of the muscle fiber under consideration. The functional form of/^ and/r are obtained from active force-length and force-velocity experimental data, whereas the functional forms of/,, and/,,r are obtained from passive forcelength and force-velocity experimental data.…”

“…Equations (23) and (25) imply that the maximum fiber stress appears at a nominal strain level EQ^ defined by c 0 (26) In our approach, fp depends explicitly on the activation state, since the passive tension of the muscle fiber is known to increase with calcium level [20,21]. We suggest a relationship of the following form for/pa!…”

“…"*''"* = <r"^;"''(eS') (28) where f^'"'^ is a dimensionless function and a^^^ is the reference stress introduced in Eq. (20). The tendon strain is defined by the amount of tendon stretch relative to its resting, or slack length, i.e., the length at which the tendon begins to transmit force when stretched [12].…”