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Why exercise builds muscles: titin mechanosensing controls skeletal muscle growth under load.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Ibata, Neil 
Terentjev, Eugene M 

Abstract

Muscles sense internally generated and externally applied forces, responding to these in a coordinated hierarchical manner at different timescales. The center of the basic unit of the muscle, the sarcomeric M-band, is perfectly placed to sense the different types of load to which the muscle is subjected. In particular, the kinase domain of titin (TK) located at the M-band is a known candidate for mechanical signaling. Here, we develop a quantitative mathematical model that describes the kinetics of TK-based mechanosensitive signaling and predicts trophic changes in response to exercise and rehabilitation regimes. First, we build the kinetic model for TK conformational changes under force: opening, phosphorylation, signaling, and autoinhibition. We find that TK opens as a metastable mechanosensitive switch, which naturally produces a much greater signal after high-load resistance exercise than an equally energetically costly endurance effort. Next, for the model to be stable and give coherent predictions, in particular for the lag after the onset of an exercise regime, we have to account for the associated kinetics of phosphate (carried by ATP) and for the nonlinear dependence of protein synthesis rates on muscle fiber size. We suggest that the latter effect may occur via the steric inhibition of ribosome diffusion through the sieve-like myofilament lattice. The full model yields a steady-state solution (homeostasis) for muscle cross-sectional area and tension and, a quantitatively plausible hypertrophic response to training, as well as atrophy after an extended reduction in tension.

Description

Keywords

Connectin, Kinetics, Muscle Fibers, Skeletal, Myofibrils, Sarcomeres

Journal Title

Biophys J

Conference Name

Journal ISSN

0006-3495
1542-0086

Volume Title

120

Publisher

Elsevier BV