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

A eukaryotic cell must be able to quickly respond to mechanical changes to its environment, pulling by neighbouring cells, or changes in its own shape during its cell cycle. Long-lasting mechanical signals can be sensed by molecules placed under load, if a globular domain of the molecule opens or unfolds and reveals a binding site for a signalling molecule. The time-integration of load in particular is a key feature of muscle hypertrophy. Here, I will explain how the opening of kinase domain of the muscle molecule titin under load provides a possible explanation for muscle growth following resistance training. To do this, we modelled the response of titin kinase to exercise and its effects on the synthesis of new proteins. We found that the titin kinase domain acts as a switch, opening and signalling most strongly above a certain force, close to 70% of the maximum muscle fibre force threshold found to be necessary for hypertrophy to occur. In addition, our model predicted that muscles adapt to a new resistance training plan over a few months, matching experimental time courses for hypertrophy. These predictions strongly suggest that muscle cells use cellular mechanical signalling directly to measure and respond to large-scale load.